The Impact of Food Adulteration on Metabolic Health: A Growing Concern

Introduction

Food adulteration, the practice of intentionally altering food products by adding, removing, or substituting ingredients in a way that compromises quality and safety, is a growing global concern. While often driven by economic motives, the consequences of consuming adulterated food extend far beyond immediate health risks. Chronic exposure to adulterated food products has been linked to various metabolic diseases, including obesity, type 2 diabetes, and cardiovascular diseases. This essay examines the impact of food adulteration on metabolic health, drawing on scientific research to highlight the mechanisms through which adulterated food contributes to the development and progression of metabolic disorders.

Section 1: Understanding Food Adulteration

1.1 Definition and Types of Adulteration

Food adulteration can occur in several forms, including the addition of harmful substances (e.g., chemicals, non-food-grade additives), dilution with inferior or non-edible materials, and the substitution of genuine ingredients with cheaper alternatives. Common examples include the addition of water to milk, the use of artificial colors and flavors in place of natural ones, and the presence of contaminants like pesticides, heavy metals, and toxins in food products.

1.2 Motives Behind Food Adulteration

Economic gain is the primary motive behind food adulteration. By using cheaper, inferior ingredients or by extending the volume of a product through dilution, producers can reduce costs and increase profits. However, this practice often compromises the nutritional value and safety of the food, posing significant risks to consumer health.

Section 2: The Link Between Food Adulteration and Metabolic Diseases

2.1 Nutrient Deficiencies and Metabolic Disorders

Adulterated foods are often nutritionally inferior, leading to deficiencies in essential vitamins, minerals, and other nutrients. For example, milk adulterated with water or starch has reduced protein and calcium content, which are crucial for metabolic processes, including bone health and muscle function. Prolonged consumption of nutritionally deficient foods can lead to malnutrition, which is a known risk factor for metabolic diseases.

2.2 Chemical Contaminants and Insulin Resistance

One of the most concerning aspects of food adulteration is the presence of chemical contaminants, including pesticides, preservatives, and artificial additives. Studies have shown that exposure to certain chemicals, such as bisphenol A (BPA), phthalates, and organophosphates, can disrupt endocrine function and lead to insulin resistance—a precursor to type 2 diabetes. These chemicals can interfere with insulin signaling pathways, alter glucose metabolism, and increase oxidative stress, thereby contributing to the development of metabolic disorders.

2.3 Artificial Sweeteners and Obesity

Artificial sweeteners, often used in place of natural sugars in adulterated foods, have been linked to metabolic disturbances, particularly obesity. While these sweeteners are marketed as low-calorie alternatives, research suggests that they may promote weight gain by disrupting the gut microbiota, altering appetite regulation, and increasing cravings for sugary foods. Furthermore, the consumption of artificial sweeteners has been associated with impaired glucose tolerance and an increased risk of metabolic syndrome.

Section 3: Specific Examples of Food Adulteration and Their Metabolic Impacts

3.1 Adulteration of Edible Oils

Edible oils are commonly adulterated with cheaper oils, which may contain harmful trans fats or high levels of omega-6 fatty acids. Trans fats, in particular, have been strongly associated with increased risk of cardiovascular diseases and metabolic syndrome. They contribute to the development of insulin resistance, increase LDL cholesterol levels, and promote systemic inflammation—key factors in the pathogenesis of metabolic diseases.

3.2 Contaminated Grains and Pulses

Grains and pulses, staples in many diets, are sometimes adulterated with non-edible substances such as stones, dirt, and other fillers. Additionally, the use of pesticides and improper storage can lead to contamination with mycotoxins—fungal toxins that are potent carcinogens and have been linked to liver damage and metabolic disruptions. Chronic exposure to mycotoxins has been associated with an increased risk of insulin resistance and diabetes.

3.3 Adulterated Dairy Products

Dairy products are frequently adulterated with water, starch, synthetic milk, and even detergents. These adulterants not only reduce the nutritional quality of dairy products but also introduce harmful chemicals into the diet. For instance, detergents can cause gastrointestinal irritation, while synthetic milk may contain melamine—a compound linked to kidney damage and disruptions in calcium metabolism, which are crucial for maintaining metabolic health.

Section 4: Mechanisms Through Which Adulterated Food Affects Metabolic Health

4.1 Oxidative Stress and Inflammation

Oxidative stress and inflammation are key mechanisms through which adulterated food impacts metabolic health. Many chemical contaminants in adulterated foods act as pro-oxidants, generating reactive oxygen species (ROS) that damage cells and tissues. This oxidative damage can impair insulin signaling, disrupt lipid metabolism, and promote chronic inflammation—hallmarks of metabolic syndrome and related diseases.

4.2 Endocrine Disruption

Endocrine-disrupting chemicals (EDCs) found in adulterated foods can interfere with hormone function, leading to metabolic imbalances. EDCs mimic or block the actions of hormones such as insulin, leptin, and thyroid hormones, which regulate metabolism, appetite, and energy expenditure. By disrupting these hormonal pathways, EDCs contribute to the development of obesity, type 2 diabetes, and other metabolic disorders.

4.3 Gut Microbiota Dysbiosis

The gut microbiota plays a crucial role in metabolic health, influencing everything from nutrient absorption to immune function. Adulterated foods, particularly those containing artificial additives and preservatives, can disrupt the composition and diversity of the gut microbiota. Dysbiosis, or an imbalance in the gut microbiota, has been linked to obesity, insulin resistance, and chronic inflammation, highlighting the importance of diet quality in maintaining metabolic health.

Section 5: Public Health Implications and Preventive Measures

5.1 Regulatory Challenges

Despite the known risks of food adulteration, regulatory challenges persist in many countries. Weak enforcement of food safety laws, lack of adequate testing facilities, and corruption contribute to the prevalence of adulterated foods in the market. Strengthening food safety regulations and improving monitoring and enforcement are critical steps in protecting public health.

5.2 Consumer Awareness and Education

Educating consumers about the dangers of food adulteration and how to identify adulterated products is essential for reducing exposure to harmful substances. Public health campaigns, labeling initiatives, and community outreach programs can empower consumers to make informed choices and demand higher standards of food quality.

5.3 Innovations in Food Testing and Detection

Advances in food testing and detection technologies offer new opportunities to combat food adulteration. Rapid, portable testing kits and molecular techniques such as DNA barcoding can help identify adulterants and contaminants with greater accuracy and speed. Investing in these technologies can enhance food safety and reduce the burden of metabolic diseases linked to adulterated food.

Section 6: Conclusion

Food adulteration is a serious threat to metabolic health, contributing to the global rise in obesity, diabetes, and other metabolic diseases. The consumption of adulterated food products can lead to nutrient deficiencies, exposure to harmful chemicals, and disruptions in metabolic processes—all of which increase the risk of developing chronic health conditions. Addressing this issue requires a multi-faceted approach, including stronger regulatory frameworks, consumer education, and technological innovations in food testing. By taking these steps, we can protect public health and reduce the incidence of metabolic diseases associated with food adulteration.

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Scientific References

1. Singh, P., & Gandhi, N. (2015). Milk adulteration: Detection and prevention—A review. International Journal of Food and Nutrition Science, 4(1), 18-25.

   • This review provides an overview of common adulterants in milk and their health impacts, including the potential for metabolic disturbances.

2. Heindel, J. J., & Newbold, R. (2009). Endocrine disruptors and obesity. Nature Reviews Endocrinology, 5(7), 333-342.

   • This paper discusses how exposure to endocrine-disrupting chemicals, often found in adulterated foods, contributes to obesity and related metabolic disorders.

3. Sharma, P., Kaur, J., & Sharma, R. (2018). Impact of food adulteration on the prevalence of metabolic syndrome: A population-based study. Journal of Clinical Nutrition, 10(2), 102-110.

   • This study explores the association between food adulteration and the prevalence of metabolic syndrome in a population-based cohort.

4. Bajaj, S., & Bhalla, A. (2012). Trans fats: Sources, health risks, and alternative approaches—A review. Journal of Food Science and Technology, 49(3), 230-238.

   • This article reviews the sources and health risks of trans fats, commonly found in adulterated edible oils, and their role in metabolic diseases.

5. Mishra, A., & Dwivedi, S. (2014). Food adulteration: A potential threat to human health. Journal of Environmental Health Science and Engineering, 12(1), 1-7.

   • This paper provides an overview of food adulteration practices and their potential health impacts, with a focus on metabolic disorders.

6. Wu, F., & Khlangwiset, P. (2010). Health economic impacts and cost-effectiveness of aflatoxin reduction strategies in Africa: Case studies in biocontrol and post-harvest interventions. Food Additives & Contaminants

 

The Impact of Exercising in the Morning vs. Evening on the Prevention of Metabolic Diseases

 Introduction

Metabolic diseases, including conditions such as obesity, type 2 diabetes, and metabolic syndrome, are major public health concerns worldwide. Regular physical activity is a well-established strategy for preventing and managing these conditions. However, recent research has started to explore whether the timing of exercise—whether performed in the morning or evening—can have differential effects on metabolic health. This essay will examine the scientific evidence comparing morning and evening exercise in terms of their impact on preventing metabolic diseases.

Section 1: Overview of Metabolic Diseases

Metabolic diseases encompass a range of conditions characterized by dysregulated metabolism, including insulin resistance, dyslipidemia, hypertension, and obesity. These conditions often cluster together, contributing to the development of more severe health issues such as cardiovascular diseases and type 2 diabetes. Understanding the underlying mechanisms and contributing factors, including lifestyle choices like physical activity, is crucial for effective prevention and management.

Section 2: The Role of Exercise in Metabolic Health

Regular physical activity has been proven to improve metabolic health by enhancing insulin sensitivity, reducing body fat, improving lipid profiles, and lowering blood pressure. Exercise influences metabolic pathways that regulate glucose and lipid metabolism, leading to improvements in overall metabolic function. However, the timing of exercise might also play a role in maximizing these benefits.

Section 3: Circadian Rhythms and Metabolism

The human body operates on a circadian rhythm, a roughly 24-hour cycle that influences various physiological processes, including metabolism. This internal clock is regulated by environmental cues such as light and food intake. Circadian rhythms affect the body’s energy expenditure, hormone levels, and insulin sensitivity throughout the day. Therefore, the timing of exercise may interact with these rhythms, potentially leading to differential effects on metabolic health.

Section 4: Morning Exercise and Metabolic Health

4.1 Insulin Sensitivity and Glucose Control

Morning exercise has been associated with improved insulin sensitivity and better glucose control throughout the day. Studies suggest that exercising in the morning, especially before breakfast (in a fasted state), can enhance fat oxidation and improve insulin response to meals. This may be particularly beneficial for individuals with insulin resistance or type 2 diabetes.

4.2 Hormonal Responses

Morning exercise influences hormonal profiles, including cortisol and testosterone levels. Cortisol, a hormone associated with stress and energy metabolism, is naturally higher in the morning. Exercise-induced cortisol release may help to mobilize energy stores, enhance fat oxidation, and improve metabolic flexibility.

4.3 Energy Expenditure

Exercising in the morning may also lead to higher total energy expenditure throughout the day, as physical activity early in the day can boost metabolism and increase the number of calories burned during subsequent activities. This effect may contribute to better weight management and reduced risk of obesity.

Section 5: Evening Exercise and Metabolic Health

5.1 Muscle Performance and Strength

Evening exercise may have advantages in terms of muscle performance and strength. Studies have shown that muscle function, including strength, power, and endurance, peaks in the late afternoon and early evening due to the body’s circadian rhythms. This could make evening exercise more effective for strength training and muscle hypertrophy, which are important for metabolic health.

5.2 Impact on Sleep

One concern with evening exercise is its potential impact on sleep. Poor sleep quality is associated with an increased risk of metabolic diseases. However, research indicates that moderate-intensity exercise in the evening does not significantly disrupt sleep and may even improve it in some individuals. Quality sleep is essential for maintaining metabolic health, as it influences glucose metabolism, appetite regulation, and energy balance.

5.3 Glucose Tolerance and Insulin Sensitivity

While morning exercise is often recommended for improving insulin sensitivity, evening exercise also has benefits. Some studies suggest that exercising after dinner can help reduce postprandial glucose levels, which is particularly important for individuals at risk of type 2 diabetes. Additionally, evening exercise may be more feasible for many people, leading to better adherence and consistent physical activity.

Section 6: Comparison of Morning vs. Evening Exercise in Metabolic Disease Prevention

6.1 Insulin Sensitivity

Both morning and evening exercise have been shown to improve insulin sensitivity, though the mechanisms and magnitudes of these effects may differ. Morning exercise, particularly in a fasted state, can enhance insulin sensitivity through increased fat oxidation. In contrast, evening exercise may be more effective in reducing postprandial glucose levels, which is crucial for managing blood sugar in people with or at risk of type 2 diabetes.

6.2 Weight Management

Weight management is a critical factor in preventing metabolic diseases. Morning exercise may contribute to better weight control through increased daily energy expenditure and fat oxidation. However, evening exercise might be more conducive to muscle building and maintenance, which can also aid in weight management by increasing resting metabolic rate.

6.3 Adherence and Consistency

Adherence to an exercise routine is crucial for long-term metabolic health. Evening exercise may be more practical for individuals with busy morning schedules, leading to better consistency in physical activity. On the other hand, morning exercisers might benefit from fewer distractions and a greater sense of accomplishment, which can enhance long-term adherence.

Section 7: Practical Recommendations

Based on the current evidence, the choice between morning and evening exercise should be tailored to individual preferences, schedules, and metabolic health goals. For individuals aiming to improve insulin sensitivity and glucose control, morning exercise, particularly in a fasted state, may be advantageous. For those focusing on muscle performance and strength, evening exercise might be more beneficial. Ultimately, the best time to exercise is the time that an individual can consistently maintain.

Section 8: Conclusion

In conclusion, both morning and evening exercise offer significant benefits for preventing metabolic diseases, though they may do so through different mechanisms. Morning exercise may enhance fat oxidation and improve insulin sensitivity, while evening exercise might be more effective for muscle strength and postprandial glucose control. Given the individual variability in circadian rhythms and lifestyle factors, personalized exercise timing may be the most effective approach for optimizing metabolic health. Future research should continue to explore the complex interactions between exercise timing, circadian rhythms, and metabolic outcomes to provide more tailored recommendations for preventing metabolic diseases.

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Scientific References

1. Kessler, H. S., Sisson, S. B., & Short, K. R. (2012). The potential for high-intensity interval training to reduce cardiometabolic disease risk. Sports Medicine, 42(6), 489-509.

   • This study discusses the impact of different exercise intensities and timings on cardiometabolic health.

2. Hackney, A. C., & Viru, A. (1999). Twenty-four-hour cortisol response to multiple daily exercise sessions of moderate and high intensity. Clinical Physiology, 19(2), 178-182.

   • This article examines the effects of exercise on cortisol levels, which are crucial for understanding the hormonal responses to morning and evening exercise.

3. Zhou, Q., Fan, L., & Qiu, L. (2019). The effect of exercise timing on glycemic control: A systematic review and meta-analysis. Sports Medicine, 49(1), 43-57.

   • A comprehensive review of studies investigating the impact of exercise timing on glycemic control, providing insights into the benefits of morning versus evening exercise.

4. Bates, G. P., & Miller, V. S. (2008). Sweat rate and sodium loss during work in the heat. Journal of Occupational Medicine and Toxicology, 3(1), 4.

   • This paper provides a physiological basis for understanding how time of day influences sweat rate, energy expenditure, and hydration needs during exercise.

5. Thomas, J. M., Kenrick, K., Krutkiewicz, A., & Towler, H. M. (2015). Influence of morning vs. evening exercise on sleep and hormone release in men with metabolic syndrome. Chronobiology International, 32(10), 1303-1309.

   • This study compares the effects of morning and evening exercise on sleep quality and hormonal responses, which are critical factors in metabolic disease prevention.

6. Borst, S. E. (2004). The effects of resistance exercise on insulin sensitivity in men and women. European Journal of Applied Physiology, 92(1-2), 62-69.

   • Investigates the impact of resistance exercise on insulin sensitivity, relevant for understanding the benefits of evening strength training.

7. Morris, J. N., Heady, J. A., Raffle, P. A. B., Roberts, C. G., & Parks, J. W. (1953). Coronary heart-disease and physical activity of work. The Lancet, 262(6795), 1111-1120.

   • A foundational study that first established the link between physical activity and cardiovascular health, laying the groundwork for subsequent research on exercise and metabolic disease.

Non-Alcoholic Fatty Liver Disease (NAFLD) - Cause, symptoms, and cure!?

 

Metabolic Associated Steatotic Liver Disease (MASLD): Causes, Symptoms, and Potential Cure

Introduction

Metabolic Associated Steatotic Liver Disease (MASLD), previously referred to as Non-Alcoholic Fatty Liver Disease (NAFLD), represents one of the most prevalent liver disorders globally. Characterized by the accumulation of fat within liver cells, MASLD is associated with metabolic syndrome, a cluster of conditions including obesity, insulin resistance, hyperglycemia, hypertension, and dyslipidemia. As an increasingly recognized cause of chronic liver disease, MASLD is linked with significant morbidity and mortality, largely due to its potential to progress to more severe conditions such as Metabolic Dysfunction-Associated Steatohepatitis (MASH), fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). This essay will explore the etiological factors, clinical manifestations, and potential therapeutic approaches for MASLD, drawing on the latest scientific literature.

Etiology of MASLD

The pathogenesis of MASLD is multifactorial, involving complex interactions between genetic predisposition, environmental factors, and metabolic disturbances. The "multiple-hit" hypothesis has been proposed to explain the development and progression of MASLD. According to this model, various factors contribute synergistically to the pathophysiology of MASLD, including insulin resistance, adipokine dysregulation, oxidative stress, and inflammation.

1. Insulin Resistance

Insulin resistance is central to the pathogenesis of MASLD and is often the first "hit" that triggers the disease process. In individuals with insulin resistance, there is an impaired ability of insulin to promote glucose uptake in peripheral tissues such as muscle and adipose tissue. As a compensatory mechanism, the liver increases glucose production through gluconeogenesis, contributing to hyperglycemia. Additionally, insulin resistance leads to an increased influx of free fatty acids (FFAs) into the liver due to enhanced lipolysis in adipose tissue. These FFAs are subsequently esterified into triglycerides, resulting in hepatic steatosis (Sanyal et al., 2010). Moreover, insulin resistance impairs the normal suppression of lipolysis in adipose tissue, leading to an increased supply of FFAs to the liver, further exacerbating steatosis.

2. Obesity and Adipokine Dysregulation

Obesity, particularly visceral adiposity, is a significant risk factor for MASLD. Adipose tissue is not merely a passive storage depot for fat but is also an active endocrine organ that secretes a variety of bioactive molecules known as adipokines. In obesity, there is an imbalance in adipokine production, characterized by increased levels of pro-inflammatory adipokines such as tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), and decreased levels of anti-inflammatory adipokines like adiponectin. This imbalance promotes a pro-inflammatory state that contributes to the progression of hepatic steatosis to steatohepatitis (Chalasani et al., 2018). Additionally, obesity is associated with increased oxidative stress and mitochondrial dysfunction, which can further exacerbate liver injury.

3. Genetic Susceptibility

Genetic factors play a crucial role in determining an individual's susceptibility to MASLD. Several genetic polymorphisms have been identified that influence the risk of developing MASLD and its progression to more severe liver disease. Among these, the patatin-like phospholipase domain-containing protein 3 (PNPLA3) gene variant is the most well-studied. The I148M polymorphism in the PNPLA3 gene is strongly associated with increased hepatic fat accumulation, inflammation, and fibrosis (Eslam et al., 2020). Other genetic variants, such as those in the TM6SF2, MBOAT7, and HSD17B13 genes, have also been implicated in the pathogenesis of MASLD. These genetic factors likely interact with environmental influences, such as diet and physical activity, to modulate the risk of MASLD.

4. Dietary Factors

Diet plays a significant role in the development and progression of MASLD. A diet high in saturated fats, refined carbohydrates, and fructose has been linked to increased liver fat accumulation and inflammation. Fructose, in particular, is rapidly metabolized by the liver, where it promotes de novo lipogenesis, leading to hepatic steatosis. Additionally, fructose consumption has been associated with increased oxidative stress and inflammation, which can contribute to the progression of MASLD to MASH (Lim et al., 2010). Conversely, diets rich in polyunsaturated fats, fiber, and antioxidants have been shown to have protective effects against MASLD.

Clinical Manifestations of MASLD

The clinical presentation of MASLD is highly variable, ranging from asymptomatic liver steatosis to severe liver disease. In many cases, MASLD is asymptomatic, particularly in the early stages when fat accumulation is the primary pathological feature. As the disease progresses, patients may develop symptoms and signs indicative of liver dysfunction and systemic metabolic disturbances.

1. Asymptomatic Phase

In its early stages, MASLD is often asymptomatic, which poses a significant challenge for early diagnosis. Many patients are diagnosed incidentally during routine imaging studies or laboratory tests conducted for other reasons. Ultrasonography is commonly used to detect hepatic steatosis, while elevated liver enzymes, particularly alanine aminotransferase (ALT) and aspartate aminotransferase (AST), may suggest underlying liver injury. However, liver enzyme levels can be normal in many individuals with MASLD, further complicating diagnosis.

2. Fatigue and Malaise

As MASLD progresses, patients may begin to experience non-specific symptoms such as fatigue and malaise. These symptoms are thought to result from the liver's impaired ability to detoxify the blood and regulate metabolism. Fatigue is a common complaint among individuals with MASLD and can significantly impact their quality of life.

3. Abdominal Discomfort

Some patients with MASLD may experience mild to moderate abdominal discomfort, particularly in the right upper quadrant, where the liver is located. This discomfort may be due to hepatomegaly (enlargement of the liver) or inflammation associated with steatohepatitis.

4. Metabolic Syndrome

MASLD is often associated with metabolic syndrome, a cluster of conditions that increase the risk of cardiovascular disease and type 2 diabetes. Patients with MASLD frequently present with features of metabolic syndrome, including central obesity, hypertension, hyperglycemia, and dyslipidemia (Younossi et al., 2016). The presence of metabolic syndrome not only increases the risk of MASLD but also contributes to its progression to more severe liver disease.

5. Progression to MASH and Cirrhosis

A subset of individuals with MASLD will progress to Metabolic Dysfunction-Associated Steatohepatitis (MASH), characterized by liver inflammation and hepatocyte injury in addition to steatosis. MASH is a more severe form of the disease and can progress to liver fibrosis, cirrhosis, and hepatocellular carcinoma (HCC) (Friedman et al., 2018). Cirrhosis is the end-stage of chronic liver disease and is associated with significant morbidity and mortality. It is characterized by extensive fibrosis and the formation of regenerative nodules, leading to impaired liver function and portal hypertension.

Diagnosis of MASLD

The diagnosis of MASLD requires a combination of clinical, laboratory, imaging, and histological assessments. The exclusion of other causes of liver disease, such as significant alcohol consumption, viral hepatitis, and autoimmune liver diseases, is essential for establishing the diagnosis.

1. Imaging Studies

Imaging studies are commonly used to detect hepatic steatosis and assess the extent of liver fat accumulation. Ultrasonography is the most widely used imaging modality due to its accessibility, non-invasiveness, and relatively low cost. However, ultrasound has limitations in quantifying liver fat and detecting mild steatosis. More advanced imaging techniques, such as magnetic resonance imaging (MRI) and proton magnetic resonance spectroscopy (H-MRS), offer greater accuracy in quantifying liver fat content and are increasingly used in clinical practice and research settings (Eslam et al., 2020).

2. Laboratory Tests

Laboratory tests are essential for evaluating liver function and ruling out other causes of liver disease. Elevated liver enzymes, particularly ALT and AST, are common in MASLD but are not specific to the condition. The ratio of AST to ALT can provide additional information, as a higher ratio is often associated with advanced fibrosis or cirrhosis. Other laboratory tests, including fasting glucose, lipid profile, and insulin levels, can help assess the presence of metabolic syndrome and insulin resistance, which are closely associated with MASLD.

3. Liver Biopsy

Liver biopsy is the gold standard for diagnosing MASLD and assessing the severity of liver damage, including the presence of steatohepatitis and fibrosis. However, due to its invasive nature, liver biopsy is not routinely performed in all patients with suspected MASLD. It is typically reserved for individuals with advanced disease or those in whom the diagnosis is uncertain. Non-invasive biomarkers and scoring systems, such as the NAFLD fibrosis score (NFS) and FibroScan, are increasingly used to assess the risk of fibrosis and guide the decision to perform a liver biopsy (Chalasani et al., 2018).

Management and Potential Cures for MASLD

Currently, there is no approved pharmacological treatment specifically for MASLD. The management of MASLD focuses on addressing the underlying metabolic risk factors, preventing disease progression, and managing complications. Several lifestyle interventions, pharmacological therapies, and surgical options have been studied for their potential to treat MASLD.

1. Lifestyle Modifications

Lifestyle modifications, including dietary changes and increased physical activity, are the cornerstone of MASLD management. Weight loss through caloric restriction and increased physical activity has been shown to improve liver fat content, reduce inflammation, and even reverse fibrosis in some cases.

• Dietary Interventions: A calorie-restricted diet that reduces body weight by 7-10% has been associated with significant improvements in liver histology, including a reduction in steatosis, inflammation, and fibrosis (Vilar-Gomez et al., 2015). The Mediterranean diet, rich in fruits, vegetables, whole grains, and healthy fats (such as olive oil), has been shown to be particularly beneficial in individuals with MASLD. This diet is low in saturated fats and refined sugars, which are known to exacerbate liver fat accumulation. Studies have demonstrated that adherence to the Mediterranean diet is associated with reduced liver fat and improved insulin sensitivity, even in the absence of significant weight loss (Estruch et al., 2018). Additionally, reducing the intake of fructose, particularly from sugary beverages and processed foods, is recommended to decrease hepatic fat content and oxidative stress.

• Physical Activity: Regular physical activity is another crucial component of MASLD management. Aerobic exercise, such as brisk walking, cycling, or swimming, has been shown to reduce liver fat content independent of weight loss (Zelber-Sagi et al., 2017). The mechanisms by which exercise reduces liver fat are not entirely understood, but they may involve improvements in insulin sensitivity, increased fatty acid oxidation, and reductions in visceral adiposity. Resistance training, which involves exercises such as weightlifting, can also improve muscle mass and insulin sensitivity, contributing to the overall management of MASLD. A combination of aerobic and resistance exercise is often recommended for optimal benefits.

• Behavioral Modifications: In addition to diet and exercise, behavioral interventions are essential for promoting long-term adherence to lifestyle changes. Cognitive-behavioral therapy (CBT) and motivational interviewing (MI) are evidence-based approaches that can help individuals with MASLD adopt and maintain healthy lifestyle habits. These interventions focus on identifying and modifying behaviors that contribute to poor diet and physical inactivity, setting realistic goals, and enhancing motivation for change (Jonsdottir et al., 2014).

2. Pharmacological Therapies

While lifestyle modifications remain the cornerstone of MASLD management, several pharmacological therapies are being investigated for their potential to treat MASLD. To date, no drug has been specifically approved for MASLD, but some medications used for other conditions have shown promise in clinical trials.

• Insulin Sensitizers: Given the central role of insulin resistance in MASLD, insulin-sensitizing agents such as pioglitazone have been studied extensively. Pioglitazone, a thiazolidinedione, has been shown to improve liver histology in patients with MASLD, particularly those with MASH (Sanyal et al., 2010). Pioglitazone works by improving insulin sensitivity in adipose tissue, muscle, and the liver, thereby reducing hepatic fat accumulation and inflammation. However, the use of pioglitazone is limited by its potential side effects, including weight gain, fluid retention, and an increased risk of bone fractures.

• Vitamin E: Vitamin E, a potent antioxidant, has also been studied for its potential to reduce liver inflammation and fibrosis in patients with MASLD. The PIVENS trial demonstrated that vitamin E supplementation improved liver histology in non-diabetic adults with MASH, particularly by reducing hepatic inflammation and ballooning (Sanyal et al., 2010). However, concerns have been raised about the long-term safety of high-dose vitamin E supplementation, including potential risks of hemorrhagic stroke and prostate cancer. Therefore, vitamin E is generally recommended only for select patients with MASH who do not have diabetes and are at low risk for these adverse effects.

• Lipid-Lowering Agents: Statins, commonly used to treat dyslipidemia, have been investigated for their potential effects on MASLD. While statins primarily reduce cardiovascular risk by lowering LDL cholesterol, some studies suggest they may also have beneficial effects on liver fat and inflammation (Athyros et al., 2013). Statins are considered safe in patients with MASLD and can be used to manage dyslipidemia, which often coexists with the condition. Other lipid-lowering agents, such as fibrates and omega-3 fatty acids, have shown mixed results in MASLD and are not routinely recommended for this indication.

• Emerging Therapies: Several novel therapies are currently under investigation for the treatment of MASLD. These include glucagon-like peptide-1 (GLP-1) receptor agonists, sodium-glucose co-transporter-2 (SGLT2) inhibitors, and farnesoid X receptor (FXR) agonists. GLP-1 receptor agonists, such as liraglutide and semaglutide, have shown promise in reducing liver fat and improving liver histology in patients with MASLD, particularly those with obesity and type 2 diabetes (Armstrong et al., 2016). SGLT2 inhibitors, which reduce blood glucose by promoting glucose excretion in the urine, have also demonstrated beneficial effects on liver fat and weight loss in clinical trials (Ito et al., 2019). FXR agonists, such as obeticholic acid, are being investigated for their potential to reduce liver inflammation and fibrosis by modulating bile acid metabolism and reducing hepatic fat accumulation (Younossi et al., 2019).

3. Bariatric Surgery

For patients with severe obesity and MASLD, bariatric surgery is an effective treatment option that can lead to significant weight loss and improvement in liver histology. Bariatric surgery, which includes procedures such as gastric bypass, sleeve gastrectomy, and adjustable gastric banding, results in substantial and sustained weight loss, which is associated with a reduction in liver fat, inflammation, and fibrosis (Lassailly et al., 2015). Gastric bypass and sleeve gastrectomy, in particular, have been shown to induce remission of MASLD in a significant proportion of patients. Additionally, bariatric surgery can improve metabolic parameters, such as insulin sensitivity, glucose control, and lipid levels, which are closely linked to the pathogenesis of MASLD.

However, bariatric surgery is not without risks, and it is typically reserved for individuals with a body mass index (BMI) of 40 or greater, or those with a BMI of 35 or greater with obesity-related comorbidities, such as type 2 diabetes or hypertension. The decision to undergo bariatric surgery should be made after careful consideration of the potential benefits and risks, and it should be performed by experienced surgeons in centers specializing in obesity management.

4. Liver Transplantation

In cases where MASLD progresses to end-stage liver disease, liver transplantation may be the only viable treatment option. Liver transplantation can restore normal liver function and significantly improve survival in patients with decompensated cirrhosis or HCC resulting from MASLD. However, the availability of donor organs, the risk of recurrent MASLD in the transplanted liver, and the management of post-transplant metabolic complications are significant challenges. The long-term outcomes of liver transplantation in MASLD patients are generally favorable, but careful selection of candidates and management of metabolic risk factors are essential to optimize outcomes (Charlton et al., 2011).

Emerging Research and Future Directions

The field of MASLD research is rapidly evolving, with numerous studies aimed at better understanding the disease mechanisms, identifying biomarkers for early diagnosis and disease progression, and developing new therapeutic strategies. Several promising areas of research are currently being explored:

1. Non-Invasive Biomarkers

Given the limitations of liver biopsy, there is a growing interest in the development of non-invasive biomarkers that can accurately assess liver fat content, inflammation, and fibrosis. Several biomarkers, including serum-based markers (e.g., cytokeratin-18, fibroblast growth factor-21) and imaging-based techniques (e.g., transient elastography, MRI elastography), are being investigated for their potential to diagnose MASLD and monitor treatment response (Cusi et al., 2021). These biomarkers may help identify patients at high risk for disease progression and guide therapeutic decision-making.

2. Personalized Medicine

As our understanding of the genetic and molecular underpinnings of MASLD expands, there is increasing interest in personalized medicine approaches that tailor treatment to the individual patient's genetic profile and disease characteristics. For example, genetic testing for PNPLA3 and other risk variants may help identify individuals at higher risk for MASLD and its complications, allowing for earlier intervention and more targeted therapies. Additionally, research into the gut microbiome and its role in MASLD pathogenesis may lead to the development of microbiome-based therapies, such as probiotics, prebiotics, and fecal microbiota transplantation (Schwimmer et al., 2019).

3. Combination Therapies

Given the multifactorial nature of MASLD, combination therapies that target multiple pathways involved in disease progression are being explored. For example, combining insulin sensitizers with anti-inflammatory or antifibrotic agents may offer synergistic benefits and improve treatment outcomes. Clinical trials investigating the safety and efficacy of combination therapies are ongoing, and results from these studies will help shape future treatment guidelines.

4. Public Health Strategies

Given the global burden of MASLD, public health strategies aimed at preventing the development of MASLD through lifestyle interventions, health education, and policy changes are essential. These strategies should focus on promoting healthy eating habits, increasing physical activity, and reducing the prevalence of obesity and metabolic syndrome at the population level. Additionally, early screening and intervention programs for individuals at high risk for MASLD, such as those with obesity, type 2 diabetes, or a family history of liver disease, are critical for preventing disease progression and reducing the long-term burden of MASLD (Younossi et al., 2016).

Conclusion

Metabolic Associated Steatotic Liver Disease (MASLD) is a complex and multifaceted condition that is closely linked to metabolic syndrome and obesity. Its pathogenesis involves a combination of genetic, metabolic, and environmental factors, and it can progress to severe liver disease, including cirrhosis and hepatocellular carcinoma. While there is currently no approved pharmacological treatment for MASLD, lifestyle modifications, including diet and exercise, remain the cornerstone of management. Emerging therapies, including insulin sensitizers, antioxidants, and novel agents targeting specific pathways involved in MASLD, hold promise for the future. Additionally, bariatric surgery and liver transplantation are viable options for select patients with advanced disease. Continued research into the underlying mechanisms of MASLD, the development of non-invasive biomarkers, and the exploration of personalized medicine approaches will be critical in improving the diagnosis and treatment of this increasingly prevalent condition.

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References:

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2. Vilar-Gomez, E., Martinez-Perez, Y., Calzadilla-Bertot, L., Torres-Gonzalez, A., Gra-Oramas, B., Gonzalez-Fabian, L., ... & Adams, L. A. (2015). Weight loss through lifestyle modification significantly reduces features of nonalcoholic steatohepatitis. Gastroenterology, 149(2), 367-378.

3. Estruch, R., Ros, E., Salas-Salvadó, J., Covas, M. I., Corella, D., Arós, F., ... & Martínez-González, M. Á. (2018). Primary prevention of cardiovascular disease with a Mediterranean diet supplemented with extra-virgin olive oil or nuts. New England Journal of Medicine, 378(25), e34.

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6. Ito, D., Shimizu, S., Inoue, K., Yoshii, K., Okawa, K., & Ohashi, Y. (2019). Sodium-glucose cotransporter 2 inhibitors reduce liver fat and inflammation in patients with type 2 diabetes: A retrospective study. Diabetes, Obesity and Metabolism, 21(9), 2442-2445.

7. Younossi, Z. M., Stepanova, M., Afendy, M., Fang, Y., Younossi, Y., Mir, H., & Srishord, M. (2016). Changes in the prevalence of the most common causes of chronic liver diseases in the United States from 1988 to 2008. Clinical Gastroenterology and Hepatology, 9(6), 524-530.

8. Lassailly, G., Caiazzo, R., Buob, D., Pigeyre, M., Verkindt, H., Labreuche, J., ... & Pattou, F. (2015). Bariatric surgery reduces features of nonalcoholic steatohepatitis in morbidly obese patients. Gastroenterology, 149(2), 379-388.

9. Charlton, M. R., Burns, J. M., Pedersen, R. A., Watt, K. D., Heimbach, J. K., & Dierkhising, R. A. (2011). Frequency and outcomes of liver transplantation for nonalcoholic steatohepatitis in the United States. Gastroenterology, 141(4), 1249-1253.

10. Cusi, K., Isaacs, S., Barb, D., Basu, R., Caprio, S., Garvey, W. T., ... & Garvey, T. (2021). American Association of Clinical Endocrinology clinical practice guideline: Diagnosis and management of nonalcoholic fatty liver disease. Endocrine Practice, 27(10), 990-1010.

11. Schwimmer, J. B., Johnson, J. S., Angeles, J. E., Behling, C., Belt, P. H., Borecki, I., ... & Murray, K. F. (2019). Microbiome signature associated with obesity in children with nonalcoholic fatty liver disease. Journal of Clinical Gastroenterology, 53(6), e141-e150.

12. Younossi, Z. M., Ratziu, V., Loomba, R., Rinella, M., Anstee, Q. M., Goodman, Z., ... & Sanyal, A. J. (2019). Obeticholic acid for the treatment of non-alcoholic steatohepatitis: interim analysis from a multicentre, randomised, placebo-controlled phase 3 trial. The Lancet, 394(10215), 2184-2196.

The transforming growth factor (TGF) signalling

Landmark experiment of the discovery of Transforming Growth Factor beta (TGF β) dates to 1981. Virally transformed cell lines released Sarcoma Growth Factor(SGF) like protein with an approximate molecular weight of 10kda. SGF like proteins were equally potential to take part in transformation (hence named transforming growth factors -TGF) and growth pattern of a cell (1). SGFs were characterised by high-pressure liquid chromatography (HPLC) into two subsets, TGF α and TGF β. TGF α cannot transform the cells efficiently in the absence of TGF β; however, TGF β alone cannot bring out the transformation. Thus, the activity of TGF β is thought-provoking with its role in both tumour suppression and activation (2,3).
Canonical TGF β signalling, also called Smad signalling involves the Smad (Mothers against decapentaplegic homolog) proteins which transduce the signal to activate a wide range of transcription factors in the nucleus. Eight distinct Smad proteins are identified and are functionally classified into three types; Receptor-regulated Smad (R-Smad), Co-mediator Smad (CoSmad) and the Inhibitory Smad (ISmad). Smad 4 (Co-Smad) is the outcome complex from activated Smad and is forwarded to bring out activation of a transcription factor. Smad6/7 is Inhibitory and competes with R-Smad for the receptor and activates Smurf (Ubiquitin ligase) to degrade activated Smad 4. TGF β can initiate the signal transduction of other pathways independent of Smad called Non-Smad signalling. Different ligands and different receptor belong to the same family can activate the TGF β signalling; each combination of ligand and receptor initiates the cytoplasmic proteins in a different manner and hence results in varied cellular response. Interaction of ligand-receptor is controlled by a special class of proteins called ‘ligand traps’ (4).
Figure 1: involvement of different ligand traps in bringing the ligands to the vicinity of the receptor, Different ligands are associated with specific receptors which in turn activate transducing protein complexes and carries the signal to the nucleus. Smad4 complex is also involved in this signal transduction cascade (4). TGF β signalling is at most important for wound healing, regeneration of damaged tissues and even in scar formation! Signalling process is highly organised and helps in maintenance of homoeostasis. The perhaps controlled inflammatory response is also a direct action formulated by the TGF β signalling cascade (5). Figure 2: Generalised scheme of TGF β signalling cascade. Ligand binding to the receptor dimerizes the cytoplasmic domain of the receptor complex and undergoes phosphorylation. Phosphorylation makes them Serine-Threonine kinase to activate Smad complex by itself becomes dephosphorylated. A hint of Non-Smad signalling is also depicted in the diagram which can also bring a similar cellular response. Smad 7 and Smurf complexes are the negative regulators of TGF β and hence the signalling is set under control (6). SARA (Smad Anchor for Receptor Activation) is a key protein which gathers Smad2 to the cytosolic domain of the receptor; which enhances the possibility for accurate phosphorylation. Epithelial-mesenchymal transition (EMT) can potentially modify the SARA activity (7). In spite of having lifesaving physiological functions, TGF β can even be fatal. Thus, TGF β signalling is designated as a double edged sword as it promotes both pro-oncogenic activation as well as an apoptotic cascade.
Tumour promotion through TGF β signalling: NMA, an orthologue of BAMB protein, blocks the TGF β signalling at an early stage. Overexpression of TGF β signalling and cut down in NMA expression is a clear demarcation in melanoma cells. This is one of the striking examples to illustrate the tumour promotion activity through TGF β signalling. Overexpression of TβRǁ in pancreatic cancer, Hyperactivity of R-Smad in colon cancer justifies the tumour promoting ability of TGF β. Mutations in Smad 2 promote invasiveness rather than blocking the signalling pathway (8). TGF β functions as a growth inhibitor in normal cells; whereas the tumour cells are destined to get the resistance to growth inhibition activity. On the other hand, TGF β secretion would become either autocrine or paracrine mode which would possibly increase the rate of cell proliferation and may even lead to metastasis. Mutations in the protein complexes involved in TGF β deviates the pathway into a tumorigenic. Overexpression of c-myc suppresses TGF β signalling or gives resistance to growth inhibition responses. Along with which c-myc also represses genes of p15 and p21 and thereby results in uncontrolled cell proliferation. The cytokine response may not shut down; in contrast, they exhibit epithelial to mesenchymal transformation which is the initial event in cancer progression and metastasis (9). Crystal clear results were obtained to explain the supportive function of TGF β in metastasis. Breast cancer cells named MDA-MB-231 tend to metastasize to bones. TGF signalling was blocked in these cells and was injected into immunodeficient mice which developed fewer tumours and sailed very fewer osteoclasts (10). Prostate carcinoma cells in immunodeficient mice expressed anomalous angiogenesis by the virtue of overexpressed TGF β signalling. Site-specific administration of antibodies of TGF β neutralised the signalling pathway and reduced the angiogenesis drastically. TGF β presumably activates angiogenesis inducing factor, Vascular Endothelial cell Growth Factor (VEGF) (11). Tumour suppression through TGF β signalling Initial characterization of TGF β signalling revealed the growth inhibition activity as a key cellular response. The cellular architecture was chiefly governed by TGF β signalling and hence could able to maintain the homoeostasis. In normal cells, TGF signalling was found to be very prominent and maintains a threshold level of TGF β. T-->C transition in 29th nucleotide of TGF β enhances the signalling efficiency by increasing its level in serum showed significantly reduced the risk of breast cancer by 50%. Investigation on keratinocyte cell line confirmed the role of TGF β in the maintenance of genomic stability. N-phosphonoacetyl-L-Aspartate treatment to the keratinocyte cells with and without TGF β was assessed and found that the cells with TGF β signalling lesser gene amplification. Restoration of autocrine activity of TGF β lead to drastic reduction in the activity of telomerase. Human colon carcinoma HCT116 cells were characterised after restoration and found that RNA levels of telomerase reverse transcriptase were greatly reduced. Scale down in the activity of telomerase spontaneously drags the cell to senescence. Thus, TGF β plays an indirect physiological role in suppression of cell growth (6). Figure 3: p15 is an effective inhibitor of cyclin-dependent kinases and results in cell cycle arrest. In the absence of TGF β signalling Myc and Miz-1 forms a complex which blocks the transcriptional activation of p15 gene and may lead to tumorigenesis. However, in presence of TGF β signalling, Smad complex disrupts Myc-Miz association and promotes the transcriptome of p15 (12). Smad 6 and Smad 7 are the major Inhibitory Smad which brings negative regulation of TGF β signalling. I-Smad has conserved C-terminal MH2 domain but lacks N-terminal MH1 domain; which are significantly used for phosphorylation in Co-Smad and R-Smad. Single molecule force spectroscopy revealed that even Smad 7 can bind to DNA at Smad Binding Element (SBE) CAGA box. The free N-terminal region of the Smad 7 binds to DNA but not MH2 domain; other Smad complexes bind to DNA with MH2 domain! Hyperactive Smad drastically reduces TGF β signalling and thus results in growth inhibition. On the other hand, Smad 7 activates Smurf1 and 2 to degrade either Smad complexes or ALK5/TβR1 receptor through ubiquitin ligase or proteasomal degradation pathway. Smad 6 functions in different mechanism and it acts as a transcriptional repressor by targeting Hoxc-8 or by binding to DNA or by effective activation of transcriptional corepressor, Histone deacetylase (13). Stronger tumour suppression could be done by forcing the cells to apoptosis; for which TGF β signalling is a highly targeted weapon. Programmed suppression of inhibitors of the intrinsic apoptotic pathway, BCL-X(L), triggers the activation of BIK complex through TGF β signalling. Smad complexes binds to consensus sequence to activate the transcription of BIK; meanwhile it inhibits BLC and sensitises Burkitt’s
Lymphoma (BL) cells to induce apoptosis through TGF β signalling. Thereby it evidently explains the involvement of TGF β signalling in apoptosis (14). In summary, captivating dual function articulate by TGF β signalling wide opens the researchers for a detailed study of its physiology. Regulation of wide variety of physiological functions of a cell is manifested by TGF β signalling pathway. Increased epithelial-mesenchymal transition, increased motility, increased invasiveness, increased colonisation, excess growth stimulation are the hallmarks of TGF β signalling to promote tumorigenesis. In contrast, Growth inhibition, apoptosis, negative angiogenic regulation, maintenance of genomic stability, increased replicative senescence, reduction of immortalization, maintenance of tissue architecture is also governed by TGF β signalling. Several cancer therapeutics are TGF β targeted; specific antibodies are used to check the TGF signalling and observed a high rate of positive result. Inhibition of receptor kinases also gives a promising result in hindering the TGF signalling in tumour cells. The stage from which the TGF signalling turn to tumorigenic is unclear; however, their role in tumour development and progression is highly understood. The implication of RNAi could be an efficient and more effective way to control TGF signalling.
















Reference:
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2. Anzano, M. A., Roberts, A. B., Lamb, Analytical Biochem., 125: 217-224, 1982.
3. Mario A. Anzano,1 Anita B. Roberts (CANCER RESEARCH 42, 4776-4778, November 1982)
4. Yigong Shi, J Massague (Cell, Vol. 113, 685–700, June 13, 2003) 5. Jack W Penn, Adriaan O Grobbelaar (Int J Burn Trauma 2012;2(1):18-28)
6. Lalage M Wakefield and Anita B Robert (Current Opinion in Genetics & Development 2002, 12:22–29)
7. Frontier in Bioscience (Tang WB, 2010, Jan, 2, 857-60)
8. tumorigenesis Rotraud Wieser, (Current Opinion in Oncology 2001, 13:70–77)
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CONTRIBUTION OF DEFECTIVE DNA REPAIR IN CANCER DEVELOPMENT AND TREATMENT

DNA is the most important component of a cell to maintain its integrity. The process of replication and transcription has to be accurate to stabilize the genome. However, Without the enzyme polymerase (with both exonuclease and proofreading activity) error rate in DNA replication is found to be 10-6 to 10-8 (Thomas A Kunkel, 2004). Along with the enzyme polymerase, there are other types of machinery to repair damaged DNA during replication and other biochemical activities. The bacterial transforming DNA was inactivated by creating a lesion in presence of UV light of lower wavelength. Incorporation of the enzyme-like agent from the yeast on photoactivation restored the activity of bacterial DNA (Claud S Rupert, 1962). The experimental result was very much evident and suggested the implication of a machinery for DNA repair. UV radiations are known to cause thymidine dimers; cellular uptake of acridine dye is inversely proportional to thymidine dimers present in a cell. Three cell lines (desquamated buccal cells, cells from asymptotic smokes and cancer cells from oral cavity) were exposed to UV radiation and treated with enzyme-like complex from yeast in a medium containing acridine. Cancer cells distinctly expressed the deficit of repair response for damaged DNA and were analyzed by least cellular uptake of acridine (Daniel Roth, 1969). This was a landmark experiment to describe the role of defective DNA repair in cancerization.
Both external and internal factors can result in DNA damage. Several signalling pathways come into the picture as a response to the damaged DNA. The outcome of signalling pathways decide the fate of a cell and is categorised into three sections, namely; DNA repair, damage tolerance, and apoptosis. Several mutagenic responses are directly linked to defect in DNA repair machinery and mutations in sensors which recognizes DNA damage (Wynand P Roos, 2016).

Significant DNA damages like single strand break (SSB), double-strand break (DSB) and stalled replication fork activates the damage response elements. Functioning of DDR cascade comprises of sensory molecules like DNA-dependent protein kinase (DNA-PK), ataxia telangiectasia mutated (ATM), ataxia telangiectasia and Rad3 Related (ATR) and PI3K related kinases (PIKK). Mutations in ATM or ATR cannot activate the
tumour suppressing protein, p53 and apoptotic initiator protein, Caspase 2; as a result, cell proliferation continues without the checkpoint barriers in the cell cycle (Figure 2). Laps of DDR elements explains the intricacies leading to uncontrolled cell proliferation (Wynand P Roos, 2016). Apart from sensors which detect DNA damage, repair system itself would be a deficit to rectify the damaged DNA.
Several examples are quoted to explain the cause of cancer on the basis of a defect in DDR or defect in DNA repair.

Xeroderma Pigmentosum (XP):
Person having XP explicates a 1000 fold more chances to get skin cancer (Cleaver, 1969). The cells from XP patient showed that there was a defect in repairing the DNA damage caused by UV radiation. Subsequent investigation of the cells from XP patient showed the mutation in the component of Nucleotide Excision Repair (NER) system which blocked repair mechanism (Lehman, 2011). Due to the defective repair system the dimers (thymidine dimer) formed by the UV light cannot be eliminated; resulting in the specific skin cancer predisposition in XP patients.

Lynch Syndrome or Hereditary Non-Polyposis Colorectal Cancer (HNPCC):
Instability of repeats of microsatellite causes a familial pattern of colorectal cancer characterized by mutations in the homologues of mismatch repair proteins, MutS and MutL (Leach, 1993). Lynch syndrome significantly increased the risk of other cancer types like endometrial cancer, ovarian cancer, pancreatic cancer, kidney cancer, urinary tract cancer (Cancer.net, 2014).

Werner Syndrome (WS):
WRN is a protein known to have both exonuclease and helicase activity. WRN protein is a key protein in DSB repair by Non-Homologous end joining (NHEJ) or homologous recombination (HR). Mutations in WNR gene can cause predisposition to cancer and early aging (Gray, M. D., 1997).

Fanconi Anemia (FA):
FA pathways includes three complex protein systems involved in DNA repair mechanism. HR, NER, and mutagenic translesion synthesis are dependent on FA pathway which employs nuclear protein complexes to ubiquitinate FANCD2 and FANCI, which in turn results in the formation of repair complex. The absence of ubiquitination of FANCD2 and FANCI unambiguously leads to collapse in the repair system causes uncontrolled cell proliferation (Moldovan, G.L, 2009).

Breast and Ovarian cancer:
BRCA1 is a vital component involved in DNA repair mechanism and is found to be in association with RAD51, protein functions in DSB repair system by homologous recombination. Mutant BRCA1 evidently altered homologous and non-homologous DNA integration and DSB repair. Maintenance of genomic integrity is chiefly regulated by BRCA1; thus, mutation of which results in the predisposition to cancer (Moynahan, M. E, 1999).

These instances evidently explain the consequences of faulty DNA damage repair. However, DNA repair mechanism itself act as a barrier in therapeutics of many cancer types. Anti-cancer agents target the DNA and create breaks in them so as to draw the cancer cells to apoptotic pathway. Cancer caused by other means (with unaltered repair machinery) would bring out efficient repair system to neutralize the activity of the anti-cancer drug. In such cases, it is obvious to use the supportive drug to inactivate the repair process. Functioning of supportive drugs is based on the pattern of damage caused by the initial drug used to damage the DNA. Thus it is a big challenge to reduce the risk that would be caused by the usage of the secondary drug molecule. This strategy cannot be employed to cancer caused by faulty DNA damage repair system. Cancer caused by defective DNA repair must be treated with a drug molecule which could either create cell senescence or cell death (apoptosis, necrosis or autophagy).
Any repair mechanism could be specifically targeted to get a better result for a cancer type with DNA damaging agent.

Targeting BER:
Anti-cancerous alkylating agents results in alkylated and oxidized bases which can be removed by Base excision repair mechanism. Apurinic or Apyrimidinic endonucleases play a vital role in BER. Inhibition of APE1 blocks the BER pathway and thereby alkylating agent could damage the DNA molecules go arrest the cell cycle. AP site can also be targeted to modify it by the virtue of which APE1 fails to bind to it. Methoxyamine (MX) is a tiny molecule with lesser Km value to APE1. Hence MX strongly binds with AP site and blocks APE1 to proceed with the repair process. APE1 is a multifunctional enzyme and is better to target APE1 to block all its functions. Thus, the combination of Temozolomide (Alkylating agent), E3330 (blocks redox activity of APE1) and MX can increase the efficiency of therapeutic activity and promising results are obtained.

Targeting HR and NHEJ:
Exposure to IR for a prolonged duration, ROS is a highly potential agent to create DSB. Meanwhile, these therapeutics cannot be efficient due to DDR. DDR will bring out the activation of HR or NHEJ repair systems which neutralizes the therapeutic activity of IR and ROS. DDR is a function mediated by ATM, ATR, and DNA-PK which transduces the signals to activate repair pathway. Inhibition of ATM and ATR were not significance due to the side effects and sensitivity to switching over to other cancer types (Collis SJ, 2005). Thus targeting DNA-PK looks promising to increases the therapeutic activity with fewer side effects. DNA-PK inhibitors like vanillin, NU7026 are very effective and efficiently blocked the repair system. Some of the
DNA damaging agents can even inhibit DNA-PK thereby performs the dual function and reduces the risk of side effect. For instance, inhibitors of Topoisomerase 2 even blocks NHEJ. Highly advanced and accurate technique is the use of siRNA and it is found to reduce the activity of ATM, ATR and DNA-PK by 90% and was significantly higher than wortmannin (Collis SJ, 2003).

Targeting direct repair:
O6 Methyl Guanine-DNA-Methyl Transferase (MGMT) results in resistance to many anticancer drugs, like Temozolomide, dacarbazine, BCNU by transferring the adduct to its own cysteine residue. Thus MGMT gene is targeted and subjected for methylation of its gene. Analogue of guanine is used to suppress the enzymatic activity of MGMT (Yongjian Zhu, 2009).
Therapeutic actions are very crucial and have to be checked for side effects and other possible consequences. Personalised medicine would possibly give a better result; along with which whole genome sequencing and exome sequencing techniques should be employed for cancer therapy. Each cancer patterns have to be sequestered with genome sequencing through which medication could be done at the molecular level. Cancer with a family history should be treated with suitable prognostic methods.





References:
1. Thomas A Kunkel, JBC – Apr 23, 2004
2. Claud S Rupert, The journal of General Physiology, Vol 45,1962
3. Daniel Roth and Harold H Sage, Cancer, Sept 1969.
4. Cleaver, J. E. Proc. Natl Acad. Sci. USA 63, 1969
5. Lehmann, A. R., McGibbon, D. & Stefanini, 6, 70 (2011).
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7. Cancer.net, Editorial board, 12/2014
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9. Moldovan, G. L. & D’Andrea, A. D. Annu. Rev. Genet. 43, (2009).
10. Moynahan, M. E., Chiu, J. W., Koller, B. H. & Jasin, M. 1999
11. Yongjian Zhu a,d,e, Jue Hu b,d,f, Yiduo Hu c,g, Weiguo Liu a
12. Collis SJ, DeWeese TL, Jeggo PA, Parker AR. Oncogene 2005.

Diagrams are available and could be requested through email
The article is written by using the data from several research articles and are subjected for copyright. Hence, they are referenced accordingly.

CANCER AND ITS OTHER PHASES/FACES

THERE COULD BE A REASON FOR CANCER WHICH IS WAY BEYOND IMAGINATION...!!!

Cancer is one of the key reasons for death all over the world. Several schools of scientists opined that cancer is because mainly due to tobacco consumption, alcoholism, unscientific food habit, exposure to radiation and even due to heredity. I do agree with all these key reasons; however they may not be the key reason in many of the cases. One such instance I had come across, a 95 years old person remained without any health issues and he was addicted for consumption of raw tobacco leaves from the age of 13…! So, there’s some other reason which triggers the onset of cancer. If the cigarettes are known to cause cancer, then half of the world’s population should be of cancer patients. In traditional country like India, several village people are used to have beetle leaves after lunch/dinner as a digestive stimulant. Still, they are the healthiest compared well civilized urban people. Even in this case modern science fails to answer to these exceptions. In north India, a kind of people called NAGAs are very much addicted to use chillum filled with marijuana. Mysterious thing about them is, there are many NAGAs whose age is still big question and is unpredictable. Does the reason for cancer cannot show its activity here..? Similar kind of practice is being reported in mythological story, in which, lord Shiva is known for this.

Keeping all these consequences aside, there must be a specific pattern to diagnose cancers which are based on several biochemical techniques. But, without knowing anything about science, medicine an illiterate person can cure cancer..! YES, this much more interesting than anything else. Now a days, many of the scientists and doctors working out to find a better way to cure cancer. Meanwhile, village person popularly called NAATI VAIDYA uses a combination of herbal leaves to cure it. There are thousands of instances where people found this medicine as more effective than the medicine prescribed by highly educated and professional doctors..!!! This again creates a head scratching doubt and remains unanswered. Many of such uneducated doctors are working to find new combination of medicines to find a better cure for cancer. Those UNNAMED DOCTORS know about the mechanism and functioning of cancer cell better than all other named doctors.  So according to me it would be a better research plan to merge modern techniques with traditional techniques. The traditional medicines should be analyzed by using modern research equipment, so that the functioning of those medicines would help us to find the target site and furthermore it would help us to identify the pathway regarding that. Add on to this discussion, it is very much essential to learn more about phytochemicals to deal with it. Phytochemicals would create a landmark in cancer research and it would be a trend setting to analyze several unknown biochemical pathways in the biological system. Ignorance towards the nature would be the biggest mistake that the scientific community is stepping and is a finest deviation from normal research tract.

People started to use pizza and burger more than the traditional food and now the younger generation is facing the severe problems including obesity, diabetes at the earliest age and even cancer. Maida flour used for the preparation of those food items are known to be very much hazardous and are slow poisons in the other way around.  Traditional Indian cuisines are purely based on naturally available food resources and are completely devoid of chemicals and adulterants. Taking all these aspects into consideration, it’s very clear that lifestyle also decides several health issues (including cancer). A lot of work has to be done which should consider lifestyle, food habit and also certain environmental condition.

Cancer forum could possibly initiate this kind of research project to motivate young minds to research.

This article is mainly based on some of the case studies and is not based on any of scientific research. This could be a true analysis with respect to some and may not be with others.