A comprehensive review on the pharmacological role of gut microbiome in neurodegenerative disorders: potential therapeutic targets.

Neurological disorders, including Alzheimer and Parkinson's, pose significant challenges to public health due to their complex etiologies and limited treatment options. Recent advances in research have highlighted the intricate bidirectional communication between the gut microbiome and the central nervous system (CNS), revealing a potential therapeutic avenue for neurological disorders. Thus, this review aims to summarize the current understanding of the pharmacological role of gut microbiome in neurological disorders. Mounting evidence suggests that the gut microbiome plays a crucial role in modulating CNS function through various mechanisms, including the production of neurotransmitters, neuroactive metabolites, and immune system modulation. Dysbiosis, characterized by alterations in gut microbial composition and function, has been observed in many neurological disorders, indicating a potential causative or contributory role. Pharmacological interventions targeting the gut microbiome have emerged as promising therapeutic strategies for neurological disorders. Probiotics, prebiotics, antibiotics, and microbial metabolite-based interventions have shown beneficial effects in animal models and some human studies. These interventions aim to restore microbial homeostasis, enhance microbial diversity, and promote the production of beneficial metabolites. However, several challenges remain, including the need for standardized protocols, identification of specific microbial signatures associated with different neurological disorders, and understanding the precise mechanisms underlying gut-brain communication. Further research is necessary to unravel the intricate interactions between the gut microbiome and the CNS and to develop targeted pharmacological interventions for neurological disorders.

A Comprehensive Review on the Significance of Cysteine in Various Metabolic Disorders; Particularly CVD, Diabetes, Renal Dysfunction, and Ischemic Stroke.

Metabolic disorders have long been a challenge for medical professionals and are a leading cause of mortality in adults. Diabetes, cardiovascular disorders (CVD), renal dysfunction, and ischemic stroke are the most prevalent ailments contributing to a high mortality rate worldwide. Reactive oxygen species are one of the leading factors that act as a fundamental root cause of metabolic syndrome. All of these disorders have their respective treatments, which, to some degree, sabotage the pathological worsening of the disease and an inevitable death. However, they pose a perilous health hazard to humankind. Cysteine, a functional amino acid shows promise for the prevention and treatment of metabolic disorders, such as CVD, Diabetes mellitus, renal dysfunction, and ischemic stroke. In this review, we explored whether cysteine can eradicate reactive oxygen species and subsequently prevent and treat these diseases.

Current Landscape of Gene Therapy for the Treatment of Cardiovascular Disorders.

Cardiovascular disorders (CVD) are the primary cause of death worldwide. Multiple factors have been accepted to cause cardiovascular diseases; among them, smoking, physical inactivity, unhealthy eating habits, age, and family history are flag-bearers. Individuals at risk of developing CVD are suggested to make drastic habitual changes as the primary intervention to prevent CVD; however, over time, the disease is bound to worsen. This is when secondary interventions come into play, including antihypertensive, anti-lipidemic, anti-anginal, and inotropic drugs. These drugs usually undergo surgical intervention in patients with a much higher risk of heart failure. These therapeutic agents increase the survival rate, decrease the severity of symptoms and the discomfort that comes with them, and increase the overall quality of life. However, most individuals succumb to this disease. None of these treatments address the molecular mechanism of the disease and hence are unable to halt the pathological worsening of the disease. Gene therapy offers a more efficient, potent, and important novel approach to counter the disease, as it has the potential to permanently eradicate the disease from the patients and even in the upcoming generations. However, this therapy is associated with significant risks and ethical considerations that pose noteworthy resistance. In this review, we discuss various methods of gene therapy for cardiovascular disorders and address the ethical conundrum surrounding it.

Obesity and risk of hypertension in preadolescent urban school children: insights from Pakistan.

BACKGROUND: Childhood obesity and hypertension are growing concerns globally, especially in developing countries. This study investigated the association between overall and central obesity at baseline, and prehypertension or hypertension at follow-up among preadolescent school children in urban Karachi, Pakistan. METHODS: This is a sub study with cohort design embedded within a feasibility trial on School Health Education Program in Pakistan (SHEPP) in preadolescents aged 6-11 years, attending two private schools conducted from 2017 to 2019. Hypertension or prehypertension at follow-up were the outcomes and obesity or central obesity at baseline were the exposure variables. Hypertension was defined as systolic blood pressure and/or diastolic blood pressure ≥ 95th percentile for age, sex, and height. Obesity was defined as body mass index for-age and sex ≥ 95th percentile, whereas central obesity was determined by waist circumference measurements ≥ 85th percentile of age, sex, and height specific cut-offs. Logistic regression analysis was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) to identify risk factors for hypertension and prehypertension. RESULTS: Analysis was conducted for 908 participants, evenly distributed with 454 boys and 454 girls. Hypertension was observed in 19.8% of the preadolescents, with rates of 18.5% in boys and 21.0% in girls. Prehypertension was found in 16.8% of preadolescents, with 18% among boys and 16% among girls. Additionally, 12.8% of preadolescents were classified as obese and 29.8% had central obesity. Obesity at baseline was associated with hypertension at followup (OR 8.7, 95% CI 3.5, 20.4) in the final model after adjusting for age, gender, physical activity, sedentary behavior, fruits, vegetable intake and hypertension at baseline. Central obesity at baseline also yielded high odds, with prehypertension (OR 1.9, 95% CI 1.4, 2.8) and hypertension (OR 2.7, 95% CI 1.9, 3.9) at follow up in the final model. CONCLUSION: This study highlights a concerning prevalence of hypertension and prehypertension among preadolescent school-going children. Obesity and central obesity at baseline emerged as significant predictive factors for hypertension or prehypertension at followup within this cohort. The findings emphasize the urgency of implementing comprehensive school health education programs aimed at early detection and effective management of hypertension during childhood and adolescence in school settings.

Obesity and Risk of Hypertension in Preadolescent Urban School Children: Insights from a Developing Country.

Background: Childhood obesity and hypertension are growing concerns globally, especially in developing countries. This study investigated the association between overall and central obesity at baseline, and prehypertension or hypertension at follow-up among preadolescent school children in Karachi, Pakistan. Methods: This is a sub study with cohort design embedded within a feasibility trial on School Health Education Program in Pakistan (SHEPP) in preadolescent aged 6-11 years, attending two private schools, were enrolled from 2017 to 2019. Hypertension or prehypertension at follow-up were the outcomes and obesity or central obesity at baseline were the exposure variables. Hypertension was defined as systolic blood pressure and/or diastolic blood pressure ≥ 95th percentile for age, sex, and height. Obesity was defined as body mass index for-age and sex ≥ 95th percentile, whereas central obesity was determined by waist circumference measurements ≥ 85th percentile of age, sex, and height specific cut-offs. Logistic regression analysis was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) to identify risk factors for hypertension and prehypertension. Results: Analysis was conducted for 908 participants, evenly distributed with 454 boys and 454 girls. Hypertension was observed in 19.8% of the preadolescents, with rates of 18.5% in boys and 21.0% in girls. Prehypertension was found in 16.8% of preadolescents, with 18% among boys and 16% among girls. Additionally, 12.8% of preadolescents were classified as obese and 29.8% had central obesity. Obesity at baseline was associated with hypertension (OR 8.7, 95% CI 3.5, 20.4) in the final model after adjusting for age, gender, physical activity, sedentary behavior, fruits, vegetable intake and hypertension at baseline. Central obesity at baseline also yielded high odds, with prehypertension (OR 1.9, 95% CI 1.4, 2.8) and hypertension (OR 2.7, 95% CI 1.9, 3.9) in the final model. Conclusion: This study highlights a concerning prevalence of hypertension and prehypertension among preadolescent school-going children. Obesity and central obesity at baseline emerged as significant predictive factors for hypertension within this cohort. The findings emphasize the urgency of implementing comprehensive school health education programs aimed at early detection and effective management of hypertension during childhood and adolescence in school settings.

Biomarkers and Novel Therapies of Diabetic Neuropathy: An Updated Review.

Diabetic neuropathy is a persistent consequence of the biochemical condition known as diabetes mellitus. As of now, the identification and management of diabetic neuropathy continue to be problematic due to problems related to the safety and efficacy of existing therapies. This study examines biomarkers, molecular and cellular events associated with the advancement of diabetic neuropathy, as well as the existing pharmacological and non-pharmacological treatments employed. Furthermore, a holistic and mechanism-centric drug repurposing approach, antioxidant therapy, Gene and Cell therapies, Capsaicin and other spinal cord stimulators and lifestyle interventions are pursued for the identification, treatment and management of diabetic neuropathy. An extensive literature survey was done on databases like PubMed, Elsevier, Science Direct and Springer using the keywords "Diabetic Neuropathy", "Biomarkers", "Cellular and Molecular Mechanisms", and "Novel Therapeutic Targets".Thus, we may conclude that non-pharmacological therapies along with palliative treatment, may prove to be crucial in halting the onset of neuropathic symptoms and in lessening those symptoms once they have occurred.

An Updated Review on Diabetic Nephropathy: Potential Mechanisms, Biomarkers, Therapeutic Targets and Interventional Therapies.

BACKGROUND: Diabetic nephropathy (DN), the primary risk factor for end-stage kidney disease (ESKD) that requires dialysis or renal transplantation, affects up to 50% of individuals with diabetes. OBJECTIVE: In this article, potential mechanisms, biomarkers, and possible therapeutic targets will be discussed, as well as their interventional therapies. METHODS: A literature review was done from databases like Google Scholar, PUBMEDMEDLINE, and Scopus using standard keywords "Diabetic Nephropathy," "Biomarkers," "Pathophysiology," "Cellular Mechanism," "Cell Therapy," "Treatment Therapies" from 2010- 2023. It has been studied that metabolic as well as hemodynamic pathways resulting from hyperglycemia act as mediators for renal disease. RESULTS: We identified 270 articles, of which 210 were reviewed in full-text and 90 met the inclusion criteria. Every therapy regimen for the prevention and treatment of DN must include the blocking of ANG-II action. By reducing inflammatory and fibrotic markers brought on by hyperglycemia, an innovative approach to halting the progression of diabetic mellitus (DN) involves combining sodium-glucose cotransporter-2 inhibitors with renin-angiotensin-aldosterone system blockers. When compared to taking either medicine alone, this method works better. AGEs, protein kinase C (PKC), and the renin-angiotensin aldosterone system (RAAS) are among the components that are inhibited in DN management strategies. CONCLUSION: Thus, it can be concluded that the multifactorial condition of DN needs to be treated at an early stage. Novel therapies with a combination of cell therapies and diet management are proven to be effective in the management of DN.

New Horizons in Diabetic Neuropathies: An Updated Review on their Pathology, Diagnosis, Mechanism, Screening Techniques, Pharmacological, and Future Approaches.

BACKGROUND: One of the largest problems for global public health is diabetes mellitus (DM) and its micro and macrovascular consequences. Although prevention, diagnosis, and treatment have generally improved, its incidence is predicted to keep rising over the coming years. Due to the intricacy of the molecular mechanisms, which include inflammation, oxidative stress, and angiogenesis, among others, discovering treatments to stop or slow the course of diabetic complications is still a current unmet need. METHODS: The pathogenesis and development of diabetic neuropathies may be explained by a wide variety of molecular pathways, hexosamine pathways, such as MAPK pathway, PARP pathway, oxidative stress pathway polyol (sorbitol) pathway, cyclooxygenase pathway, and lipoxygenase pathway. Although diabetic neuropathies can be treated symptomatically, there are limited options for treating the underlying cause. RESULT: Various pathways and screening models involved in diabetic neuropathies are discussed, along with their possible outcomes. Moreover, both medicinal and non-medical approaches to therapy are also explored. CONCLUSION: This study highlights the probable involvement of several processes and pathways in the establishment of diabetic neuropathies and presents in-depth knowledge of new therapeutic approaches intended to stop, delay, or reverse different types of diabetic complications.

Current Landscape of Various Techniques and Methods of Gene Therapy through CRISPR Cas9 along with its Pharmacological and Interventional Therapies in the Treatment of Type 2 Diabetes Mellitus.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is frequently referred to as a "lifestyle illness". In 2000, India (31.7 million) had the greatest global prevalence of diabetes mellitus, followed by China (20.8 million), the United States (17.7 million), and other countries. In recent years, the treatment of gene therapy (T2DM) has attracted intensive interest. OBJECTIVE: We aimed to critically review the literature on the various techniques and methods, which may be a possible novel approach through the gene therapy CRISPR Cas9 and some other gene editing techniques for T2DM. Interventional and pharmacological approaches for the treatment of T2DM were also included to identify novel therapies for its treatment. METHOD: An extensive literature survey was done on databases like PubMed, Elsevier, Science Direct and Springer. CONCLUSION: It can be concluded from the study that recent advancements in gene-editing technologies, such as CRISPR Cas9, have opened new avenues for the development of novel therapeutic approaches for T2DM. CRISPR Cas9 is a powerful tool that enables precise and targeted modifications of the genome.

Aortic stenosis: a review on acquired pathogenesis and ominous combination with diabetes mellitus.

BACKGROUND: Aortic stenosis (AS) is a progressive disease, with no pharmacological treatment. The prevalence of diabetes mellitus (DM) among AS patients is higher than in the general population. DM significantly increases the risk of AS development and progression from mild to severe. The interplay between AS and DM's mechanism is not entirely known yet. MAIN BODY: The increased accumulation of advanced glycation end products (AGEs) was linked to increased valvular oxidative stress, inflammation, expression of coagulation factors, and signs of calcification, according to an analysis of aortic stenotic valves. It is interesting to note that in diabetic AS patients, valvular inflammation did not correlate with serum glucose levels but rather only with long-term glycemic management markers like glycated haemoglobin and fructosamine. Transcatheter aortic valve replacement, which has been shown to be safer than surgical aortic valve replacement, is advantageous for AS patients who also have concurrent diabetes. Additionally, novel anti-diabetic medications have been proposed to lower the risk of AS development in DM patients, including sodium-glucose cotransporter-2 inhibitors and glucagon-like peptide-1 receptor agonist that target reduction of AGEs-mediated oxidative stress. CONCLUSIONS: There are little data on the effects of hyperglycemia on valvular calcification, but understanding the interactions between them is essential to develop a successful treatment strategy to stop or at least slow the progression of AS in DM patients. There is a link among AS and DM and that DM negatively impacts the quality of life and longevity of AS patients. The sole successful treatment, despite ongoing efforts to find new therapeutic modalities, involves aortic valve replacement. More research is required to find methods that can slow the advancement of these conditions, enhancing the prognosis and course of people with AS and DM.

Challenges of managing hypertension in Pakistan - a review.

BACKGROUND: This review aims to describe existing evidence on the state of hypertension in Pakistan, including the prevalence, associated risk factors, preventive strategies, and challenges in the management of hypertension. METHODS: A comprehensive literature search was conducted electronically using PubMed and Google Scholar. Using specific screening methodology, 55 articles were selected to be included. RESULTS: We found from this extensive review that several small studies report high prevalence of hypertension but there is a lack of population based prevalence of hypertension in Pakistan. Lifestyle risk factors such as obesity, unhealthy diet, decreased physical activity, low socioeconomic status, and lack of access to care were the main associated factors with hypertension. Lack of blood pressure monitoring practices and medication non-adherence were also linked to uncontrolled hypertension in Pakistan and were more evident in primary care setups. The evidence presented is essential for delineating the burden of the disease, hence allowing for better management of this underserved population. CONCLUSION: There is a need for updated surveys to depict the true prevalence and management of hypertension in Pakistan. Cost-effective implementation strategies and policies at the national level are needed for both prevention and control of hypertension.

Myocardial Infarction as a Consequence of Mitochondrial Dysfunction.

Acute myocardial infarction is an event of myocardial necrosis caused by unstable ischemic syndrome. Myocardial infarction (MI) occurs when blood stops flowing to the cardiac tissue or myocardium and the heart muscle gets damaged due to poor perfusion and reduced oxygen supply. Mitochondria can serve as the arbiter of cell fate in response to stress. Oxidative metabolism is the function of mitochondria within the cell. Cardiac cells being highly oxidative tissue generates about 90% of their energy through oxidative metabolism. In this review, we focused on the role of mitochondria in energy generation in myocytes as well as its consequences on heart cells causing cell damage. The role of mitochondrial dysfunction due to oxidative stress, production of reactive oxygen species, and anaerobic production of lactate as a failure of oxidative metabolism are also discussed.