Development, In-Vitro Characterization and Preclinical Evaluation of Esomeprazole-Encapsulated Proniosomal Formulation for the Enhancement of Anti-Ulcer Activity.

Objective: The present study aimed to develop and optimize esomeprazole loaded proniosomes (EZL-PNs) to improve bioavailability and therapeutic efficacy. Method: EZL-PNs formulation was developed by slurry method and optimized by 33 box-Bhekhen statistical design software. Span 60 (surfactant), cholesterol, EZL concentration were taken as independent variables and their effects were evaluated on vesicle size (nm), entrapment efficiency (%, EE) and drug release (%, DR). Furthermore, optimized EZL-PNs (EZL-PNs-opt) formulation was evaluated for ex vivo permeation, pharmacokinetic and ulcer protection activity. Result: The EZL-PNs-opt formulation showed 616 ± 13.21 nm of vesicle size, and 81.21 ± 2.35% of EE. EZL-PNs-opt exhibited negative zeta potential and spherical confirmed scanning electron microscopy. EZL-PNs-opt showed sustained release of EZL (95.07 ± 2.10% in 12 h) than pure EZL dispersion. The ex-vivo gut permeation result exhibited a significantly (p < 0.05) enhanced flux than pure EZL. The in vivo results revealed 4.02-fold enhancement in bioavailability and 61.65% protection in ulcer than pure EZL dispersion (43.82%). Conclusion: Our findings revealed that EZL-PNs formulation could be an alternative delivery system of EZL to enhance oral bioavailability and antiulcer activity.

Role of atrial natriuretic peptide in ischemic preconditioning-induced cardioprotection in the diabetic rat heart.

BACKGROUND: It has been noted that nitric oxide (NO) is involved in the ischemic preconditioning (IPC)-mediated cardioprotection. Diabetes is a downregulator of atrial natriuretic peptide (ANP), resulting in low expression of endothelial nitric oxide synthase (eNOS) by which NO level get reduced. The purpose of the present study was to investigate the role of ANP in attenuated cardioprotective effect of IPC in the diabetic rat heart. METHODS: The heart was isolated from the diabetic rat and mounted on Langendorff's apparatus, subjected to 30-min ischemia and 120-min reperfusion. IPC was mediated by four cycles of 5-min ischemia and 5-min reperfusion. The infarct size was estimated using triphenyltetrazolium chloride stain, and coronary effluent was analyzed for lactate dehydrogenase and creatinine kinase-MB release to assess the degree of myocardial injury. The cardiac release of NO was estimated indirectly by measuring the release of nitrite in coronary effluent. RESULTS: IPC-mediated cardioprotection was significantly attenuated in the diabetic rat as compared with the normal rat. Perfusion of ANP (0.1 µM/L) in the diabetic rat heart significantly restored the attenuated cardioprotective effect of IPC and also increased the release of NO. However, this observed cardioprotection was significantly attenuated by perfusion of N-nitro L-arginine methyl ester, an eNOS inhibitor (100 µM/L) noted in terms of increase in myocardial infarct size, release of lactate dehydrogenase and creatinine kinase-MB, and also decreases in release of NO. CONCLUSIONS: Thus, it is suggested that ANP restores the attenuated cardioprotective effect in the diabetic heart which may be due to increase in the expression of eNOS and subsequent increase in the activity of NO.

The Pharmacological Potential of Resveratrol in Reducing Soft Tissue Damage in Osteoarthritis Patients.

Osteoarthritis is a degenerative joint disease that causes the cartilage and bone underneath the joint to break down. This causes pain and stiffness. Resveratrol, a polyphenolic compound found in various vegetables, fruits, and red wine, has been studied for its beneficial effects on osteoarthritis. Resveratrol has been shown to target a variety of pathways, including the NF-κB, PI3K/Akt, MAPK/ERK, and AMPK pathways. In particular, resveratrol has been studied for its potential use in treating osteoarthritis, and it has been shown to reduce inflammation, reduce cartilage degradation, and improve joint function. In this review, we discuss the evidence for the pharmacological use of resveratrol in minimizing soft tissue damage associated with osteoarthritis. We summarize the studies on how resveratrol has anti-inflammatory, anti-oxidant, and anti-apoptotic effects, as well as effects on cartilage degradation, osteoblast and synoviocyte proliferation, and cytokine production. We also discuss the possible mechanisms of action of resveratrol in osteoarthritis and its potential as a therapeutic agent. Finally, we discuss the potential risks and adverse effects of long-term resveratrol supplementation. Overall, resveratrol has been found to be a possible treatment for osteoarthritis because of its anti-inflammatory, anti-oxidant, and anti-apoptotic properties, and its ability to control the production of enzymes that break down cartilage, osteoblasts, and synoviocytes. Although numerous clinical studies have demonstrated resveratrol's efficacy as an osteoarthritis management agent, further long-term studies are needed to better understand the safety and potential benefits of using resveratrol for osteoarthritis management.

Investigating In Silico and In Vitro Therapeutic Potential of Diosmetin as the Anti-Parkinson Agent.

AIM: This study aimed to investigate how diosmetin interacts with seven target receptors associated with oxidative stress (OS) and validate its antioxidant properties for the potential management of Parkinson's disease (PD). BACKGROUND: In PD, the degeneration of dopaminergic cells is strongly influenced by OS. This stressor is intricately connected to various mechanisms involved in neurodegeneration, such as mitochondrial dysfunction, neuroinflammation, and excitotoxicity induced by nitric oxide. OBJECTIVE: The aim of this research was to establish a molecular connection between diosmetin and OS-associated target receptors was the goal, and it investigated how this interaction can lessen PD. MATERIAL AND METHODS: Seven molecular targets - Adenosine A2A (AA2A), Peroxisome Proliferator- Activated Receptor Gamma (PPARγ), Protein Kinase AKT1, Nucleolar Receptor NURR1, Liver - X Receptor Beta (LXRß), Monoamine Oxidase - B (MAO-B) and Tropomyosin receptor kinase B (TrkB) were obtained from RCSB. Molecular docking software was employed to determine molecular interactions, while antioxidant activity was assessed through in-vitro assays against various free radicals. RESULTS: Diosmetin exhibited interactions with all seven target receptors at their binding sites. Notably, it showed superior interaction with AA2A and NURR1 compared to native ligands, with binding energies of -7.55, and -6.34 kcal/mol, respectively. Additionally, significant interactions were observed with PPARγ, AKT1, LXRß, MAO-B, and TrkB with binding energies of -8.34, -5.42, -7.66, -8.82, -8.45 kcal/mol, respectively. Diosmetin also demonstrated antioxidant activity against various free radicals, particularly against hypochlorous acid (HOCl) and nitric oxide (NO) free radicals. CONCLUSION: Diosmetin possibly acts on several target receptors linked to the pathophysiology of PD, demonstrating promise as an OS inhibitor and scavenger.

Understanding Mechanisms and Key Factors Influencing Melanogenesis for the Management of Melasma: An Updated Review.

Melanocytes are highly specialized dendritic cells that deliver melanin to keratinocytes in melanosomes, which are subcellular organelles where melanin is produced and stored. Mammal's skin, hair, and eyes all contain the complex pigment melanin, which gives them color and ultraviolet protection. Melanins have the potential to be free radical sinks and are strong cation chelators. Amino acid tyrosine and its metabolite, dopa, are the precursors to complex metabolic processes that end with melanin production. Melanocytes generate different types and amounts of melanin, which is defined genetically and is impacted by several extrinsic and intrinsic factors such as hormone fluctuations, inflammation, age, and ultraviolet radiation exposure, leading to the stimulation of numerous melanogenesis pathways. Melasma, a common skin pigmentation condition, is associated with the overproduction of melanin and is characterized by brown to gray-brown and black spots that mostly affect the face. The present review addresses the regulatory mechanisms and signaling pathways involved in skin pigmentation with an emphasis on the altered melanogenesis that causes melasma and hyperpigmentation. The current study also illustrates the available treatment options with cellular and molecular mechanisms for the management of melasma. Understanding the mechanism of the pigmentation process may help researchers develop new therapeutic strategies and novel drugs for the management of melasma.

Unveiling the Molecular Mechanism of Diosmetin and its Impact on Multifaceted Cellular Signaling Pathways.

BACKGROUND: Diosmetin is an O-methylated flavone and the aglycone part of the flavonoid glycosides diosmin that occurs naturally in citrus fruits. Pharmacologically, diosmetin is reported to exhibit anticancer, antimicrobial, antioxidant, oestrogenic, and anti-inflammatory activities. OBJECTIVE: This comprehensive review was aimed to critically explore diverse pharmacological activities exhibited by diosmetin. Along with that, this review can also identify potential research areas with an elucidation of the multifactorial underlying signaling mechanism of action of diosmetin in different diseases. METHODS: A comprehensive collection of evidence and insights was obtained from scientific journals and books from physical libraries and electronic platforms like Google Scholar and PubMed. The time frame selected was from year 1992 to July 2023. RESULTS: The review delves into diosmetin's impact on cellular signaling pathways and its potential in various diseases. Due to its ability to modulate signaling pathways and reduce oxidative stress, it can be suggested as a potential versatile therapeutic agent for mitigating oxidative stressassociated pathogenesis. CONCLUSION: The amalgamation of the review underscores diosmetin's promising role as a multifaceted therapeutic agent, highlighting its potential for drug development and clinical applications.

A Review of the Common Neurodegenerative Disorders: Current Therapeutic Approaches and the Potential Role of Bioactive Peptides.

Neurodegenerative disorders, which include Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS), represent a significant and growing global health challenge. Current therapies predominantly focus on symptom management rather than altering disease progression. In this review, we discuss the major therapeutic strategies in practice for these disorders, highlighting their limitations. For AD, the mainstay treatments are cholinesterase inhibitors and N-methyl-D-aspartate (NMDA) receptor antagonists. For PD, dopamine replacement therapies, including levodopa, are commonly used. HD is managed primarily with symptomatic treatments, and reusable extends survival in ALS. However, none of these therapies halts or substantially slows the neurodegenerative process. In contrast, this review highlights emerging research into bioactive peptides as potential therapeutic agents. These naturally occurring or synthetically designed molecules can interact with specific cellular targets, potentially modulating disease processes. Preclinical studies suggest that bioactive peptides may mitigate oxidative stress, inflammation, and protein misfolding, which are common pathological features in neurodegenerative diseases. Clinical trials using bioactive peptides for neurodegeneration are limited but show promising initial results. For instance, hemiacetal, a γ-secretase inhibitor peptide, has shown potential in AD by reducing amyloid-beta production, though its development was discontinued due to side effects. Despite these advancements, many challenges remain, including identifying optimal peptides, confirming their mechanisms of action, and overcoming obstacles related to their delivery to the brain. Future research should prioritize the discovery and development of novel bioactive peptides and improve our understanding of their pharmacokinetics and pharmacodynamics. Ultimately, this approach may lead to more effective therapies for neurodegenerative disorders, moving beyond symptom management to potentially modify the course of these devastating diseases.

Exploring Therapeutic Frontiers: Unveiling the Potential of Natural Diterpenoid Derivatives in Addressing Neurological Disorders.

Neurological disorders present a formidable challenge in healthcare, necessitating the continuous exploration of innovative therapeutic avenues. This review delves into the burgeoning field of natural diterpenoid derivatives and their promising role in addressing neurological disorders. Derived from natural sources, these compounds exhibit a diverse range of pharmacological properties, positioning them as potential agents for treating conditions such as Alzheimer's and Parkinson's disease. The review highlights recent advancements, shedding light on the multifaceted mechanisms through which diterpenoid derivatives exert their effects, from antiinflammatory to neuroprotective actions. As the scientific community navigates the translational journey from bench to bedside, integrating these natural compounds into neurotherapeutics emerges as a compelling prospect. This exploration of the therapeutic frontiers of natural diterpenoid derivatives signifies a significant step towards innovative and effective strategies in the management of neurological disorders. It highlights the potential of natural compounds to revolutionize neurotherapeutics.

Impact of Bioactive Compounds in the Management of Various Inflammatory Diseases.

Inflammation is an individual's physiological response to a sequence of physical, chemical, or infectious stressors acting mainly to provide localized protection. Although inflammation is a protective and thus beneficial process, its excess or prolonged action can be harmful to the body. An increasing number of the population worldwide are changing their lifestyles, which leads to a rise in inflammatory diseases, such as atherosclerosis, angina pectoris, myocardial infarction, ulcerative colitis, cancer, and many more. Their treatment is based majorly on the pharmacological approach. However, natural products or bioactive compounds are of great significance in inflammation therapy because they show minimum side effects and maximum bioavailability. Therefore, it is critical to investigate bioactive substances that can modify target functions associated with oxidative stress defense and might be used to achieve various health benefits. This review accentuates the essence of bioactive chemicals used in the treatment of inflammation and other inflammatory illnesses. These bioactive compounds can be of any origin, such as plants, animals, bacteria, fungi, marine invertebrates, etc. Bioactive compounds derived from plant sources, such as glycyrrhizin, lignans, lycopene, resveratrol, indoles, and phenolic and polyphenolic compounds, work mainly by reducing oxidative stress and thereby preventing various inflammatory disorders. A large diversity of these anti-inflammatory bioactive compounds has also been discovered in marine environments, giving rise to an increase in the interest of various scientists in marine invertebrates and microbes. The vast diversity of microbes found in the marine environment represents an enormous supply to extract novel compounds, such as from bacteria, cyanobacteria, fungi, algae, microalgae, tiny invertebrates, etc. In the present review, an attempt has been made to summarize such novel bioactive compounds that help prevent inflammatory responses via different mechanisms of action.

Advances in gene therapy approaches targeting neuro-inflammation in neurodegenerative diseases.

Over the last three decades, neurodegenerative diseases (NDs) have increased in frequency. About 15% of the world's population suffers from NDs in some capacity, which causes cognitive and physical impairment. Neurodegenerative diseases, including Amyotrophic Lateral Sclerosis, Parkinson's disease, Alzheimer's disease, and others represent a significant and growing global health challenge. Neuroinflammation is recognized to be related to all NDs, even though NDs are caused by a complex mix of genetic, environmental, and lifestyle factors. Numerous genes and pathways such as NFκB, p38 MAPK, Akt/mTOR, caspase, nitric oxide, and COX are involved in triggering brain immune cells like astrocytes and microglia to secrete inflammatory cytokines such as tumor necrosis factor-α, interleukin (IL)-1ß, and IL-6. In AD, the binding of Aß with CD36, TLR4, and TLR6 receptors results in activation of microglia which start to produce proinflammatory cytokines and chemokines. Consequently, the pro-inflammatory cytokines worsen and spread neuroinflammation, causing the deterioration of healthy neurons and the impairment of brain functions. Gene therapy has emerged as a promising therapeutic approach to modulate the inflammatory response in NDs, offering potential neuroprotective effects and disease-modifying benefits. This review article focuses on recent advances in gene therapy strategies targeting neuroinflammation pathways in NDs. We discussed the molecular pathways involved in neuroinflammation, highlighted key genes and proteins implicated in these processes, and reviewed the latest preclinical and clinical studies utilizing gene therapy to modulate neuroinflammatory responses. Additionally, this review addressed the prospects and challenges in translating gene therapy approaches into effective treatments for NDs.

Emerging pharmacological approaches for Huntington's disease.

Huntington's disease (HD) is a progressive neurodegenerative disorder characterized by cognitive, motor, and psychiatric symptoms. Despite significant advances in understanding the underlying molecular mechanisms of HD, there is currently no cure or disease-modifying treatment available. Emerging pharmacological approaches offer promising strategies to alleviate symptoms and slow down disease progression. This comprehensive review aims to provide a critical appraisal of the latest developments in pharmacological interventions for HD. The review begins by discussing the pathogenesis of HD, focusing on the role of mutant huntingtin protein, mitochondrial dysfunction, excitotoxicity, and neuro-inflammation. It then explores emerging therapeutic targets, including the modulation of protein homeostasis, mitochondrial function, neuro-inflammation, and neurotransmitter systems. Pharmacological agents targeting these pathways are discussed, including small molecules, gene-based therapies, and neuroprotective agents. In recent years, several clinical trials have been conducted to evaluate the safety and efficiency of novel compounds for HD. This review presents an update on the outcomes of these trials, highlighting promising results and challenges encountered. Additionally, it discusses the potential of repurposing existing drugs approved for other indications as a cost-effective approach for HD treatment. The review concludes by summarizing the current state of pharmacological approaches for HD and outlining future directions in drug development. The integration of multiple therapeutic strategies, personalized medicine approaches, and combination therapies are highlighted as potential avenues to maximize treatment effectiveness.

Recent Advances in the Synthesis of Antioxidant Derivatives: Pharmacological Insights for Neurological Disorders.

Neurological disorders, characterized by oxidative stress (OS) and inflammation, have become a major global health concern. Redox reactions play a vital role in regulating the balance of the neuronal microenvironment. Specifically, the imbalance leads to a significant weakening of the organism's natural defensive mechanisms. This, in turn, causes the development of harmful oxidative stress, which plays a crucial role in the onset and progression of neurodegenerative dis-eases. The quest for effective therapeutic agents has led to significant advancements in the syn-thesis of antioxidant derivatives. This review provides a comprehensive overview of the recent developments in the use of novel antioxidant compounds with potential pharmacological applica-tions in the management of neurological disorders. The discussed compounds encompass a di-verse range of chemical structures, including polyphenols, vitamins, flavonoids, and hybrid mole-cules, highlighting their varied mechanisms of action. This review also focuses on the mechanism of oxidative stress in developing neurodegenerative disease. The neuroprotective effects of these antioxidant derivatives are explored in the context of specific neurological disorders, including Alzheimer's disease, Parkinson's disease, and Huntington's disease. The ultimate goal is to pro-vide effective treatments for these debilitating conditions and improve the quality of life for pa-tients.

Exploring the Pharmacological Effects of Bioactive Peptides on Human Nervous Disorders: A Comprehensive Review.

A family of peptides known as bioactive peptides has unique physiological properties and may be used to improve human health and prevent illness. Because bioactive peptides impact the immunological, endocrine, neurological, and cardiovascular systems, they have drawn a lot of interest from researchers. According to recent studies, bioactive peptides have a lot to offer in the treatment of inflammation, neuronal regeneration, localized ischemia, and the blood-brain barrier. It investigates various peptide moieties, including antioxidative properties, immune response modulation, and increased blood-brain barrier permeability. It also looks at how well they work as therapeutic candidates and finds promising peptide-based strategies for better outcomes. Furthermore, it underscores the need for further studies to support their clinical utility and suggests that results from such investigations will enhance our understanding of the pathophysiology of these conditions. In order to understand recent advances in BPs and to plan future research, academic researchers and industrial partners will find this review article to be a helpful resource.

Revolutionizing Diabetes Care: The Role of Marine Bioactive Compounds and Microorganisms.

Diabetes is a metabolic condition characterized by high blood glucose levels. Aquatic products like microalgae, bacteria, seagrasses, macroalgae, corals, and sponges have been investigated for potential anti-diabetic properties. We looked at polyphenols, peptides, pigments, and sterols, as well as other bioactive substances found in marine resources, to see if they could help treat or manage diabetes, in addition to describing the several treatment strategies that alter diabetes and its implications, such as inhibition of protein tyrosine phosphatases 1B (PTP1B), α-glucosidase, α-amylase, dipeptidyl peptidase IV (DPP-IV), aldose reductase, lipase, glycogen synthase kinase 3ß (GSK-3ß), and insulin resistance prevention, promotion of liver antioxidant capacity, natural killer cell stimulant, anti-inflammatory actions, increased AMP-activated protein kinase (AMPK) phosphorylation and sugar and metabolism of the lipid, reducing oxidative stress, and ß-pancreatic cell prevention. This study highlights the revolutionary potential of marine bioactive compounds and microorganisms in transforming diabetes care. We believe in a future in which innovative, sustainable, and efficient therapeutic approaches will result in improved quality of life and better outcomes for people with diabetes mellitus by forging a new path for treatment, utilizing the power of the world's oceans, and capitalizing on the symbiotic relationship between humans and the marine ecosystem. This study area offers optimism and promising opportunities for transforming diabetes care.

Association of air pollution with risk and severity of obstructive sleep apnea: A systematic review and meta-analysis.

BACKGROUND: Obstructive Sleep Apnea (OSA) is a significant health concern characterized by recurrent upper airway blockages during sleep, causing various health issues. There's growing evidence of a link between air pollution and OSA, though research results have been inconsistent. This systematic review and meta-analysis aims to consolidate and examine data on the relationship between air pollution and OSA's risk and severity. METHODS: A literature search across PubMed, EMBASE, and Web of Science was conducted until January 10, 2024. The selection criteria targeted studies involving OSA participants or those at risk, with quantitative air pollution assessments. The Nested Knowledge software facilitated screening and data extraction, while the Newcastle-Ottawa Scale was used for quality assessment. Meta-analyses, utilizing random-effects models, computed pooled odds ratios (ORs) for the OSA risk associated with PM2.5 and NO2 exposure, analyzed using R software version 4.3. RESULTS: The systematic review included twelve studies, four of which were analyzed in the meta-analysis. The meta-analysis revealed diverse results on the association of PM2.5 and NO2 with OSA risk. PM2.5 exposure showed a pooled OR of 0.987 (95 % CI: 0.836-1.138), indicating no substantial overall impact on OSA risk. Conversely, NO2 exposure was linked to a pooled OR of 1.095 (95 % CI: 0.920-1.270), a non-significant increase in risk. Many studies found a relationship between air pollution exposure and elevated Apnea-Hypopnea Index (AHI) levels, indicating a relationship between air pollution and OSA severity. CONCLUSION: The findings suggest air pollutants, especially NO2, might play a role in worsening OSA risk and severity, but the evidence isn't definitive. This highlights the variability of different pollutants' effects and the necessity for more research. Understanding these links is vital for shaping public health policies and clinical approaches to address OSA amidst high air pollution.

Monoterpenoid synergy: a new frontier in biological applications.

Monoterpenoids, compounds found in various organisms, have diverse applications in various industries. Their effectiveness is influenced by the oil's chemical composition, which in turn is influenced by plant genotype, environmental conditions, cultivation practices, and plant development stage. They are used in various industries due to their distinctive odor and taste, serving as ingredients, additives, insecticides, and repellents. These compounds have synergistic properties, resulting in superior combined effects over discrete ones, potentially beneficial for various health purposes. Many experimental studies have investigated their interactions with other ingredients and their antibacterial, insecticidal, antifungal, anticancer, anti-inflammatory, and antioxidant properties. This review discusses potential synergistic interactions between monoterpenoids and other compounds, their sources, and biological functions. It also emphasizes the urgent need for more research on their bioavailability and toxicity, underlining the importance and relevance of this comprehensive study in the current scientific landscape.

Osseous implications of proton pump inhibitor therapy: An umbrella review.

Background: Proton pump inhibitors (PPIs) are among the most commonly prescribed medications worldwide for acid-related disorders. While their short-term efficacy and safety are well-established, concerns regarding their long-term effects on bone health have emerged. This umbrella review aimed to synthesize the available findings on the associations between PPI use and bone metabolism outcomes. Methods: An electronic search was conducted using PubMed, Web of Science, Embase, and the Cochrane Database up to September 16, 2023. Systematic reviews and meta-analyses of randomized controlled trials (RCTs) and observational studies that evaluated the relationship between PPIs and bone metabolism outcomes were included. Data extraction, quality appraisal, and synthesis were performed in line with the Joanna Briggs Institute and PRISMA guidelines. The strength of the evidence was graded using the GRADE criteria. Statistical analysis was performed in R version 4.3. Results: Out of 299 records, 27 studies met the inclusion criteria. The evidence indicated a statistically significant increased risk of fractures, notably hip, spine, and wrist fractures, in PPI users. PPI use was associated with changes in Bone Mineral Density (BMD) across various bones, though the clinical relevance of these changes remains uncertain. Furthermore, PPI-induced hypomagnesemia, which can influence bone health, was identified. A notable finding was the increased risk of dental implant failures in PPI users. However, the certainty of most of the evidence ranged from very low to low based on GRADE criteria. Conclusion: The long-term use of PPIs may be associated with adverse bone health outcomes, including increased fracture risk, alterations in BMD, hypomagnesemia, and dental implant failure. While these findings highlight potential concerns for long-term PPI users, the current evidence's low certainty underscores the need for robust, high-quality research to clarify these associations.

Efficacy and safety of stem cell therapy in patients with dilated cardiomyopathy: An umbrella review of systematic reviews.

BACKGROUND: Stem cell therapy (SCT) has emerged as a potential therapeutic avenue, with various cell types being explored for their efficacy in treating DCM. However, the safety and efficacy of these therapies have been the subject of numerous systematic reviews. This umbrella review aims to consolidate the existing evidence on stem cell interventions for DCM, providing a comprehensive overview of the current research landscape. METHODS: This review was conducted following the JBI and PRISMA guidelines. Systematic reviews and meta-analyses of randomized controlled trials (RCTs) evaluating the safety and efficacy of SCT for DCM were included. Outcomes such as 6MWT, LVEDD, LVEF, MACE, NYHA, and QoL, among others, were considered. A literature search was executed across databases like PubMed, Embase, Web of Science, and Cochrane Database up to October 07, 2023. The quality of the included reviews was assessed using the JBI Checklist for Systematic Reviews and Research Syntheses. Data synthesis was carried out in both narrative and tabular formats, with the GRADE criteria guiding the determination of evidence certainty. RESULTS: Nine systematic reviews met the inclusion criteria. LVEF found to be significantly improved with SCT. LVEDD and LVEDV assessments yielded mixed results, with some reviews observing significant changes. LVESV showed consistent reductions across multiple studies. BNP concentrations post-interventions were explored in several studies, with mixed findings. Health-related quality of life (HRQL) showed varied results, with some studies noting improvements and others finding no significant differences. NYHA classifications and 6-MWT results indicated potential benefits from stem cell treatments. SCT was observed to be generally safe. The certainty of evidence was low or very low for most of outcomes. CONCLUSION: SCT showed has shown promise in treating DCM, with many studies highlighting its safety and potential benefits. Nonetheless, the existing data has its limitations due to biases in the RCTs studies. To truly establish the benefits of SCT for DCM, future high quality RCTS, are crucial.

Alkaloid-based modulators of the PI3K/Akt/mTOR pathway for cancer therapy: Understandings from pharmacological point of view.

This review aims to summarize the role of alkaloids as potential modulators of the PI3K/Akt/mTOR (PAMT) pathway in cancer therapy. The PAMT pathway plays a critical role in cell growth, survival, and metabolism, and its dysregulation contributes to cancer hallmarks. In healthy cells, this pathway is tightly controlled. However, this pathway is frequently dysregulated in cancers and becomes abnormally active. This can happen due to mutations in genes within the pathway itself or due to other factors. This chronic overactivity promotes cancer hallmarks such as uncontrolled cell division, resistance to cell death, and increased blood vessel formation to nourish the tumor. As a result, the PAMT pathway is a crucial therapeutic target for cancer. Researchers are developing drugs that specifically target different components of this pathway, aiming to turn it off and slow cancer progression. Alkaloids, a class of naturally occurring nitrogen-containing molecules found in plants, have emerged as potential therapeutic agents. These alkaloids can target different points within the PAMT pathway, inhibiting its activity and potentially resulting in cancer cell death or suppression of tumor growth. Research is ongoing to explore the role of various alkaloids in cancer treatment. Berberine reduces mTOR activity and increases apoptosis by targeting the PAMT pathway, inhibiting cancer cell proliferation. Lycorine inhibits Akt phosphorylation and mTOR activation, increasing pro-apoptotic protein production and decreasing cell viability. In glioblastoma models, harmine suppresses mTORC1. This review focuses on alkaloids such as evodiamine, hirsuteine, chaetocochin J, indole-3-carbinol, noscapine, berberine, piperlongumine, and so on, which have shown promise in targeting the PAMT pathway. Clinical studies evaluating alkaloids as part of cancer treatment are underway, and their potential impact on patient outcomes is being investigated. In summary, alkaloids represent a promising avenue for targeting the dysregulated PAMT pathway in cancer, and further research is warranted.

The role of aldose reductase in polyol pathway: An emerging pharmacological target in diabetic complications and associated morbidities.

The expression of aldose reductase leads to a variety of biological and pathological effects. It is a multifunctional enzyme which has a tendency to reduce aldehydes to the corresponding sugar alcohol. In diabetic conditions, the aldose reductase enzyme converts glucose into sorbitol using nicotinamide adenine dinucleotide phosphate as a cofactor. It is a key enzyme in polyol pathway which is a surrogate course of glucose metabolism. The polyol pathway has a significant impact on the aetiology of complications in individuals with end-stage diabetes. The exorbitant level of sorbitol leads to the accumulation of intracellular reactive oxygen species in diabetic heart, neurons, kidneys, eyes and other vasculatures, leading to many complications and pathogenesis. Recently, the pathophysiological role of aldose reductase has been explored with multifarious perspectives. Research on aldose reductase suggest that besides implying in diabetic complications, the enzyme also turns down the lipid-derived aldehydes as well as their glutathione conjugates. Although aldose reductase has certain lucrative role in detoxification of toxic lipid aldehydes, its overexpression leads to intracellular accumulation of sorbitol which is involved in secondary diabetic complications, such as neuropathy, cataractogenesis, nephropathy, retinopathy and cardiovascular pathogenesis. Osmotic upset and oxidative stress are produced by aldose reductase via the polyol pathway. The inhibition of aldose reductase alters the activation of transcription factors like NF-ƙB. Moreover, in many preclinical studies, aldose reductase inhibitors have been observed to reduce inflammation-related impediments, such as asthma, sepsis and colon cancer, in diabetic subjects. Targeting aldose reductase can bestow a novel cognizance for this primordial enzyme as an ingenious strategy to prevent diabetic complications and associated morbidities. In this review article, the significance of aldose reductase is briefly discussed along with their prospective applications in other afflictions.