Targeting Peroxisome Proliferator-Activated Receptor-ß/δ, Reactive Oxygen Species and Redox Signaling with Phytocompounds for Cancer Therapy.

Significance: Peroxisome proliferator-activated receptors (PPARs) have a moderately preserved amino-terminal domain, an extremely preserved DNA-binding domain, an integral hinge region, and a distinct ligand-binding domain that are frequently encountered with the other nuclear receptors. PPAR-ß/δ is among the three nuclear receptor superfamily members in the PPAR group. Recent Advances: Emerging studies provide an insight on natural compounds that have gained increasing attention as potential anticancer agents due to their ability to target multiple pathways involved in cancer development and progression. Critical Issues: Modulation of PPAR-ß/δ activity has been suggested as a potential therapeutic strategy for cancer management. This review focuses on the ability of bioactive phytocompounds to impact reactive oxygen species (ROS) and redox signaling by targeting PPAR-ß/δ for cancer therapy. The rise of ROS in cancer cells may play an important part in the initiation and progression of cancer. However, excessive levels of ROS stress can also be toxic to the cells and cancer cells with increased oxidative stress are likely to be more vulnerable to damage by further ROS insults induced by exogenous agents, such as phytocompounds and therapeutic agents. Therefore, redox modulation is a way to selectively kill cancer cells without causing significant toxicity to normal cells. However, use of antioxidants together with cancer drugs may risk the effect of treatment as both act through opposite mechanisms. Future Directions: It is advisable to employ more thorough and detailed methodologies to undertake mechanistic explorations of numerous phytocompounds. Moreover, conducting additional clinical studies is recommended to establish optimal dosages, efficacy, and the impact of different phytochemicals on PPAR-ß/δ.

Different Strategies Targeting Gut Microbiota for the Management of Several Disorders: A Sustainable Approach.

BACKGROUND: A potential limelight is flashed on the Gut Microbiota (GM) in the human body, which confers additional psychological as well as physiological attributes to health. Other than just occupying a wide portion of the gastrointestinal tract, it also plays numerous functions in the systems of the body. Gut Microbiota is largely responsible for a considerably vast array of conditions such as obesity, diabetes ,other metabolic disorders, and cardiovascular disorders. Strategies targeting the gut microbiota have been proposed as a promising approach for the management of these disorders. OBJECTIVE: This review aims to summarize the different strategies targeting the gut microbiota for the management of several disorders and to highlight the importance of a sustainable approach. METHODS: A comprehensive literature search was conducted using various databases between 2008 and 2022 that focused on the use of prebiotics, probiotics, synbiotics, postbiotics, fecal microbiota transplantation, dietary interventions, and antibiotics. RESULTS: Different strategies targeting the gut microbiota for the management of several disorders were identified, including probiotics, prebiotics, synbiotics, postbiotics, fecal microbiota transplantation, and dietary interventions. Modification in diet and lifestyle, allowing favorable microbiota growth in the stomach, intake of prebiotics and probiotics, and fecal microbiota transplantation are amongst the widely accepted recent approaches allowing the application of GM in the field of treatment. CONCLUSION: Although considerable steps in enhancing and understanding the mechanism of treatment with the help of gut microbiota are under progress, much diversified and elaborate research must be conducted in order to enhance and implement the use of GM with high effectiveness.

An Insight into the Development of Potential Antidiabetic Agents along with their Therapeutic Targets.

Diabetes is a metabolic disorder that has been reported to increase the mortality rate worldwide. About 40 million people across the globe suffer from diabetes, with people living in developing countries being affected the most due to this deadly disease. Although the therapeutic management of hyperglycaemia can treat diabetes, metabolic disorders associated with this disease are a greater challenge in its treatment. Hence, potential strategies to treat hyperglycaemia and its side effects are needed. In this review, we have summarized several therapeutic targets, like dipeptidyl peptidase-4 (DPP-4), glucagon receptor antagonists, glycogen phosphorylase or fructose-1,6- biphosphatase inhibitors, SGLT inhibitors, 11beta-HSD-1 inhibitors, glucocorticoids receptor antagonists, glucose-6-phosphatase and glycogen phosphorylase inhibitors. These targets can help in designing and developing novel antidiabetic agents.

Trophic transfer patterns of arsenic in freshwater ecosystem layers in arsenic-endemic Ganges Delta and its potential human health risk.

Arsenic (As) is a toxic environmental contaminant with global public health concern. In aquatic ecosystems, the quantification of total As is restricted chiefly to the individual organisms. The present study has quantified the total As in different trophic layers (sediment-water-phytoplankton-periphyton-zooplankton-fish-gastropod-hydrophytes) of lentic freshwater ecosystems. As transfer pathways quantifying the transmission rate across trophic-level compartmental route were delineated using a novel model-based approach along with its potential contamination risk to humans. Lentic water bodies from Indo-Gangetic region, a core area of groundwater As, were selected for the present investigation. The study revealed that among the lower biota, zooplankton were the highest accumulator of total As (5554-11,564 µg kg-1) with magnification (rate = 1.129) of the metalloid, followed by phytoplankton (2579-6865 µg kg-1) and periphytic biofilm (1075 to 4382 µg kg -1). Muscle tissue of zooplanktivore Labeo catla is found to store higher As (80-115 µg kg-1 w.w.) compared to bottom-dwelling omnivore Cirrhinus mrigala (58-92 µg kg-1 w.w.). Whereas, Amblypharyngodon mola has accumulated higher As (203-319 µg kg-1 w.w.) than Puntius sophore (30-98 µg kg-1 w.w.) that raised further concern. The hepatic concentration indicated arsenic-mediated stress based on As stress index (threshold value = 1). Mrigal and Mola showed significant biomagnification among fishes while biodiminution was observed in Catla, Bata, Rohu and Punti. All the studied fishes were under the arsenic mediated stress. In the 'sediment-water-periphytic biofilm-gastropod' compartment, the direct grazing accumulation was higher (rate = 0.618) than the indirect path (rate = 0.587). Stems of edible freshwater macrophytes accumulated lesser As (32-190 µg kg-1 d.w.) than roots (292-946 µg kg-1 d.w.) and leaves (62-231 µg kg-1 d.w.). The target cancer risk (TCR) revealed a greater concern for adults consuming edible macrophyte regularly. Similarly, the varied level of target hazard quotient and TCR for adults consuming fishes from these waterbodies further speculated significant health concerns. The trophic transfer rate of environmental As in soil-water-biota level at an increasing trophic guild and consumer risk analysis have been unravelled for the first time in the Indo-Gangetic plains, which will be helpful for the strategic mitigation of As contamination.

Comprehensive Review on Recent Strategies for Management of Prostate Cancer: Therapeutic Targets and SAR.

Prostate cancer is a disease that is affecting a large population worldwide. Androgen deprivation therapy (ADT) has become a foundation for the treatment of advanced prostate cancer, as used in most clinical settings from neo-adjuvant to metastatic stage. In spite of the success of ADT in managing the disease in the majority of men, hormonal manipulation fails eventually. New molecules are developed for patients with various hormone-refractory diseases. Advancements in molecular oncology have increased understanding of numerous cellular mechanisms which control cell death in the prostate and these insights can lead to the development of more efficacious and tolerable therapies for carcinoma of the prostate. This review is focused on numerous therapies that might be a boon for prostate therapy like signaling inhibitors, vaccines, and inhibitors of androgen receptors. Along with these, various bioactive molecules and their derivatives are highlighted, which act as potential anti-prostate cancer agents. This article also emphasized the recent advances in the field of medicinal chemistry of prostate cancer agents.

Assessment of environmental and human health risk from pesticide residues in river Gomti, Northern India.

Rivers get polluted with diverse types of hazardous and toxic substances, pesticides being one of them. The water and sediment of rivers get contaminated with pesticide residues coming through the run-off of vast agricultural fields along the catchment area and also from domestic sewage water. The residues get bio-concentrated and bio-accumulated in different aquatic organisms and animals including fishes along the food chain. Fish, one of the important and chief sources of proteins, are consumed by humans. The presence of toxic substances like pesticides in any food item is undesirable for the fear of health hazards. We have monitored the status of pesticide residue in river Gomti, a tributary of River Ganga that passes through the Uttar Pradesh state of India. Water, sediment, and fish samples collected from the different locations along the river stretch were analyzed for 34 targeted pesticide compounds belonging to organochlorines (OC), organophosphates (OP), and synthetic pyrethroids (SP) groups. In 52% of water, 30% of sediment, and 43% of fish samples residues of OCs were detected while the OPs were present in 33%, 25%, and 39% of samples respectively. However, none of the SPs could be recorded in any sample. The concentrations of the pesticides in water indicate stress conditions to some extent to aquatic life, but based on the human health risk assessment it can be concluded that consumption of fishes from the river contaminated with different OC or OP residues would not pose any direct risk to the consumers.

Therapeutic Management with Repurposing Approaches: A Mystery During COVID-19 Outbreak.

The ubiquitous pandemic that emerged due to COVID-19 affected the whole planet. People all over the globe became vulnerable to the unpredictable emergence of coronavirus. The sudden emergence of respiratory disease in coronavirus infected several patients. This affected human life drastically, from mild symptoms to severe illness, leading to mortality. COVID-19 is an exceptionally communicable disease caused by SARS-CoV-2. According to a genomic study, the viral spike RBD interactions with the host ACE2 protein from several coronavirus strains and the interaction between RBD and ACE2 highlighted the potential change in affinity from the virus causing the COVID-19 outbreak to a progenitor type of SARS-CoV-2. SARS-CoV-2, which could be the principal reservoir, is phylogenetically related to the SARS-like bat virus. Other research works reported that intermediary hosts for the transmission of viruses to humans could include cats, bats, snakes, pigs, ferrets, orangutans, and monkeys. Even with the arrival of vaccines and individuals getting vaccinated and treated with FDA-approved repurposed drugs like Remdesivir, the first and foremost steps aimed towards the possible control and minimization of community transmission of the virus include social distancing, self-realization, and self-health care. In this review paper, we discussed and summarized various approaches and methodologies adopted and proposed by researchers all over the globe to help with the management of this zoonotic outbreak by following repurposed approaches.

Review deciphering potent therapeutic approaches targeting Notch signaling pathway in breast cancer.

In the current period of drug development, natural products have provided an unrivaled supply of anticancer medications. By modifying the cancer microenvironment and various signaling pathways, natural products and their derivatives and analogs play a significant role in cancer treatment. These substances are effective against several signaling pathways, particularly the cell death pathways (apoptosis and autophagy) and embryonic developmental pathways (Notch, Wnt, and Hedgehog pathways). Natural products have a long history, but more research is needed to understand their current function in the research and development of cancer treatments and the potential for natural products to serve as a significant source of therapeutic agents in the future. Several target-specific anticancer medications failed to treat cancer, necessitating research into natural compounds with multiple target properties. To help develop a better treatment plan for managing breast cancer, this review has outlined the anticancerous potential of several therapeutic approaches targeting the notch signaling system in breast tumors.

Adverse events of clenbuterol among athletes: a systematic review of case reports and case series.

Clenbuterol is a potent beta-2 agonist widely misused by professional athletes and bodybuilders. Information on clenbuterol associated adverse events is present in case reports and case series, though it may not be readily available. This systematic review aimed to critically evaluate the evidence of adverse events associated with clenbuterol among athletes. The search strategy was in accordance with PRISMA guidelines. Databases such as PubMed, Science Direct, Scopus, and Google Scholar were searched from 1990 to October 2021 to find out the relevant case reports and case series. There were 23 included studies. Using a suitable scale, the included studies' methodological quality analysis was evaluated. In total, 24 athletes experienced adverse events. Oral ingestion of clenbuterol was the most preferred route among them. The daily administered dose of clenbuterol was ranging from 20 µg to 30 mg. Major adverse events experienced by athletes were supraventricular tachycardia, atrial fibrillation, hypotension, chest pain, myocardial injury, myocarditis, myocardial ischemia, myocardial infarction, cardiomyopathy, hepatomegaly, hyperglycemia, and death. The cardiac-related complications were the most commonly occurring adverse events. Clenbuterol is notorious to produce life-threatening adverse events including death. Lack of evidence regarding the performance-enhancing effects of clenbuterol combined with its serious toxicities questions the usefulness of this drug in athletes.

A Geostatistical Framework Predicting Zooplankton Abundance in a Large River: Management Implications towards Potamoplankton Sustainability.

The zooplankton community is a widely used bioindicator for the biological assessment of riverine aquatic ecosystems. Phyto-zooplankton interaction and spatially varying river environment parameters perceivably govern their spatial distribution in a large river. This invites the challenge of predicting zooplankton abundance along the river channel. The present article has proposed a geostatistical framework to predict zooplankton abundance along the river course while decoupling phyto-zooplankton relationship from spatial dependency. The strength of secondary data on the river Narmada-a large tropical river in India-has been utilised to accomplish the goal. The nonlinear logistic regression kriging has been found to be the most effective framework. The phyto-zooplankton relationship captured 66% of zooplankton variability, having moderate (37%) residual spatial dependence. The results have shown longitudinally fluctuating spatial variability, which supports the river serial discontinuity concept. The proposed framework has generated smooth zooplankton abundance and sustainability predictive maps that have allowed detection of the change point locations of zooplankton abundance. The map has precisely identified the most productive zone of zooplankton sustainability. The study also has appraised obtaining approximate data in the areas where sampling is infeasible, which will be helpful for location-specific management strategies on a lower spatial scale.

Recent Developments in the Synthesis and Anticancer Activity of Indole and Its Derivatives.

Heterocyclic compounds are a class of compounds that is deeply intertwined with biological processes and is found in about 90% of commercially available medicines. They serve a critical function in medicinal chemistry and are focused in the field of medication development for their intensive research due to their broad variety of biological effects because of their intriguing molecular architecture, such as indoles are good candidates for drug development. It is a bicyclic structure consisting of a six-membered benzene ring fused to a five-membered pyrrole ring with several pharmacophores that yield a library of different lead compounds. Human cancer cells have been demonstrated to be inhibited by indoles in the development of new anticancer medicines. This is the first comprehensive review to focus on current methodologies for incorporating indole moiety, with their mechanistic targets as anticancer drugs, in order to shed light on the logical development of indole-based anticancer treatment options with high efficacy. This compiled data may serve as a benchmark for modifying existing ligands in order to design novel potent molecules through excellent yield synthesis techniques.

Marine-derived Natural Products as Anticancer Agents.

Cancer is a deadly human disease on the rise due to changes in lifestyle, nutrition, and global warming. Cancer is characterized by uncontrolled, disordered, and undesired cell division. About 60% of cancer medicines approved by the FDA are made from natural ingredients. Intensive efforts over the last decade to better understand the vast chemical diversity provided by marine life have resulted in an intriguing "marine pipeline" of potential anticancer clinical and preclinical treatments. The molecular targets of marine products as anticancer drugs, as well as different reported compounds acting on distinct targets, are the topic of this review.

A Review on Modern Approaches to Benzimidazole Synthesis.

Cancer is the second most source of cessation of life globally, with 9.6 million expirations at each stage around the globe. The resistance to the current chemotherapies urges researchers to develop new drugs to be available in the market. Among the wide range of drugs synthesized, heterocyclic compounds play a major role due to the abundance of heterocyclic rings in biological substances. In medicinal chemistry, benzimidazole is an important pharmacophore and a privileged structure. This bicyclic compound is made up of the fusion of a six-membered benzene ring and a five-membered imidazole ring with two nitrogen atoms at 1,3-positions. The benzimidazole ring has a great deal of stability. Many strong acids and alkalis do not affect benzimidazoles. The benzene ring of benzimidazole cleaves only under extreme conditions. Except in certain circumstances, the benzimidazole ring is also quite resistant to reduction. It is the most popular nucleus to study because of its wide range of biological functions. The recently developed methods for preparing benzimidazoles, such as condensation of o-phenylene diamines (OPDs) with aldehydes and many others using a wide range of nano, metal-based catalysts under solventfree conditions, are discussed in detail in the current studies.

Ability of machine learning models to identify preferred habitat traits of a small indigenous fish (Chanda nama) in a large river of peninsular India.

Physical and chemical parameters of river influence the habitat of fish species in aquatic ecosystems. Fish showed a complex relationship with different aquatic factors in river. Machine learning modeling is a useful tool to identify relationships between components of a complex environmental system. We identified the preferred habitat indicators of Chanda nama (a small indigenous fish), in the Krishna River located in peninsular India, using machine learning modeling. Using data on Chanda nama fish distribution (presence/absence) and associated ten physical and chemical parameters of water at 22 sampling sites of the river collected during the year 2001-2002, machine learning models such as random forest, artificial neural network, support vector machine, and k-nearest neighbors were used for classification of Chanda nama distribution in the river. The machine learning model efficiency was evaluated using classification accuracy, Cohen's kappa coefficient, sensitivity, specificity, and receiver-operating-characteristics. Results showed that random forest is the best model with higher classification accuracy (82%), Cohen's kappa coefficient (0.55), sensitivity (0.57), specificity (0.76), and receiver-operating-characteristics (0.72) for prediction of the occurrence of Chanda nama in the Krishna River. Random forest model identified three preferred physicochemical habitat traits such as altitude, temperature, and depth for Chanda nama distribution in Krishna River. Our results will be helpful for researcher and policy maker to understand important physical and chemical variables for sustainable management of a small indigenous fish (Chanda nama) in a large tropical river.

Emerging quinoline- and quinolone-based antibiotics in the light of epidemics.

Pandemics are large-scale outbreaks of infectious disease that can greatly increase morbidity and mortality all the globe. Since past 1990 till twentieth century, these infectious diseases have been major threat all over the globe associated with poor hygiene and sanitation. In light of these epidemics, researches have gained enormous rise in the developing the potential therapeutic treatment. Thus, revolutionized antibiotics have led to the near eradication of such ailments. Around 50 million prescription of antibiotics written in US per year according to center for disease control and prevention (CDC) report. There is a wide range of antibiotics available which differ in their usage and their mechanism of action. Among these quinoline and quinolone class of antibiotics get attention as they show tremendous potential in fighting the epidemics. Quinoline and quinolone comprise of two rings along with substitutions at different positions which is synthetically obtained by structural modifications of quinine. Quinoline and quinolone antibiotics exhibit extensive activities approved by FDA in the treatment of the several ailments such as gastrointestinal infections, urinary tract infections, prostate inflammation, malaria, gonorrhea, skin infection, colorectal cancer, respiratory tract infections. These are active against both gram-negative and gram-positive bacteria. This basic core of quinoline and quinolone is vital due to its capability of targeting the pathogen causing disease and beneficial in treating the infectious disease. They inhibit the synthesis of nucleic acid of bacteria which results in the rupture of bacterial chromosome due to the interruption of enzymes such as DNA gyrase and topoisomerase IV. There are various quinoline and quinolone compounds that are synthetically derived by applying different synthesis approaches which show a wide range of pharmacological activities in several diseases. The most commonly used are fluoro, chloro, and hydroxychloro derivatives of quinoline and quinolone. These compounds are helpful in the treatment of numerous epidemics as a chief and combination therapy. These quinoline and quinolone pharmacophore fascinate the interest of researchers as they inhibit the entry of virus in host cell and cease its replication by blocking the host receptor glycosylation and proteolytic processing. They act as immune modulator by inhibiting autophagy and reduction of both lysosomal activity and production of cytokine. Therefore, quinoline and quinolone derivatives attain significance in area of research and treatment of various life-threatening epidemics such as SARS, Zika virus, Ebola virus, dengue, and COVID-19 (currently). In this chapter, the research and advancements of quinoline- and quinolone-based antibiotics in epidemic management are briefly discussed.

A new insight into the treatment of diabetes by means of pan PPAR agonists.

PPARs stand for 'peroxisome proliferator-activated receptors' and are ligand-activated transcription factors of nuclear hormone receptor superfamily. A list of the most commonly used single receptor PPAR agonists, that is α (alpha) PPAR agonists, ß/δ(beta/delta) PPAR agonists, γ(gamma) PPAR agonists, along with pan PPAR agents, that are being researched on, are marketed, are in clinical trials or are being studied for further derivative findings, has been listed. Type 2 diabetes constitutes about 90% of total diabetes cases. Pan PPAR ligands could very well pave the foundation for a new class of agents, that can act on all 3 PPAR receptors, and produce better effects in general, than the individual receptor-acting ligands or dual combination ligands (α/ γ). In this review paper, we have detailed various pan PPAR agonists that can be used to treat type 2 diabetes, which can generate potential derivatives as well.

Withdrawal Notice: Therapeutic Targets Underlying the Evolution of Po-tential Anti-Diabetic Agents: A Comprehensive Review

The article has been withdrawn at the request of the editor of the journal Current Diabetes Reviews due to incoherent content.Bentham Science apologizes to the readers of the journal for any inconvenience this may have caused.The Bentham Editorial Policy on Article Withdrawal can be found at https://benthamscience.com/editorial-policies-main.php BENTHAM SCIENCE DISCLAIMER: It is a condition of publication that manuscripts submitted to this journal have not been published and will not be simultaneously submitted or published elsewhere. Furthermore, any data, illustration, structure or table that has been published elsewhere must be reported, and copyright permission for reproduction must be obtained. Plagiarism is strictly forbidden, and by submitting the article for publication the authors agree that the publishers have the legal right to take appropriate action against the authors, if plagiarism or fabricated information is discovered. By submitting a manuscript, the authors agree that the copyright of their article is transferred to the publishers if and when the article is accepted for publication.

Alpha-amylase as molecular target for treatment of diabetes mellitus: A comprehensive review.

The alpha (α)-amylase is a calcium metalloenzyme that aids digestion by breaking down polysaccharide molecules into smaller ones such as glucose and maltose. In addition, the enzyme causes postprandial hyperglycaemia and blood glucose levels to rise. α-Amylase is a well-known therapeutic target for the treatment and maintenance of postprandial blood glucose elevations. Various enzymatic inhibitors, such as acarbose, miglitol and voglibose, have been found to be effective in targeting this enzyme, prompting researchers to express an interest in developing potent alpha-amylase inhibitor molecules. The review mainly focused on designing different derivatives of drug molecules such as benzofuran hydrazone, indole hydrazone, spiroindolone, benzotriazoles, 1,3-diaryl-3-(arylamino) propan-1-one, oxadiazole and flavonoids along with their target-receptor interactions, IC50 values and other biological activities.

Assessment of the impact of fish seed stocking on fish yield in small reservoirs of Central India: towards sustainable management.

The present study assessed the impact of fingerling stocking of Indian major carps (Gibelion catla, Labeo rohita, and Cirrhinus mrigala) on fish yield in 24 small reservoirs of Central India. The time series data on fish stocking and yield were collected from the State Fisheries Department, Govt. of Chhattisgarh, for the year 2008 to 2016. The fish yield increased significantly (p < 0.05) from 87.11 to 379.13 kg/ha/year due to stocking indicating significant impact on fish production. The relationships between area, stocking density, and fish yield of reservoirs were also assessed. Stocking had a significant positive impact on fish yield (t test, p < 0.05). The important water quality parameters were also studied to have a conspicuous picture of eco-hydrological characteristics of these selected small reservoirs. The study forms a baseline for the small tropical reservoir fisheries of Central India (Chhattisgarh state) and suggests regional strategies for sustainable fisheries enhancement and management, employment generation, and nutritional security of a large number of fish-eating population.

Antidiabetic potential of polyphenolic-rich fraction of Tamarindus indica seed coat in alloxan-induced diabetic rats.

BACKGROUND: Tamarindus is a monotypic genus and belongs to the subfamily Caesalpinioideae of the family Leguminosae (Fabaceae), Tamarindus indica L., commonly known as Tamarind tree is one of the most important multipurpose tropical fruit tree species in the India, Sudan, Nigeria, Bangladesh and entire subcontinent. METHODS: Hydroethanolic seed coat extract of Tamarindus indica (HETI) was assessed for presence of phytoconstituents and selection of optimum dose through acute and sub acute toxicity study. The single and multidose (14 days) study were conducted to evaluate antidiabetic potential of HETI in alloxan induced rats via determine of blood glucose level, body weight, hematological profile, extra-pancreatic glucose utilization of isolated rat hemi-diaphragm as well as histopathology of rat pancreas. RESULTS: Phytochemical analysis of HETI showed the presence of polyphenol like flavonoids. Single and multidose of HETI significantly (p<0.05; p<0.001) reduced blood glucose level in normoglycaemic, glucose loaded and alloxan induced hyperglycaemic animals. HETI exerts the protective effect on pancreatic ß-cells as per results obtained from histopathology of animals. Moreover, HETI increased glucose uptake in isolated rat hemi-diaphragm and prevents decrease in body weight along with recovery of altered hematological parameters. CONCLUSIONS: The study revealed that HETI have potent hypoglycaemic action by virtue of its phytoconstituents and it can be used as a herbal medicine for diabetes.