Connecting the Dots: Gender, Sexuality, and Societal Influences on Cognitive Aging and Alzheimer's Disease.

Alzheimer's disease (AD) has many etiologies and the impact of gender on AD changes throughout time. As a consequence of advancements in precision medical procedures and methodology, Alzheimer's disease is now better understood and treated. Several risk factors may be addressed to lower one's chances of developing Alzheimer's disease or associated dementia (ADRD). The presence of amyloid-α protein senile plaques, intracellular tau protein neurofibrillary tangles (NfTs), neurodegeneration, and neuropsychiatric symptoms (NPS) characterizes Alzheimer's disease. NPS is common in persons with Alzheimer's disease dementia, although its presentation varies widely. Gender differences might explain this clinical variability. The fundamental goal of this review research is to 1) emphasize the function of old age, sex, and gender in the development of Alzheimer's disease, dementia, and ADRD, and 2) explain the importance of sexual hormones, education, and APOE (Apolipoprotein E) status. This is a narrative summary of new ideas and concepts on the differences in the chance of developing dementia or Alzheimer's disease between men and women. A more thorough examination of risk and protective variables in both men and women might hasten research into the epidemiology of neurological illnesses such as dementia and Alzheimer's disease. Similarly, future preventive efforts should target men and women separately.

Investigation, scaffold hopping of novel donepezil-based compounds as anti-Alzhiemer's agents: synthesis, in-silico and pharmacological evaluations.

Alzheimer's disease (AD) is a multifaceted neurodegenerative condition. The pathogenesis of AD is highly intricate and the disease is apparent in the aged population ~ 50-70 years old. Even after > 100 years of research, the root origin of AD and its pathogenesis is unclear, complex and multifaceted. Herein, we have designed and synthesized 9 novel molecules with three different heterocyclic scaffolds namely pyrrolidone-2-one, quinoline & indoline-2-one to imitate and explore the novel chemical space around donepezil. The synthesized molecules were evaluated for their potential as anti-Alzheimer's agents through in-vitro and in-vivo studies in appropriate animal models. To further understand their interaction with acetylcholinesterase enzyme (AChE), extra-precision docking, and molecular dynamics simulation studies were carried out. As the number of compounds was limited to thoroughly explore the structure-activity relationship, atom-based 3D-quantitative structure-activity relationships (QSAR) studies were carried out to get more insights. All the designed compounds were found to inhibit AChE with IC50 in the micromolar range. From pyrrolidone-2-one series, 6-chloro-N-(1-(1-(3,4-dimethoxybenzyl)-2-oxopyrrolidin-3-yl)piperidin-4-yl)pyridine-3-sulfonamide (9), 2-(1-benzylpiperidin-4-yl)-6,7-dimethoxy-4-(4-methoxyphenyl)quinoline (18) from quinoline series and N-(1-benzylpiperidin-4-yl)-2-(2-oxoindolin-3-yl)acetamide (23) from indolin-2-one series inhibited AChE with an IC50 value of 0.01 µM. Based on other biochemical studies like lipid peroxidation, reduced glutathione, superoxide dismutase, catalase, nitrite, and behavioural studies (Morris water maze), compound 9 was found to be a potent AChE inhibitor which can be further explored as a lead molecule to design more potent and effective anti-Alzheimer's agents.

Recent Developments and Applications of Biocatalytic and Chemoenzymatic Synthesis for the Generation of Diverse Classes of Drugs.

Biocatalytic and chemoenzymatic biosynthesis are powerful methods of organic chemistry that use enzymes to execute selective reactions and allow the efficient production of organic compounds. The advantages of these approaches include high selectivity, mild reaction conditions, and the ability to work with complex substrates. The utilization of chemoenzymatic techniques for the synthesis of complicated compounds has lately increased dramatically in the area of organic chemistry. Biocatalytic technologies and modern synthetic methods are utilized synergistically in a multi-step approach to a target molecule under this paradigm. Chemoenzymatic techniques are promising for simplifying access to essential bioactive compounds because of the remarkable regio- and stereoselectivity of enzymatic transformations and the reaction diversity of modern organic chemistry. Enzyme kits may include ready-to-use, reproducible biocatalysts. Its use opens up new avenues for the synthesis of active therapeutic compounds and aids in drug development by synthesizing active components to construct scaffolds in a targeted and preparative manner. This study summarizes current breakthroughs as well as notable instances of biocatalytic and chemoenzymatic synthesis. To assist organic chemists in the use of enzymes for synthetic applications, it also provides some basic guidelines for selecting the most appropriate enzyme for a targeted reaction while keeping aspects like cofactor requirement, solvent tolerance, use of whole cell or isolated enzymes, and commercial availability in mind.

Decalepis hamiltonii root fraction alleviates CCl4 hepatotoxicity in a rat model.

BACKGROUND: Decalepis hamiltonii (D. hamiltonii) is Indian folk medicine in herbal preparations, to reduce appetite, and cures dysentery, bronchitis, uterine hemorrhage, and other ailments. OBJECTIVE: The current investigation focused on the hepatoprotective effect of D. hamiltonii roots fractions against liver damage. MATERIALS AND METHODS: The current research discussed the fraction from D. hamiltonii root extracts was used. Male Wistar rats (albino strain) were grouped into 4 distinct groups of six animals each. Group I: plain water and vehicle whereas Group II (CCl4 control): CCl4 (1 ml/kg, 20 % v/v in olive oil) over 7 days and vehicle; Over 7 days, Group III received Silymarin 100 mg/kg/day and tap water with 20 % v/v of CCl4, whereas Group IV (treatment group) received DHE 50 mg/kg/day, 100 mg/kg/day, and water. Assessment of biochemical parameters, Mitochondrial modulation, gene expression analysis, and RT-PCR, was used to estimate the protective action of DHEF in CCl4-intoxicated rats. RESULTS: The administration of CCl4 increased levels of total bilirubin (0.63 ± 0.97 mg/dl) plasma amino transferases (110.36 ± 1.13 U/L, 86.56 ± 2.41 U/L and 1.51 ± 1.36 mg/dl respectively) which were mitigated by D. hamiltonii treatment. Activity like Lipid peroxidation and content of nitric oxide also augmented, while the antioxidant action measured by GSH (9.64 ± 0.18 U/mg protein), SOD (3.69 ± 0.22 U/mg protein), and CAT (1.47 ± 0.01 U/mg protein) was reduced. Decalepis hamiltonii root provided substantial restoration of GSH (14.92 ± 0.04 nmol/gm protein), SOD (4.20 ± 0.18 U/mg protein), and CAT (2.71 ± 0.04 U/mg protein) levels. In addition, the acute phase reactants stimulated by CCl4 administration enhanced mRNA expressions of IL-6, IL-10, TNF-a, NF-κß, and COX-2, which were enhanced by D. hamiltonii treatment. CONCLUSIONS: In summary, DHEF protects the liver against CCl4-induced damage, possibly by mitochondrial modulation mechanism. These findings indicate that D. hamiltonii significantly moderates oxidative stress of CCl4-induced hepatotoxicity.

QSAR Studies and Scaffold Optimization of Predicted Novel ACC 2 Inhibitors to treat Metabolic Syndrome.

BACKGROUND: Metabolic syndrome is one of the major non-communicable global health hazards of the modern world owing to its amplifying prevalence. Acetyl coenzyme-A carboxylase 2 (ACC 2) is one of the most crucial enzymes involved in the manifestation of this disease because of its regulatory role in fatty acid metabolism. OBJECTIVE: To find novel potent ACC 2 inhibitors as therapeutic potential leads for combating metabolic syndrome. METHODS: In the present study, a two-dimensional quantitative structure-activity relationship (2D QSAR) approach was executed on biologically relevant thiazolyl phenyl ether derivatives as ACC 2 inhibitors for structural optimization. The physiochemical descriptors were calculated and thus a correlation was derived between the observed and predicted activity by the regression equation. The significant descriptors i.e. log P (Whole Molecule) and Number of H-bond Donors (Substituent 1) obtained under study were considered for the design of new compounds and their predicted biological activity was calculated from the regression equation of the developed model. The compounds were further validated by docking studies with the prepared ACC 2 receptor. RESULTS: The most promising predicted leads with the absence of an H-bond donor group at the substituted phenyl ether moiety yet increased overall lipophilicity exhibited excellent amino acid binding affinity with the receptor and showed predicted inhibitory activity of 0.0025 µM and 0.0027 µM. The newly designed compounds were checked for their novelty. Lipinski's rule of five was applied to check their druggability and no violation of this rule was observed. CONCLUSION: The compounds designed in the present study have tremendous potential to yield orally active ACC 2 inhibitors to treat metabolic syndrome.

Mitochondrial transfer restores impaired liver functions by AMPK/ mTOR/PI3K-AKT pathways in metabolic syndrome.

AIM: We investigated the effect of mitochondria transfer in high fat diet and streptozotocin (HFD + STZ) induced metabolic syndrome (MeS) in rats. The effect of mitochondria transfer in MeS with co-existing hypertension, hyperlipidaemia, diabetes and fatty liver together, has not been reported. MATERIALS AND METHODS: Heathy mitochondria was transferred intravenously and the effect on several physiological parameters and biochemical parameters were examined in HFD + STZ rats. In addition, RNA-sequencing of healthy liver tissues was performed to elucidate the molecular pathways affected by mitochondria transfer in restoring metabolic health. KEY FINDINGS: We observed reduction in both systolic and diastolic blood pressure levels, reduced blood glucose levels, and a marked reduction in serum lipid profiles. The levels of alanine transaminase (ALT) and aspartate transaminase (AST) also improved along with evident restoration of liver morphology demonstrated by histopathological analysis. Enhanced mitochondrial biogenetics and reduction in oxidative stress and inflammatory markers was also observed. The pathway enrichment analysis revealed reduction in insulin resistance, inflammatory markers, regulation of mitochondrial bioenergetics, calcium ion homeostasis, fatty-acid ß-oxidation, cytokine immune regulators, and enhanced lipid solubilisation. The significant effect of healthy mitochondria transfer in restoration of metabolic functions was observed by the activation of PI3K-AKT, AMPK/mTOR pathways and cytokine immune regulators, suggesting that inflammatory mediators were also significantly affected after mitochondria transfer. SIGNIFICANCE: This study, provides insights on molecular processes triggered by mitochondria transfer in fatty liver regeneration and improvement of overall metabolic health.

Current Insight on the Role of Glucokinase and Glucokinase Regulatory Protein in Diabetes.

The glucokinase regulator (GCKR) gene encodes an inhibitor of the glucokinase enzyme (GCK), found only in hepatocytes and responsible for glucose metabolism. A common GCKR coding variation has been linked to various metabolic traits in genome-wide association studies. Rare GCKR polymorphisms influence GKRP activity, expression, and localization. Despite not being the cause, these variations are linked to hypertriglyceridemia. Because of their crystal structures, we now better understand the molecular interactions between GKRP and the GCK. Finally, small molecules that specifically bind to GKRP and decrease blood sugar levels in diabetic models have been identified. GCKR allelic spectrum changes affect lipid and glucose homeostasis. GKRP dysfunction has been linked to a variety of molecular causes, according to functional analysis. Numerous studies have shown that GKRP dysfunction is not the only cause of hypertriglyceridemia, implying that type 2 diabetes could be treated by activating liver-specific GCK via small molecule GKRP inhibition. The review emphasizes current discoveries concerning the characteristic roles of glucokinase and GKRP in hepatic glucose metabolism and diabetes. This information has influenced the growth of directed molecular therapies for diabetes, which has improved our understanding of lipid and glucose physiology.

Nanotechnology-Based Drug Delivery of Topical Antifungal Agents.

Among the various prominent fungal infections, superficial ones are widespread. A large number of antifungal agents and their formulations for topical use are commercially available. They have some pharmacokinetic limitations which cannot be retracted by conventional delivery systems. While nanoformulations composed of lipidic and polymeric nanoparticles have the potential to overcome the limitations of conventional systems. The broad spectrum category of antifungals i.e. azoles (ketoconazole, voriconazole, econazole, miconazole, etc.) nanoparticles have been designed, prepared and their pharmacokinetic and pharmacodynamic profile was established. This review briefly elaborates on the types of nano-based topical drug delivery systems and portrays their advantages for researchers in the related field to benefit the available antifungal therapeutics.

An insight into PI3k/Akt pathway and associated protein-protein interactions in metabolic syndrome: A recent update.

Akt, a known serine/threonine-protein kinase B has been revealed to be an imperative protein of the PI3K/Akt pathway. Akt is available in three isoforms, Akt1, Akt2, and Akt3. Ubiquitously expressed Akt1 & Akt2 are essential for cell survival and are believed to be involved in regulating glucose homeostasis. PI3K/Akt pathway has been evidenced to be associated with metabolic diseases viz. hypertension, dyslipidemia, and diabetes. Akt interacting proteins have been revealed to be scaffold proteins of the PI3K/Akt pathway. Notably, some protein-protein interactions are imperative for the inhibition or uncontrolled activation of these signaling pathways. For instance, Akt interacting protein binds with other protein namely, FOXO1 and mTOR, and play a key role in the onset and progression of metabolic syndrome (MS). The purpose of this review is to highlight the role of the PI3K/Akt pathway and associated protein-protein interactions which might serve as a valuable tool for investigators to develop some new promising therapeutic agents in the management of MS.

Tylophora indica (Burm. f.) Merr alleviates tracheal smooth muscle hyperresponsiveness in ovalbumin-induced allergic-asthma model in guinea-pigs: Evidences from ex vivo, in silico and in vivo studies.

BACKGROUND: Tylophora indica (Burm. f.) Merr is a climbing perennial plant reported in Indian traditional system of medicine for its use in allergy and asthma. However, only few scientific studies have been performed in the past to validate its antiasthmatic potential. OBJECTIVES: The present study deals with investigation of airway smooth muscle relaxant and antiasthmatic potential of extract and subsequent fractions prepared from T. indica. METHODS: The most active fraction of T. indica leaves selected through bio-guided activity was subjected to liquid chromatography-mass spectrometry (LC-MS) analysis for chemical profiling. The binding affinity of identified compounds in fraction towards M3 and H1 receptors was determined by molecular docking study. F-2 (chloroform fraction prepared from methanolic extract of T. indica leaves) was examined for its smooth muscle relaxant properties using isolated trachea of guinea-pig. Further, F-2 was evaluated through in vivo studies employing ovalbumin-induced asthma model in guinea-pigs. RESULTS: F-2 was found most effective in bioassay-guided fractionation. Characterization by LC-MS analysis revealed presence of five major bioactive compounds in F-2 that showed good docking interactions with M3 and H1 receptors. The ex vivo study demonstrated that F-2 could significantly relax tracheal rings via targeting multiple signalling pathways videlicet, namely, noncompetitive antagonism of the histamine and muscarinic receptors, ß2-adrenergic stimulation and activation of soluble guanylyl cyclase. In in vivo studies, F-2 ameliorated airway hyperresponsiveness and decreased broncho alveolar lavage fluid (BALF) levels of inflammatory cytokines and immunoglobulin E (IgE). CONCLUSION: These results confirm the traditional use of T. indica as an antiasthmatic agent which are evidenced through ex vivo, in silico and in vivo studies.

Promising Schiff bases in antiviral drug design and discovery.

Emerging and re-emerging illnesses will probably present a new hazard of infectious diseases and have fostered the urge to research new antiviral agents. Most of the antiviral agents are analogs of nucleosides and only a few are non-nucleoside antiviral agents. There is quite a less percentage of marketed/clinically approved non-nucleoside antiviral medications. Schiff bases are organic compounds that possess a well-demonstrated profile against cancer, viruses, fungus, and bacteria, as well as in the management of diabetes, chemotherapy-resistant cases, and malarial infections. Schiff bases resemble aldehydes or ketones with an imine/azomethine group instead of a carbonyl ring. Schiff bases have a broad application profile not only in therapeutics/medicine but also in industrial applications. Researchers have synthesized and screened various Schiff base analogs for their antiviral potential. Some of the important heterocyclic compounds like istatin, thiosemicarbazide, quinazoline, quinoyl acetohydrazide, etc. have been used to derive novel Schiff base analogs. Keeping in view the outbreak of viral pandemics and epidemics, this manuscript compiles a review of Schiff base analogs concerning their antiviral properties and structural-activity relationship analysis.

Synthesis, Characterization, and Antibacterial Activity of New Isatin Derivatives.

1H-indol-2,3-dione (isatin) class of biologically active compounds have analgesic, anti-microbial, anti-inflammatory, anti-tubercular, anti-proliferative properties, and is also useful for the treatment of SARS-CoV. Schiff bases containing isatin moiety are known to have broad spectrum of biological activities like anti-viral, anti-tubercular, anti-fungal, and anti-bacterial. In this work, several Schiff base derivatives have been synthesized using two methods (synthetic and microwave) by reacting isatin with o-phenylenediamine. The synthesized compounds were structurally characterized and their in-vivo antimicrobial activity was tested against Gram-negative and Gram-positive bacteria using the inhibition zone method. Several newly synthesized isatin derivatives were found effective as antimicrobial agents and showed good potency (compounds 3c, 3d, 6a, 6b, 6d). Compound 3c displayed higher antimicrobial activity than standard drug (Amoxicillin) against Staphylococcus aureus at higher concentration (16 µg/mL) and against Escherichia coli at lower concentration (1 µg/mL).

Targeting Neuroinflammation as Disease Modifying Approach to Alzheimer's Disease: Potential and Challenges.

Alzheimer's disease (AD) is the most common form of dementia, having characteristic clinical features of progressive memory loss and visuospatial, language, and cognitive impairment. In addition, patients often suffer from comorbid depression and aggression. Aging is a major contributing factor, though the exact pathophysiological involvement in the disease progression is debatable. Biologists demonstrate that AD is not a result of a single pathological incident. However, an uncontrolled myriad of events is responsible for the pathophysiological condition; hence, it is regarded as a multifaceted disease. Pathophysiologically, AD is described by having a long preclinical stage (proteinopathy accumulation stage), followed by a short prodromal/dementia stage (clinical symptom onset), as evident via biomarker studies. Specific and sensitive biomarkers are needed to track disease progression and treatment. Neuroinflammation is one of the cardinal pathophysiological events of AD that form a positive activation loop between proteinopathy and pro-inflammatory mediators. However, the starting point is inconclusive. The vital cells, like glia, known as brain scavenger cells, remain in harmony between their quiescent and activated morphological states during any stimulus and help to regulate the neuroinflammatory microenvironment. Hence, focusing on the dysfunctional microglia could be a novel therapeutic approach to managing neuroinflammation condition in AD. This review focuses on the translational evidence of anti-diabetic and anti-inflammatory candidates in AD management. It also highlights the importance of the microglia activation spectrum, eicosanoid signaling, cytokine signaling, and inflammatory mediators responsible for the neuroinflammation cascade. The repeated failure of single-approached therapies has diverted researchers' attention to AD-modifying approaches and AD multimodal treatment plans. This review is an effort to brief the role of new players (like micronutrients and nutraceutical applications) that have been reported as helpful in suppressing AD severity. Apart from anti-diabetic candidates, various insulin-mimetic and insulin-sensitizer drugs have also been assessed to target insulin insensitivity to mitigate AD progression. However, these possibilities are in the investigational stage and not clinically established yet, though various AD animal models have verified the positive outcome.

New insights on mode of action of vasorelaxant activity of simvastatin.

Simvastatin is a semisynthetic inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and is used extensively to treat atherosclerotic cardiovascular disease. Apart from the lipid-lowering effect, simvastatin has been documented to offer impressive vasorelaxant activity. However, the mechanism associated with this vasorelaxant activity has yet not been substantially explored. Thus, the present study has aimed to elucidate the mechanism(s) associated with simvastatin-induced vasorelaxation using an established rat aortic ring model. The results from the study depicted that simvastatin caused significant relaxation in aortic rings pre-contracted with phenylephrine and potassium chloride (KCl). The vasorelaxant effect of simvastatin was attenuated by methylene blue (sGC-dependent cyclic guanosine monophosphate (cGMP) inhibitor), NG-nitro-L-arginine methyl ester (L-NAME; NO synthase inhibitor), 4-aminopyridine (Kv blocker), glibenclamide (KATP blocker), and barium chloride (Kir blocker). In addition, the vasorelaxant effect of simvastatin was slightly reduced by PD123319 (angiotensin II type 2 receptor (AT2R) antagonist). However, indomethacin (COX inhibitor), 1H-[1,2,4]Ox adiazolol [4,3-α]quinoxalin-1-one (ODQ; selective soluble guanylate cyclase (sGC) inhibitor), losartan (angiotensin II type 1 receptor (AT1R) antagonist), atropine (muscarinic receptor blocker), and tetraethyl ammonium (TEA; KCa blocker) did not affect the vasorelaxant effect of simvastatin. Furthermore, simvastatin was found to attenuate the release of calcium (Ca2+) from intracellular stores in the presence of ruthenium red (ryanodine receptor, RyR inhibitor) and extracellular stores via nifedipine (voltage-operated Ca2+ channels, VOCC blocker) and SK&F96365 (receptor-operated Ca2+ channel, ROCC blocker). Thus, it can be concluded that the vasorelaxant effect of simvastatin involves NO/cGMP pathways, AT2R receptors, Ca2+ channels, and K+ channels.

Metabolic Syndrome: The Constellation of Co-morbidities, A Global Threat.

BACKGROUND: Metabolic syndrome, also referred to as Syndrome X or obesity syndrome is a cluster of diseases prevalent worldwide in both developed and developing countries. According to WHO, it is referred to as a pathological condition wherein multiple disorders are manifested in the same individual. These include hypertension, hyperglycemia, dyslipidemia and abdominal obesity. AIMS: Metabolic syndrome is one of the most serious non-communicable health hazards that have gained pivotal importance in the present scenario. The increasing prevalence affecting around 25 % of the world populace, mainly attributes to the acceptance of western culture, i.e. the intake of highcalorie food along with a substantial decrease in manual labor and adoption of sedentary lifestyles. Therefore, its timely prevention and management are the dire need in the present scenario. METHODS: For successful accomplishment of the present review, an exhaustive analysis was performed utilizing a pool of previous related literature. The terms used during the search included 'metabolic syndrome, prevalence, etiology, current pharmacotherapy for metabolic syndrome, etc. PUBMED, Medline and SCOPUS were explored for the study of abstracts, research and review papers in the quest for related data. The articles were downloaded and utilized for a meta-analysis study approach. CONCLUSION: In this review, an attempt was made to apprehend and summarize the epidemiology and treatment strategies for metabolic syndrome with a better understanding of its pathogenesis. It was postulated that an early diagnostic approach and subsequent line of treatment is required to prevent the deterioration of an individual's health and life.

Synthesis, characterization, and in silico studies of 1,8-naphthyridine derivatives as potential anti-Parkinson's agents.

1,8-Naphthyridine scaffold is a nitrogen-containing heterocyclic compound known for its versatile biological activities. The structure-activity relationship (SAR) has shown that modification at the 3rd position of the nucleus with various secondary amines enhances the binding efficiency and potency towards the Adenosine receptor (A2A type). In this paper, we have reported some newly synthesized derivatives of 1,8- Naphthyridine, and the prepared compounds were assessed for their potential to constrain A2A receptors through molecular docking. Based on the SAR studies, modifications were done at the 3rd position of the nucleus by incorporating secondary amines. The synthesized compounds were characterized by FT-IR, 1H and 13C NMR. All the synthesized compounds 10a-f and 13a-e showed good binding efficiency towards the A2A receptors and might act as an A2A receptor antagonist, as predicted by in-silico studies. 1-Ethyl-7-methyl-3-(pyrrolidine-1-carbonyl)-1,8-naphthyridine-4(1H)-one (10c) in first series showed the highest docking score of -8.407 and binding energy (MMGBSA dG bind) of -56.60 kcal/mol and N-(4-2-diethylaminoethoxyphenyl)-1-ethyl-7-methyl-4-oxo-1, 4, 4a, 8a- tetrahydro-1,8-naphthyridine-3-carboxamide (13b) showed the highest docking score of -8.562 and free binding energy (MMGBSA dG bind) score of -64.13 kcal/mol which was comparable to the bound ligand. MD simulations study also suggested that compounds 10c and 13b would form stable complex human A2A receptor. These findings need to be validated by further in vitro assays.Communicated by Ramaswamy H. Sarma.

Therapeutic potential of reserpine in metabolic syndrome: An evidence based study.

Reserpine is as old as the scientific diagnosis of hypertension. For many years' clinicians have used it for the treatment of high blood pressure, but with the passage of time and introduction of new anti-hypertensive drugs, the usage of reserpine has gone down drastically most probably due to poorly understood mechanism of action and multiple misleading adverse effects precisely due to high dosing of reserpine. With an aim to elucidate the specific mechanism of action, we screened reserpine against various targets associated with regulation of blood pressure. Surprisingly reserpine showed remarkable inhibitory potential for soluble epoxide hydrolase an enzyme responsible for pathophysiology of not only hypertension but also hyperlipidemia, diabetes and inflammation collectively known as metabolic syndrome. The in-silico, in-vitro and in-vivo results showed that reserpine has the ability to treat metabolic syndrome effectively by inhibiting soluble epoxide hydrolase.

Asthma History, Current Situation, an Overview of Its Control History, Challenges, and Ongoing Management Programs: An Updated Review.

Asthma is a disease of the airways that is characterized by chronic inflammation and disordered airway function. The purpose of writing the current review paper is to review the history, current situation, control history, challenges, and ongoing management programs of asthma. Some official websites of known respiratory professional bodies were consulted for asthma guidelines, and information from Google Scholar® and PubMed® was also consulted. We reviewed around two hundred eight papers, and then, inclusion and exclusion criteria were applied to prepare this manuscript. Out of these papers, thirty papers, factsheets, and some official websites were used to prepare this manuscript. Physicians should follow already existing asthma guidelines in order to manage asthma. All prescribed medications should be continued. The government should make and adopt more strategies to promote the rational use of anti-asthmatic drugs and healthcare facilities and also make plans to disseminate more awareness among people about the schemes and programs made for safeguarding people against this life-threatening disease. We have done so much advancement to fight against this deadly disease, and we still need time to make the globe asthma-free. The number of people suffering from asthma is more than the number of people suffering from HIV infection and tuberculosis. Understanding the recommendations of professional bodies will assist in medical decision-making in asthma management. The individual needs of patients should be considered by healthcare professionals.

Repositioning of tubocurarine as analgesic and anti-inflammatory agent: Exploring beyond myorelaxant activity.

BACKGROUND AND PURPOSE: Tubocurarine (d-TC), a non-depolarizing competitive blocker of nicotinic acetylcholine receptors is extensively utilized for the relaxation of skeletal muscles. Drug repositioning is a forthright approach to reduce the cost and speed up drug development process. Herein, we have attempted to evaluate the analgesic and anti-inflammatory activity of d-TC for its possible repurposing in pain and inflammation-related issues. EXPERIMENTAL APPROACH: We examined the soluble epoxide hydrolase inhibitory (sEHI) activity of d-TC employing in silico high throughput screening protocols, in vitro cell-free sEH inhibitory assay, and in in vivo rodent models for its repositioning in pain and inflammation-related disorders. KEY RESULTS: In molecular docking study, d-TC displayed impressive hydrogen bonding interactions within the cavity of sEH enzyme with good docking score. d-TC also exhibited notable sEH inhibitory activity (IC50 3.72 nm) at the in vitro assay. Oral absorption capability of d-TC (0.1 and 0.2 mg/mL) was determined using an in vitro everted intestinal sac model employing rat ileum tissue that revealed significant oral absorption of d-TC. Besides, in vivo studies revealed that oral administration of d-TC (0.1 and 0.2 mg/kg) in rodents significantly attenuated hyperalgesia (cold plate test, tail immersion test and formalin test) and inflammation (estimation of rectal temperature, acetic acid induced pleurisy test and cotton pellet-induced granuloma test) induced in robust preclinical models. Conclusion and implications These findings are novel and warrant immediate efforts to reposition d-TC as a new therapeutic candidate in the management of hyperalgesia, inflammation, and associated conditions.