Therapeutic Interventions for Diabetes Mellitus-Associated Complications.

BACKGROUND: Diabetes Mellitus (DM) is an alarming health concern, affecting approximately 537 million people worldwide. As a leading cause of morbidity and mortality, DM demands a comprehensive understanding of its diverse pathophysiological mechanisms and disease progression. METHODS: This traditional review has consolidated literature on the pathogenesis of hyperglycemia, its progression into complications, and advances in optimal treatment strategies. The literature in the last two decades has been reviewed using several keywords, including "diabetes," "diabetes-associated complications", "novel therapeutic interventions for diabetes-associated diseases", "phyto-extracts as antidiabetic drugs", etc. in prominent databases, such as PubMed, Scopus, Google Scholar, Web of Science, and ClinicalTrials.gov. RESULTS: We have discussed macrovascular and microvascular complications, such as atherosclerosis, cardiovascular disease, Peripheral Arterial Disease (PAD), stroke, diabetic nephropathy, retinopathy, and neuropathy, as well as various pharmacological and non-pharmacological interventions that are currently available for the management of DM. We have also focused on the potential of natural products in targeting molecular mechanisms involved in carbohydrate metabolism, insulin production, repair of pancreatic cells, and reduction of oxidative stress, thereby contributing to their antidiabetic activity. Additionally, novel therapeutic approaches, like genetic, stem cell, and immunomodulatory therapies, have been explored. We have also discussed the benefits and limitations of each intervention, emerging research and technologies, and precision medicine interventions. CONCLUSION: This review has emphasized the need for an improved understanding of these advancements, which is essential to enhance clinicians' ability to identify the most effective therapeutic interventions.

Integration of network pharmacology, molecular docking, and simulations to evaluate phytochemicals from Drymaria cordata against cervical cancer.

Introduction: Cervical cancer is prevalent among women worldwide. It is a type of cancer that occurs in the cells of the cervix, the lower part of the uterus. Mostly, it is observed in developing nations due to limited access to screening tools. Natural products with anticancer properties and fewer side effects have gained attention. Therefore, this study evaluates the potential of Drymaria cordata as a natural source for treating cervical cancer. Methodology: Phytocompounds present in Drymaria cordata were screened for their molecular properties and drug-likeness. The selected compounds were studied using systems biology tools such as network pharmacology, molecular docking, and molecular dynamics simulations, including MMGBSA studies. Results: Through network pharmacology, molecular docking, and molecular dynamics simulations, quercetin 3-O-ß-d-glucopyranosyl-(1→2)-rhamnopyranoside was identified as a hit compound targeting HRAS and VEGFA proteins. These proteins were found to be responsible for the maximum number of pathway modulations in cervical cancer. Conclusion: Drymaria cordata exhibits potential for treating cervical cancer due to the presence of quercetin 3-O-ß-d-glucopyranosyl-(1→2)-rhamnopyranoside. Further validation of these findings through in vitro and in vivo studies is required.

Netting into the Sophoretin pool: An approach to trace GSTP1 inhibitors for reversing chemoresistance.

Chemoresistance, a significant challenge in cancer treatment, is often associated with the cellular glutathione-related detoxification system. The GSTP1 isoenzyme (glutathione S-transferases) plays a critical role in the cytoplasmic inactivation of anticancer drugs. This suggests the identification of GSTP1 inhibitors to combat chemoresistance. We screened Sophoretin (also called quercetin) derivatives for molecular properties, pharmacokinetics, and toxicity profiles. Following that, we conducted molecular docking and simulations between selected derivatives and GSTP1. The best-docked complex, GSTP1-quercetin 7-O-ß-D-glucoside, exhibited a binding affinity of -8.1 kcal/mol, with no predicted toxicity and good pharmacokinetic properties. Molecular dynamics simulations confirmed the stability of this complex. Quercetin 7-O-ß-D-glucoside shows promise as a lead candidate for addressing chemoresistance in cancer patients, although further experimental studies are needed to validate its efficacy and therapeutic potential.

Evaluation of Antioxidant and Anti-Inflammatory Activities, and Metabolite Profiling of Selected Medicinal Plants of Nepal.

This study aimed to evaluate the antioxidant, antiarthritic, and anti-inflammatory properties of extracts from the leaves of twelve different medicinal plants in Nepal. We then evaluated the total phenolic, flavonoid, and tannin contents of the extract using in-vitro assays and characterized it using GC-MS analysis. Results revealed that most of the leaf extracts contained phenolic compounds, flavonoids, tannins, alkaloids, and saponins. Few plants also showed the presence of glycosides, phytate, and vitamin C. Among the studied plants, Neolamarckia cadamba exhibited the highest total phenolic and tannin contents, as 241.53 ± 0.20 µg of gallic acid equivalent/mg and 74.48 ± 1.081 µg of tannic acid equivalent/mg, respectively. Ipomoea batatas exhibited the highest total flavonoid content, as 53.051 ± 1.11 µg of quercetin equivalent/mg. Moreover, Raphanus sativus demonstrated significant ferrous ion chelating, 2,2-diphenyl-1-picrylhydrazyl, hydrogen peroxide scavenging, and total antioxidant activities with IC50 value of 4.76 ± 0.68 µg/mL, 5.84 ± 0.14 µg/mL, 6.89 ± 0.16 µg/mL, and 8.99 ± 0.20 µg/mL, respectively. Similarly, Colocasia esculenta and Cicer arietinum exhibited the highest hydroxyl radical and nitric oxide scavenging activities, measuring IC50 value of 7.22 ± 0.56 µg/mL and 9.06 ± 0.10 µg/mL, respectively. Among all the extracts, Amorphophallus paeoniifolius displayed significant human red blood cell (HRBC) membrane stabilization activity (IC50 = 6.22 ± 0.78 µg/mL). Furthermore, Raphanus sativus, Chenopodium album, Cicer arietinum, and Murraya koenigii exhibited the highest inhibitory activities against protein denaturation with bovine serum albumin, antiarthritic, lipoxygenase inhibitory, and proteinase inhibitory, measuring IC50 of 7.48 ± 0.48 µg/mL, 9.44 ± 1.62 µg/mL, 14.67 ± 1.94 µg/mL, and 28.57 ± 2.39 µg/mL, respectively. In conclusion, this study demonstrated the twelve leaf extracts' significant antioxidant, antiarthritic, and anti-inflammatory activities.

Targeting Melanoma with a phytochemical pool: Tailing Makisterone C.

BACKGROUND AND OBJECTIVE: According to World Health Organization, melanoma claims the lives of about 48000 people worldwide each year. The purpose of this study was to identify potential phytochemical pool from Diplazium esculentum against proteins that contribute to melanoma development. METHODS: The research was carried to locate potentially bioactive molecules and conduct a theoretical analysis of active ingredients from DE to impact melanoma. Network pharmacology, pharmacokinetics, protein network interaction, gene enrichment, survival, and infiltration analysis were conducted. Furthermore, molecular docking and molecular dynamics simulation was carried out for makisterone C-MAPK1, MAPK3, and AKT1 complexes. RESULTS: The potential phytochemical pool were identified (stigmast-5-en-3-ol, esculentic acid, rutin, and makisterone C) and based on network pharmacology and molecular docking studies, makisterone-C was proposed to be the most promising ingredient. Furthermore, the investigation revealed 14 genes as critical "hubs" involved in combating melanoma that are manipulated by the above-mentioned 4 active ingredients and modulate multiple signaling in melanoma development. CONCLUSION: This study insights into the potential anti-melanoma effects of phytochemical pool from Diplazium esculentum using network pharmacology analysis, molecular docking, and simulation tailing makisterone C as a lead moiety and suggests the need for makisterone C further evaluation in intervening melanoma progression.

The marijuana-schizophrenia multifaceted nexus: Connections and conundrums towards neurophysiology.

Delta-9-tetrahydrocannabinol, a component of marijuana, interacts with cannabinoid receptors in brain involved in memory, cognition, and emotional control. However, marijuana use and schizophrenia development is a complicated and contentious topic. As a result, more investigation is needed to understand this relationship. Through the functional enrichment analysis, we report the delta-9-tetrahydrocannabinol to manipulate the homeostatic biological process and molecular function of different macromolecules. Additionally, using molecular docking and subsequent processing for molecular simulations, we assessed the binding ability of delta-9-tetrahydrocannabinol with the estrogen-related protein, dopamine receptor 5, and hyaluronidase. It was found that delta-9-tetrahydrocannabinol may have an impact on the brain's endocannabinoid system and may trigger the schizophrenia progression in vulnerable people. Delta-9-tetrahydrocannabinol may interfere with the biological function of 18 proteins linked to schizophrenia and disrupt the synaptic transmission (dopamine, glutamine, and gamma-aminobutyric acid). It was discovered that it may affect lipid homeostasis, which is closely related to membrane integrity and synaptic plasticity. The negative control of cellular and metabolic processes, fatty acids binding /activity, and the manipulated endocannabinoid system (targeting cannabinoid receptors) were also concerned with delta-9-tetrahydrocannabinol. Hence, this may alter neurotransmitter signaling involved in memory, cognition, and emotional control, showing its direct impact on brain physiological processes. This may be one of the risk factors for schizophrenia development which is also closely tied to some other variables such as frequency, genetic vulnerability, dosage, and individual susceptibility.

Effect of Varying Normal Stiffness on Soft Rock Joints under Cyclic Shear Loads.

The evaluation of changes in shear resistance on soft (or weathered) rock joints under cyclic shear loads with constant normal load (CNL) and constant normal stiffness (CNS) significantly contributes to increasing the safety and stability of rock slopes and underground structures. In this study, a series of cyclic shear tests were conducted on simulated soft rock joints with regular (15°-15°, 30°-30°) and irregular (15°-30°) asperities under different normal stiffnesses (kn). The results indicated that the first peak shear stress increases with the increase in kn up to the normal stiffness of the joints (knj). Beyond knj, no significant change was observed in the peak shear stress. The difference in peak shear stress between regular (30°-30°) and irregular joints (15°-30°) increases as kn increases. The minimum difference of peak shear stress between regular and irregular joints was observed (8.2%) under CNL and the maximum difference was found (64.3%) on knj under CNS. The difference in peak shear stress between the first and subsequent cycles significantly increases as both the joint roughness and kn increases. A new shear strength model is developed to predict peak shear stress of the joints for different kn and asperity angles under cyclic shear loads.

Analysis of conventional and helical soil nails using finite element method and limit equilibrium method.

The infrastructure of roads, bridges, tunnels, subways, etc. is grooming day by day. In the recent era, soil nailing is the developing method for slope stability, road widening projects, and constructing deep foundations. This paper suggests a new and improved helical soil nail (HN) that offers an alternative to conventional soil nail (CN). Till now pullout studies on different model nails in c-Φ soil are still rare. In addition, the stability analysis for conventional soil nails was only studied using FEM analysis, whereas for helical soil nails the estimation of stability of slope is still mysterious. So, the present study includes the behavior of conventional and helical soil nails based on both laboratory and analytical methods in c-Φ soil. The present study also incorporated the use of theoretical equations and finite element analysis (using PLAXIS 2D) for comparing the stability of different profiles of soil nails (e.g., CN and HN) in c-Φ soil, which was unique to this study. By using the finite element method (FEM) and the limit equilibrium method (LEM), a factor of safety was also estimated for both types of nails (CN and HN). According to the experimental, analytical, and numerical findings, it is clear that helical soil nails (HN) exhibit less deformation and more factor of safety than conventional soil (CN) nails under similar loading and soil conditions.

Effect of aqueous extract of barley and wheat grass in stress induced depression in Swiss mice.

BACKGROUND: The consumption of green juice of Barley and wheat grass is widely increases because of its therapeutic benefits. OBJECTIVE: The study aimed to investigate phytochemicals and evaluate the antioxidant and antidepressant activity of aqueous extract of barley and wheat grass. MATERIAL AND METHODS: This study included phytochemical screening, evaluation of antioxidant and antidepressant activities. Four groups consisting of six mice in each group. Negative control with stressed induced mice; imipramine group (100 mg/kg), barley and wheat extract group (400 mg/kg) respectively. Forced swim, tail suspension and elevated plus maize test were carried out to evaluate the antianxiety and antidepressant activity. RESULTS: Phytochemical screening of barley and wheat grass extract showed secondary metabolites such as alkaloids, Saponin, Tannins, Phenolic, Carbohydrate, Glycosides, Flavonoids, and Proteins. The mean total phenolic content of aqueous extract of barley and wheat grass was 160.996 ± 0.656, 135.63 ± 1.184 mg equivalent of GAE/g respectively. The total flavonoid content of aqueous extract of barley and wheat grass was 153.42 ± 0.40, 133.14 ± 0.43 mg equivalent of quercetin/g respectively. The extracts were proved to be an effective radical scavenger in all antioxidant assays. Forced swim and tail suspension test showed a significant (∗p < 0.05 and ∗∗p < 0.01) decrease in an immobility time. In elevated plus maize, there was a significant (∗∗p < 0.01) increase in average time spent on the open arm of the extract-treated group as compared to the negative control. CONCLUSION: It shows that barley and wheat grass extract has antidepressant effect.

Flavonol morin targets host ACE2, IMP-α, PARP-1 and viral proteins of SARS-CoV-2, SARS-CoV and MERS-CoV critical for infection and survival: a computational analysis.

A sudden outbreak of a novel coronavirus SARS-CoV-2 in 2019 has now emerged as a pandemic threatening to efface the existence of mankind. In absence of any valid and appropriate vaccines to combat this newly evolved agent, there is need of novel resource molecules for treatment and prophylaxis. To this effect, flavonol morin which is found in fruits, vegetables and various medicinal herbs has been evaluated for its antiviral potential in the present study. PASS analysis of morin versus reference antiviral drugs baricitinib, remdesivir and hydroxychloroquine revealed that morin displayed no violations of Lipinski's rule of five and other druglikeness filters. Morin also displayed no tumorigenic, reproductive or irritant effects and exhibited good absorption and permeation through GI (clogP <5). In principal component analysis, morin appeared closest to baricitinib in 3D space. Morin displayed potent binding to spike glycoprotein, main protease 3CLPro and papain-like protease PLPro of SARS-CoV-2, SARS-CoV and MERS-CoV using molecular docking and significant binding to three viral-specific host proteins viz. human ACE2, importin-α and poly (ADP-ribose) polymerase (PARP)-1, further lending support to its antiviral efficacy. Additionally, morin displayed potent binding to pro-inflammatory cytokines IL-6, 8 and 10 also supporting its anti-inflammatory activity. MD simulation of morin with SARS-CoV-2 3CLPro and PLPro displayed strong stability at 300 K. Both complexes exhibited constant RMSDs of protein side chains and Cα atoms throughout the simulation run time. In conclusion, morin might hold considerable therapeutic potential for the treatment and management of not only COVID-19, but also SARS and MERS if studied further. Communicated by Ramaswamy H. Sarma.

Chick Embryo: A Preclinical Model for Understanding Ischemia-Reperfusion Mechanism.

Ischemia-reperfusion (I/R)-related disorders, such as stroke, myocardial infarction, and peripheral vascular disease, are among the most frequent causes of disease and death. Tissue injury or death may result from the initial ischemic insult, primarily determined by the magnitude and duration of the interruption in blood supply and then by the subsequent reperfusion-induced damage. Various in vitro and in vivo models are currently available to study I/R mechanism in the brain and other tissues. However, thus far, no in ovo I/R model has been reported for understanding the I/R mechanisms and for faster drug screening. Here, we developed an in ovo Hook model of I/R by occluding and releasing the right vitelline artery of a chick embryo at 72 h of development. To validate the model and elucidate various underlying survival and death mechanisms, we employed imaging (Doppler blood flow imaging), biochemical, and blotting techniques and evaluated the cell death mechanism: autophagy and inflammation caused by I/R. In conclusion, the present model is useful in parallel with established in vitro and in vivo I/R models to understand the mechanisms of I/R development and its treatment.

Serial measurement of lipid profile and inflammatory markers in patients with acute myocardial infarction.

Serum concentration of lipids and lipoproteins changes during the course of acute coronary syndrome as a consequence of the inflammatory response. The objective of this study was to evaluate the effect of acute myocardial infarction (AMI) on the levels of lipid profile and inflammatory markers. We investigated 400 patients with AMI who were admitted within 24 h of onset of symptoms. Serum levels of total cholesterol (TC), triglyceride (TG), low density lipoprotein (LDL) and high density lipoprotein (HDL) were determined by standard enzymatic methods along with high sensitive C-reactive protein (hs-CRP) (latex enhanced immunoturbidimetric assay) and cytokines, interleukin (IL)-6 and IL-10 (quantitative ''sandwich'' enzyme-linked immunosorbent assay). The results indicate a trend of reduced TC, LDL, and HDL, and elevated TG levels, along with pro- and anti-inflammatory markers (p < 0.001), between day 1 and the day 2 serum samples of AMI patients. However, corrections in the serum levels have been observed at day 7. Our results demonstrate significant variations in the mean lipid levels and inflammatory markers between days 1, 2 and 7 after AMI. Therefore, it is recommended that the serum lipids should be assessed within 24 hours after infarction. Early treatment of hyperlipidemia provides potential benefits. Exact knowledge regarding baseline serum lipids and lipoprotein levels as well as their varying characteristics can provide a rational basis for clinical decisions about lipid lowering therapy.

Neuron specific enolase and c-reactive protein levels in stroke and its subtypes: correlation with degree of disability.

Stroke is an emergency which threatens life and third leading cause of death and long term disability in developed countries. The use of biomarkers in diagnosing stroke and assessing prognosis is an emerging and rapidly evolving field. The study aimed to investigate the predictive value of biochemical marker of brain damage neuron-specific enolase (NSE) and systemic inflammatory marker C-reactive protein (CRP) with respect to degree of disability at the time of admission and short term in stroke patients. We investigated 120 patients with cerebrovascular stroke who were admitted within 72 h of onset of stroke in the Department of Neurology at Sri Aurobindo Institute of Medical Sciences, Indore, India. NSE and CRP were analyzed by solid enzyme linked immunosorbent assay using analyzer and micro plate reader from Biorad 680. In all patients, the neurological status was evaluated by a standardized neurological examination and the National Institutes of Health Stroke Scale on admission and on day 7. Serum NSE and CRP concentration were found significantly increased in acute stroke cases as compared to control in present study (<0.05 and <0.001 respectively). The maximum serum NSE and CRP levels within 72 h of admission were significantly higher in patients with greater degree of disability at the time of admission. Both biomarkers were found significantly correlated with neurological disability and short term outcome. Our study showed that serum biomarkers NSE and CRP have high predictive value for determining severity and early neurobehavioral outcome after acute stroke.

Atherogenic lipid profile and high sensitive C-reactive protein in patients with rheumatoid arthritis.

OBJECTIVES: The objective of this study was to investigate the lipid profile and high sensitive C-reactive protein (hs-CRP) levels in rheumatoid arthritis (RA) patients, and compare them with healthy controls, and also compare the different patterns of these parameters during active RA between male and female patients. DESIGN AND METHODS: We studied 60 RA patients and 65 controls matched by age and sex. All cases were selected from the Rheumatology Department of a tertiary care hospital, Delhi, India and fulfilled the 1987 American College of Rheumatology revised criteria for RA. RESULTS: We found that male RA patients had significantly higher levels of hs-CRP (p<0.001), low density lipoprotein cholesterol (LDL-C)/high density lipoprotein cholesterol (HDL-C) (p<0.001), total cholesterol (TC)/HDL-C (p<0.05), and lower level of HDL-C (p<0.01), than male controls. The mean levels of HDL-C and TC were high (p<0.05), and LDL-C, LDL-C/HDL-C (p<0.01), and hs-CRP (p<0.001) were low in healthy females as compared to female RA patients. Between RA patients, females had significantly high level of HDL-C (p<0.001), and low levels of TC/HDL-C and LDL-C/HDL-C (p<0.001) as compared to RA males. Mean levels of TC and HDL-C were higher in healthy females (p<0.05) and triglyceride (TG) was lower (p<0.05) than in healthy males. CONCLUSIONS: Results demonstrate that the RA patients have high levels of inflammatory marker hs-CRP and altered lipid profile, and these are affected by the gender of the RA patients. Lipid levels should be monitored and managed in patients with RA to minimize the long-term risk of cardiovascular disease.

Prognostic value of neuron specific enolase and IL-10 in ischemic stroke and its correlation with degree of neurological deficit.

BACKGROUND: The blood-brain barrier is compromised in stroke patients. The release of neuro-biochemical protein markers, such as Neuron Specific Enolase (NSE) into the circulation may allow the pathophysiology and prognosis of patients with cerebrovascular diseases to be evaluated further. METHOD: Present study aimed to investigate the predictive value of NSE and Interleukin-10 (IL-10) with respect to early neurobehavioral outcome which evaluated by National Institute of Health Stroke Scale (NIHSS). We investigated 100 patients of ischemic stroke and blood samples were taken within first 72 h of stroke onset. NSE and IL-10 were analyzed by commercially available ELISA kits. The neurological status was evaluated by a standardized NIHSS at the time of admission. RESULTS: NSE was significantly increased (17.95±4.54 vs 7.48±1.51 {ng/ml} p≤0.05) and IL-10 significantly decreased (11.79±2.77 vs 15.72±2.69 {pg/ml} p≤0.05) in patients when compared with controls. NSE also significantly (r=0.8, p≤0.001) correlated with degree of neurological deficit but IL-10 level in serum did not show any significant correlation with NIHSS score at the time of admission. CONCLUSIONS: Serum concentrations of NSE and IL-10 have a high predictive value for early neurobehavioral outcome after acute stroke.