Machine learning-based virtual screening and molecular modelling studies for identification of butyrylcholinesterase inhibitors as anti-Alzheimer's agent.

Butyrylcholinesterase (BChE) is a hydrolase involved in the metabolism and detoxification of specific esters in the blood. It is also implicated in the progression of Alzheimer's disease, a type of dementia. As the disease progresses, the level of BChE tends to increase, opting for a major role as an acetylcholine-degrading enzyme and surpassing the role of acetylcholinesterase. Hence, the development of BChE inhibitors could be beneficial for the latter stages of the disease. In the present study, machine learning (ML) models were developed and employed to identify new BChE inhibitors. Further, the identified molecules were subjected to molecular property filters. The filtered ligands were studied through molecular modelling techniques, viz. molecular docking and molecular dynamics (MD). Support vector machine-based ML models resulted in the identification of 3291 compounds that would have predicted IC50 values less than 200 nM. The docking study showed that compounds ART13069594, ART17350769 and LEG19710163 have mean binding energies of -9.62, -9.26 and -8.93 kcal/mol, respectively. The MD study displayed that all the selected ligands showed stable complexes with BChE. The trajectories of all the ligands were stable similar to the standard BChE inhibitors.Communicated by Ramaswamy H. Sarma.

Gene Therapy for Chronic Traumatic Brain Injury: Challenges in Resolving Long-term Consequences of Brain Damage.

The gene therapy is alluring not only for CNS disorders but also for other pathological conditions. Gene therapy employs the insertion of a healthy gene into the identified genome to replace or replenish genes responsible for pathological disorder or damage due to trauma. The last decade has seen a drastic change in the understanding of vital aspects of gene therapy. Despite the complexity of traumatic brain injury (TBI), the advent of gene therapy in various neurodegenerative disorders has reinforced the ongoing efforts of alleviating TBI-related outcomes with gene therapy. The review highlights the genes modulated in response to TBI and evaluates their impact on the severity and duration of the injury. We have reviewed strategies that pinpointed the most relevant gene targets to restrict debilitating events of brain trauma and utilize vector of choice to deliver the gene of interest at the appropriate site. We have made an attempt to summarize the long-term neurobehavioral consequences of TBI due to numerous pathometabolic perturbations associated with a plethora of genes. Herein, we shed light on the basic pathological mechanisms of brain injury, genetic polymorphism in individuals susceptible to severe outcomes, modulation of gene expression due to TBI, and identification of genes for their possible use in gene therapy. The review also provides insights on the use of vectors and challenges in translations of this gene therapy to clinical practices.

Neuroprotective effects of combined trimetazidine and progesterone on cerebral reperfusion injury.

Cerebral ischemia-reperfusion injury induces multi-dimensional damage to neuronal cells through exacerbation of critical protective mechanisms. Targeting more than one mechanism simultaneously namely, inflammatory responses and metabolic energy homeostasis could provide additional benefits to restrict or manage cerebral injury. Being proven neuroprotective agents both, progesterone (PG) and trimetazidine (TMZ) has the potential to add on the individual therapeutic outcomes. We hypothesized the simultaneous administration of PG and TMZ could complement each other to synergize, or at least enhance neuroprotection in reperfusion injury. We investigated the combination of PG and TMZ on middle cerebral artery occlusion (MCAO) induced cerebral reperfusion injury in rats. Molecular docking on targets of energy homeostasis and apoptosis assessed the initial viability of PG and TMZ for neuroprotection. Animal experimentation with MCA induced ischemia-reperfusion (I/R) injury in rats was performed on five randomized groups. Sham operated control group received vehicle (saline) while the other four I-R groups were pre-treated with vehicle (saline), PG (8 â€‹mg/kg), TMZ treated (25 â€‹mg/kg), and PG â€‹+ â€‹TMZ (8 and 25 â€‹mg/kg) for 7 days by intraperitoneal route. Neurological deficit, infarct volume, and oxidative stress were evaluated to assess the extent of injury in rats. Inflammatory reactivity and apoptotic activity were determined with alterations in myeloperoxidase (MPO) activity, blood-brain barrier (BBB) permeability, and DNA fragments. Reperfusion injury inflicted cerebral infarct, neurological deficit, and shattered BBB integrity. The combination treatment of PG and TMZ restricted cellular damage indicated by significant (p â€‹< â€‹0.05) decrease in infarct volume and improvement in free radical scavenging ability (SOD activity and GSH level). MPO activity and LPO decreased which contributed in improved BBB integrity in treated rats. We speculate that inhibition of inflammatory and optimum energy utilization would critically contribute to observed neuroprotection with combined PG and TMZ treatment. Further exploration of this neuroprotective approach for post-recovery cognitive improvement is worth investigating.

Protective effect of co-administration of caffeine and piracetam on scopolamine-induced amnesia in Wistar rats.

Alzheimer's disease is a cerebrovascular disorder characterized by progressive loss of the mental capabilities. The novel therapeutic agent piracetam is a cyclic derivative of γ-aminobutyric acid and one of the oldest recognized synthetic nootropics. Piracetam improves cognitive function without stimulation or sedation. Caffeine is a central nervous system stimulant with nootropic activity. Caffeine promotes the performance of tasks that involve working memory to a limited extent, and it also retards cognitive decline in healthy individuals. The present study aimed to determine the protective effect of co-administering piracetam and caffeine on scopolamine-induced amnesia in rats. Pre-treatment with caffeine and piracetam decreased scopolamine-induced cognitive damage and amnesia. The preventive response was demonstrated by an improved learning tendency. The mechanism responsible for these effects requires further investigation. The co-administration of caffeine and piracetam has potential as a novel therapeutic strategy for combating amnesia.

Preferential cyclooxygenase inhibition by Jasminum sambac: A possible relationship with potent anti-arthritic activity.

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Aging of Brain Related with Mitochondrial Dysfunctions.

Advancing age presents a major challenge for the elderly population in terms of quality of life. The risk of cognitive impairment, motor in-coordination, and behavioral inconsistency due to neuronal damage is relatively higher in aging individuals of society. The brain, through its structural and functional integrity, regulates vital physiological events; however, the susceptibility of the brain to aging-related disturbances signals the onset of neurodegenerative diseases. Mitochondrial dysfunctions impair bioenergetic mechanism, synaptic plasticity, and calcium homeostasis in the brain, thus sufficiently implying mitochondria as a prime causal factor in accelerating aging-related neurodegeneration. We have reviewed the fundamental functions of mitochondria in a healthy brain and aimed to address the key issues in aging-related diseases by asking: 1) What goes wrong with mitochondria in the aging brain? 2) What are the implications of mitochondrial damage on motor functions and psychiatric symptoms? 3) How environmental chemicals and metabolic morbidities affect mitochondrial functions? Further, we share insights on opportunities and pitfalls in drug discovery approaches targeting mitochondria to slow down the progression of aging and related neurodegenerative diseases.

Natural RNA dependent RNA polymerase inhibitors: Molecular docking studies of some biologically active alkaloids of Argemone mexicana.

COVID-19 has become disastrous for world and spread all over. Researchers all around the globe are working to discover a drug to cure from COVID-19. RNA dependent RNA polymerase plays a key role in SARS-CoV-2 replication and thus it could be a potential target for SARS-CoV-2. This study revealed that Protopine, Allocryptopine and (±) 6- Acetonyldihydrochelerythrine could be potential RdRp inhibitors of SARS-CoV-2.

Evaluation of Antiarthritic Effect of Culinary-Medicinal Oyster Mushroom Pleurotus ostreatus cv. Florida (Agaricomycetes) on Complete Freund's Adjuvant Induced Arthritis in Rats.

The present study evaluates the antiarthritic effect of hydroethanolic extract of Pleurotus ostreatus cv. Florida, which was tested against adjuvant induced arthritis in rat models. Arthritis was induced by administration of complete Freund's adjuvant into the subplantar surface of left paw of rats. The extract was given orally at doses 200 mg/ kg and 400 mg/kg and piroxicam was administered intraperitonially (4 mg/kg). In vitro testing on parameters including antiproteinestrase, albumin denaturation and heat induce hemolysis was also carried out. There was significant decrease (p < 0.001) in proteinase activity and membrane stabilization in vivo studies on cv. Florida extract treated rats showed a significant (p < 0.001) decrease in paw volume, joint diameter, and spontaneous change in body weight recorded for 21 days. The treatment also resulted in an increase in rats' gripping activity compared with arthritic control rats. X-ray examinations showed a decrease in joint swelling. Histopathological examination of the extract treated group showed a significant decrease in joint space. There was also an increase in antibody levels. The antioxidant parameters showed a significant (p < 0.001) increase in superoxide dismutase and catalase enzymatic activities. Thus P. ostreatus cv. Florida extract demonstrates a potent antioxidant activity in a rat model. It is concluded that the P. ostreatus cv. Florida extract contains medicinally important constituents that show antiarthritic activity in rats.

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.

Protective effect of catechin on humoral and cell mediated immunity in rat model.

The present study was focused on examining the effect of catechin on the cellular and humoral immunity in rat model. Immunomodulatory effect of catechin was determined by delayed-type hypersensitivity (DTH) response, carbon clearance assay, leucocyte mobilization test and cyclophosphamide-induced myelosuppression and hemagglutinating antibody (HA) titer assay. Catechin in experimental dose (25, 50 and 100mg/kg, p.o.) elevated a significant increase in antibody titer in the hemagglutination test with increased levels of immunoglobulin. There was an enhancement in the delayed-type hypersensitivity reaction produced by sheep red blood cells. There was also restoration in the functioning of leucocytes in cyclophosphamide-treated rats with an increased clearance of carbon particles. The results of the present study signify that catechin possesses sufficient potential for modulating immune activity by cellular and humoral mechanisms.

Protective effect of rutin on humoral and cell mediated immunity in rat model.

Diet and dietary intake can persuade the development, safeguard and proper functioning of immune system. Ruin, an important bioflavonoid, is abundantly found in various foodstuffs. Rutin has been acknowledged for its protective and beneficial effects on various aspects of the biological system. The present study was aimed to examine the effect of rutin on the regulation of the immune response in experimental animal models. Effect of rutin of cellular immunity was determined by delayed-type hypersensitivity (DTH) response, carbon clearance assay, leucocyte mobilization test, and cyclophosphamide-induced myelosuppression, whereas humoral immunity was analyzed by the haemagglutinating antibody (HA) titre assay. Rutin (25, 50 and 100 mg/kg, p.o.) evoked a significant increase in antibody titre in the haemagglutination test, increased immunoglobulin levels, and enhanced the delayed type hypersensitivity reaction induced by sheep red blood cells. It also significantly restored the functioning of leucocytes in cyclophosphamide treated rats and augmented phagocytic index in the carbon clearance assay. The outcomes from the present study indicate that rutin possesses sufficient potential for increasing immune activity by cellular and humoral mediated mechanisms.

The Pharmacological Potential of Rutin.

The contemporary scientific community has presently recognized flavonoids to be a unique class of therapeutic molecules due to their diverse therapeutic properties. Of these, rutin, also known as vitamin P or rutoside, has been explored for a number of pharmacological effects. Tea leaves, apples, and many more possess rutin as one of the active constituents. Today, rutin has been observed for its nutraceutical effect. The present review highlights current information and health-promoting effects of rutin. Along with this, safety pharmacology issues and SAR of the same have also been discussed.

Study of Antimicrobial and Cytotoxic Potential of the Oyster Mushroom Pleurotus ostreatus cv. Florida (Agaricomycetes).

This work was undertaken to evaluate in vitro antimicrobial and cytotoxic potential of Pleurotus ostreatus cv. Florida. Mushroom basidiocarps were extracted in water:ethanol (1:1, v/v), and the resulting extract was subjected to antimicrobial studies against Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, Klebsiella oxytoca, Bacillus subtilis, and Candida albicans. Cytotoxic potential on viable human leukocytes was studied. In vitro results showed excellent antimicrobial and cytotoxic potentials of the mushroom extract. Thus, functional properties of P. ostreatus cv. Florida could be used in the search for novel therapeutics.

Hematopoietic Effect of Amaranthus cruentus Extract on Phenylhydrazine-Induced Toxicity in Rats.

Amaranthus cruentus (Amaranthaceae) is one of the popularly grown leafy vegetables in the Indian subcontinent. Leaves of the plant are rich in polyphenols, tannins, flavonoids, steroids, terpenoids, saponins, and betalains. The plant also contains rich amounts of protein, calcium, iron, vitamins A, E, and C, and folic acid. The present work was undertaken to evaluate the antianemic effect of Amaranthus cruentus. Ethanol extract of Amaranthus cruentus was prepared. Acute oral toxicity of the extract was determined by Organization for Economic Cooperation and Development (OECD) Guideline 423. Doses of 200 and 400 mg/kg were used in the present study. Phenylhydrazine (60 mg/kg, intraperitoneal injection for three consecutive days) was used to induce anemia in rats. After anemia induction, animals were treated with standard preparation and extract. Amaranthus cruentus extract significantly aided in restoring the levels of red blood cells, white blood cells (WBCs), and hemoglobin. There was also an increase in hematocrit. Thus, it can be concluded that Amaranthus cruentus is a rich source of phytochemicals that are responsible for demonstrating hematopoietic effects. Isolation and structure elucidation of constituents, responsible for antianemic activity, is necessary to affirm the aforementioned effect.

Lactobionic acid coupled liposomes: an innovative strategy for targeting hepatocellular carcinoma.

INTRODUCTION: Liver cancer or hepatocellular carcinoma (HCC) is a major cause of death worldwide. Targeted delivery of drug to the carcinoma cell can be achieved by conjugation of ligand on the carrier system. METHODS AND MATERIALS: In this study, oxaliplatin-loaded hepatoma-targeted liposome were designed and prepared using galactosylated distearoylphosphatidylethanolamine. The liposomes were prepared by cast film method and coupled with lactobionic acid (LA-LP) using 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide as a coupling agent. The coupling was confirmed by infrared spectroscopy. They were further characterized for various parameters such as vesicle shape and surface morphology, size, entrapment efficiency and in vitro release pattern. RESULTS AND DISCUSSION: The vesicle size of the uncoupled liposome (256 nm) was found to be less than LA-LP (310 nm). The uptake of LA-LP and uncoupled liposomes by BEL7402 HCC cell lines was visualized using fluorescence microscopy that revealed the dependence of liposomal recognition and higher uptake of the LA-LP. Organ distribution studies provided evidence that coupling of lactobionic acid on liposomal surface significantly enhanced the tumor uptake of drug, which is reflected by recovery of higher percentage of drug from tumor as compared to uncoupled liposomes or free drug. CONCLUSION: These studies suggest them as effective vectors for HCC targeting.

Immunoprophylactic potential of wheat grass extract on benzene-induced leukemia: An in vivo study on murine model.

OBJECTIVES: Wheat grass (Triticum aestivum) is a gift of nature given to mankind. A number of scientific research on wheatgrass establishes its anticancer and antioxidant potential. Current work was focused to determine antileukemic effect of wheat grass. MATERIALS AND METHODS: The commercial wheatgrass powder was extracted with 95% of methanol. Methanol extract of wheat grass was studied for acute oral toxicity as per revised Organization for Economic Cooperation and Development Guidelines number 423. Leukemia was successfully induced in Wister rats by intravenous injection of benzene. The blood was collected and analyzed for hematological parameters. Phagocytotic activity of the extract was determined. RESULTS: Phytochemical screening revealed the presence of flavonoids, phenolics, carbohydrates, and amino acids. From acute toxicity studies, it was found that the methanol extract of wheatgrass was safe up to a dose level of 2000 mg/kg of body weight. Outcomes of hematological parameters in various experimental groups of murine model demonstrated antileukemic effect of extract. Methanol extract of wheatgrass aroused the process of phagocytosis of killed Candida albicans and also demonstrated a significant chemotactic activity at all tested concentrations. CONCLUSION: In the current work, methanol extract of wheat grass demonstrated antileukemic potential that might be due to the presence of flavonoids and polyphenolics in it. Further isolation, structural characterization of active constituents is necessary to extrapolate the mechanism of action.

Antioxidant Potential of White Oyster Culinary-Medicinal Mushroom, Pleurotus florida (Higher Basidiomycetes).

The present work was focused to evaluate in vitro antioxidant of Pleurotus florida. The hydroethanolic extract was prepared by macerating basidiocarp with water:ethanol (1:1). The antioxidant potential was evaluated by 1,1-diphenyl-2-picryl-hydrazyl (DPPH) radical scavenging activity, reducing power, chelating effects on ferrous ions, total antioxidant capacity, and lipid peroxidation inhibitory activity. Further total flavonoid and phenolic content was also estimated. The comparison between different antioxidant assays was done by correlation coefficient. The results from the antioxidant assays showed that hydroethanolic extract (HEE) might act as radical scavenger to a certain extent. The distinct scavenging activities of HEE can be due to the diverse phytochemical constituents. Being a rich source of antioxidants, P. florida can be used as an accessible source of natural antioxidants with consequential health benefits.

Protective effect of rutin on impairment of cognitive functions of due to antiepileptic drugs on zebrafish model.

AIM: The severity of adverse reactions due to antiepileptics is observed during initiation and early treatment in which impairment of cognitive effects are common. Since long time, herbal medicine is a natural remedy to treat neural symptoms. Phytochemicals have been proven to be potent neuro-protective agents. Rutin, a bioflavonoid is established to be nootropic in many studies. In this study, we aimed to determine the protective effect of rutin in zebrafish against the side effects produced by AEDs. MATERIALS AND METHODS: Seizures were induced in zebrafish by phenylenetetrazole. Rutin pretreatment (50 mg/kg, single injection, i.p.) was done before commencement of the study. Behavioral studies were performed as: latency to move high in the tank, locomotion effects, color effect, shoal cohesion, light/dark test on Zebrafish. RESULTS: Treatment with rutin reverted the locomotor behavior to normal. Treatment with AEDs caused fishes to move in all regions while, in case of treatment with rutin, the response reverted to normal. Treatment with AEDs altered swimming behavior of zebrafish, however, rutin showed a positive effect over this behavior. Treatment with AEDs resulted in restricted movement of zebrafish to the dark zone. Treatment with rutin caused increased latency of zebrafish to move in the light compartment. Similarly, time spent in the light compartment by zebrafish treated with rutin was significantly (P < 0.01) higher as compared to zebrafish treated with AEDs. CONCLUSION: The results suggest a protective role of rutin on cognition impaired by AEDs.

Chemopreventive role of Coriandrum sativum against gentamicin-induced renal histopathological damage in rats.

Drug induced nephrotoxicity is one of the most common causes of renal failure. Gentamicin belongs to aminoglycosides, which elicit nephrotoxic potential. Natural antioxidants from plants demonstrate a number of biotherapeutic activities. Coriander is an important medicinal plant known for its hepatoprotective, diuretic, carminative, digestive and antihelminthic potential. This study was designed to investigate whether the extract of Coriandrum sativum ameliorates the nephrotoxicity induced by gentamicin in rats. Dried coriander powder was coarsely grinded and subjected to defatting by petroleum ether and further with ethyl acetate. The extract was filtered and subjected to phytochemical and phytoanalytical studies. Acute toxicity in Wistar rats was determined by the OECD Guideline (423). Animals were divided into four groups. The first group served as positive control, while the second group was toxic control (gentamicin treated). The third and fourth group were treated with the extract (200 and 400 mg/kg gentamicin). After 8 days, the animals were sacrificed and biochemical and histopathological studies were carried out. Phytochemical screening of the extract demonstrated Coriandrum sativum to be rich in flavonoids, polyphenolics and alkaloids. Results of acute toxicity suggested the use of 200 mg/kg and 400 mg/kg for Coriandrum sativum in the study. Coriandrum sativum extract at the dose of 400 mg/kg significantly (p<0.01) decreased creatinine levels in the animals, along with a decrease in serum urea and blood urea nitrogen. Treatment with Coriandrum sativum extract ameliorated renal histological lesions. It is concluded that Coriandrum sativum is a potential source of nephroprotective phytochemical activity, with flavonoids and polyphenols as the major components.

Protective effect of rutin on cognitive impairment caused by phenytoin.

OBJECTIVE: To study the effect of the co-administration of phenytoin (PHT) and rutin in comparison with PHT and piracetam (PIM) on seizure control, cognitive, and motor functions in mice. MATERIALS AND METHODS: Increasing current electroshock seizure (ICES) test was used to evaluate the effect of the co-administration of PHT and PIM on convulsions. Cognitive functions in mice were assessed by a spontaneous alternation in behavior on a plus maze while motor functions were screened using rolling roller apparatus and by counting the number of arms entries on a plus maze. Brain acetyl-cholinesterase (AChE) activity was also estimated. STATISTICAL ANALYSIS: The expression of data was done as mean ± standard error of the mean. The normally distributed data were subjected to one-way ANOVA followed by Dunnett's test. P < 0.05 was considered significant. RESULTS: The study showed that rutin when co-administered with PHT, significantly reversed PHT-induced reduction in spontaneous alternation without altering the efficacy of PHT against ICES, in both acute and chronic studies. Further, it also reversed PHT-induced increase in AChE activity. CONCLUSION: Rutin alleviated the PHT-induced cognitive impairment without compromising its antiepileptic efficacy.