The entrancing role of dietary polyphenols against the most frequent aging-associated diseases.

Aging, a fundamental physiological process influenced by innumerable biological and genetic pathways, is an important driving factor for several aging-associated disorders like diabetes mellitus, osteoporosis, cancer, and neurodegenerative diseases including Alzheimer's and Parkinson's diseases. In the modern era, the several mechanisms associated with aging have been deeply studied. Treatment and therapeutics for age-related diseases have also made considerable advances; however, for the effective and long-lasting treatment, nutritional therapy particularly including dietary polyphenols from the natural origin are endorsed. These dietary polyphenols (e.g., apigenin, baicalin, curcumin, epigallocatechin gallate, kaempferol, quercetin, resveratrol, and theaflavin), and many other phytochemicals target certain molecular, genetic mechanisms. The most common pathways of age-associated diseases are mitogen-activated protein kinase, reactive oxygen species production, nuclear factor kappa light chain enhancer of activated B cells signaling pathways, metal chelation, c-Jun N-terminal kinase, and inflammation. Polyphenols slow down the course of aging and help in combatting age-linked disorders. This exemplified in the form of clinical trials on specific dietary polyphenols in various aging-associated diseases. With this context in mind, this review reveals the new insights to slow down the aging process, and consequently reduce some classic diseases associated with age such as aforementioned, and targeting age-associated diseases by the activities of dietary polyphenols of natural origin.

NMDA receptor modulation by Esculetin: Investigating behavioral, biochemical and neurochemical effects in schizophrenic mice model.

Schizophrenia, a global mental health disorder affecting approximately 1 % of the population, is characterized by neurotransmitter dysregulation, particularly dopamine, serotonin, and glutamate. Current antipsychotic therapies, despite their efficacy, are accompanied by adverse effects, which has motivated researchers to investigate more secure substitutes. This study examines the potential antipsychotic effects of esculetin, a natural coumarin derivative recognized for its wide-ranging pharmacological activities (anti-inflammatory, antioxidant, anti-pathogenic, anticancer, and neuroprotective), in animal model of schizophrenia induced by ketamine. In order to induce disease, acute and chronic ketamine administration was performed on Swiss albino mice, supplemented with esculetin (as the test substance) and clozapine (as the reference standard). Behavioral studies and biochemical assays were performed to evaluate positive, negative, and cognitive symptoms of schizophrenia, as well as antioxidant and oxidant levels in various brain regions. Esculetin demonstrated significant improvements in behavioral symptoms, attenuated oxidative stress and neuroinflammation, and modulated neurotransmitter levels. Afterwards, ELISA was performed to evaluate levels of schizophrenia biomarkers AChE, BDNF. Moreover, proinflammatory cytokines (IL-6 and TNF-α) and NF-κB were also determined. Histopathological parameters of under study brain parts i.e., hippocampus, cortex and striata were also assessed. Esculetin and clozapine significantly (***p < 0.0001) altered ketamine induced behavioral symptoms and attenuated ketamine induced oxidative stress and neuroinflammation. Additionally, esculetin significantly (***p < 0.0001) altered neurotransmitter (dopamine, serotonin, glutamate) levels. ELISA analysis depicts ketamine reduced BDNF levels in hippocampus, cortex and striata while esculetin significantly (***p < 0.0001) increased BDNF levels in under study three parts of brain. Histopathological changes were seen in test groups. The findings of this study indicate that esculetin may have therapeutic potential in the treatment of schizophrenia induced by ketamine. As a result, esculetin may have the potential to be utilized as a treatment for schizophrenia.

Pharmacological and toxicological evaluation of methyl 4-hydroxy-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxoide against haloperidol induced Parkinson like symptoms in animal model: In-vitro and in-vivo studies.

In Parkinson's disease (PD), degradation of dopaminergic neurons in substantia nigra causes striatal deficiency of dopamine, which results in tremors, bradykinesia with instability in posture, rigidity and shuffled gait. Prevalence of PD increases with age as from 65 to 85 years. In an attempt to devise targeted safe therapy, nanoparticles of methyl 4-hydroxy-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxide (MBD) (MBDN), were prepared and their acute toxicity and safety was evaluated. Thirty-six healthy albino mice were randomly divided into six groups (n = 6): normal control, diseased control, standard (levodopa/carbidopa (100/25 mg/kg) and the remaining three groups were administered 1.25, 2.5 and 5 mg/kg MBDN during 21 days study. Except control, all mice, were injected haloperidol (1 mg/ kg i.p.) 1-h prior to treatment to induce PD. Acute toxicity test showed, no effect of MBDN on lipid profile, brain, renal and liver function and histoarchitecture of kidney, liver and heart, except decreased (p < 0.05) platelet count. Behavioral studies showed significant improvement (p < 0.001) in motor function and reduction of oxidation status in a MBDN in a dose dependent manner. Thus, the study findings revealed significance of MBDN as a selective MAO-B inhibitor for the improvement of Parkinson's symptoms in animal model.

Sarcococca saligna ameliorated D-galactose induced neurodegeneration through repression of neurodegenerative and oxidative stress biomarkers.

Sarcococca saligna is a valuable source of bioactive secondary metabolites exhibiting antioxidant, anti-inflammatory and acetylcholinesterase inhibitory activities. The study was intended to explore the therapeutic pursuits of S. saligna in amelioration of cognitive and motor dysfunctions induced by D-galactose and linked mechanistic pathways. Alzheimer's disease model was prepared by administration of D-galactose subcutaneous injection100 mg/kg and it was treated with rivastigmine (100 mg/kg, orally) and plant extract for 42 days. Cognitive and motor functions were evaluated by behavioral tasks and oxidative stress biomarkers. Level of acetylcholinesterase, reduced level of glutathione, protein and nitrite level, and brain neurotransmitters were analyzed in brain homogenate. The level of apoptosis regulator Bcl-2, Caspases 3 and heat shock protein HSP-70 in brain homogenates were analyzed by ELISA and colorimetric method, respectively. AChE, IL-1ß, TNF-α, IL-1α and ß secretase expressions were analyzed by RT-PCR. S. saligna dose dependently suppressed the neurodegenerative effects of D-galactose induced behavioral and biochemical impairments through modulation of antioxidant enzymes and acetylcholinesterase inhibition. S. saligna markedly (P < 0.05) ameliorated the level of brain neurotransmitters, Bcl-2, HSP-70 and Caspases-3 level. S. saligna at 500-1000 mg/kg considerably recovered the mRNA expression of neurodegenerative and neuro-inflammatory biomarkers, also evident from histopathological analysis. These findings suggest that S. saligna could be applicable in cure of Alzheimer's disease.

Antidepressant activity of phytochemicals of Mangifera indica seeds assisted by integrated computational analysis.

Mangifera indica L., also known as mango, is a tropical fruit that belongs to the Anacardiaceae family and is prized for its juiciness, unique flavour, and worldwide popularity. The current study aimed to probe into antidepressant power (ADP) of MIS in animals and confirmation of ADP with in silico induced-fit molecular docking. The depression model was prepared by exposing mice to various stressors from 9:00 am to 2:00 pm during 42 days study period. MIS extract and fluoxetine were given daily for 30 min before exposing animals to stressors. ADP was evaluated by various behavioural tests and biochemical analysis. Results showed increased physical activity in mice under behavioural tests, plasma nitrite and malondialdehyde (MDA) levels and monoamine oxidase A (MAO-A) activity decreased dose-dependently in MIS treated mice and superoxide dismutases (SOD) levels increased in treated groups as compared to disease control. With the peculiar behaviour and significant interactions of the functional residues of target proteins with selected ligands along with the best absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties, it is concluded that catechin could be the best MAO-A inhibitor at a binding energy of -8.85 kcal/mol, and two hydrogen bonds were generated with Cys406 (A) and Gly443 (A) residues of the active binding site of MAO-A enzyme. While catechin at -6.86 kcal/mol generated three hydrogen bonds with Ala263 (A) and Gly434 (A) residues of the active site of monoamine oxidase B (MAO-B) enzyme and stabilized the best conformation. Therefore, it is highly recommended to test the selected lead-like compound catechin in the laboratory with biological system analysis to confirm its activity as MAO-A and MAO-B inhibitors so it can be declared as one of the novel therapeutic options with anti-depressant activity. Our findings concluded that M. indica seeds could be a significant and alternative anti-depressant therapy.

Administration of α-lipoic acid and silymarin attenuates aggression by modulating endocrine, oxidative stress and inflammatory pathways in mice.

Aggression, a highly prevalent behavior among all the psychological disorders having strong association with psychiatric imbalance, neuroendocrine changes and neurological disturbances (including oxidative stress & neuroinflammation) require both pharmacological and non-pharmacological treatments. Focusing the preclinical neuroendocrine determinants of aggression, this interventional study was designed to elucidate the curative effect of antioxidants on aggression in male mice. Adult albino male mice (n = 140) randomly divided into two main treatment groups for α-lipoic acid (ALA) and silymarin with 5 subgroups (n = 10) for each curative study, namely control, disease (aggression-induced), standard (diazepam, 2.5 mg/kg), low dose (100 mg/kg) and high dose (200 mg/kg) treatment groups of selected antioxidants. Resident-intruder paradigm and levodopa (L-dopa 375 mg/kg, p.o.) induced models were used for aggression. Effect of antioxidant treatment (i.e., 21 days bid) on aggression was assessed by evaluating the changes in aggressive behavior, oxidative stress biomarkers superoxide dismutase, catalase, glutathione, nitrite and malondialdehyde (SOD, CAT, GSH, nitrite & MDA), neurotransmitters (dopamine, nor-adrenaline and serotonin), pro-inflammatory cytokines tumor necrosis factor-α and interleukin- 6 (TNF-α & IL-6) along with serum testosterone examination. This study showed potential ameliorative effect on aggressive behavior with both low (100 mg/kg) and high (200 mg/kg) doses of antioxidants (ALA & silymarin). Resident-intruder or L-dopa induced aggression in male mice was more significantly tuned with ALA treatment than silymarin via down regulating both oxidative stress and inflammatory biomarkers. ALA also exhibited notable effects in managing aggression-induced disturbances on plasma testosterone levels. In conclusion, ALA is more effective than silymarin in attenuating aggression in mice.

The curative and mechanistic acumen of curcuminoids formulations against haloperidol induced Parkinson's disease animal model.

Parkinson's disease (PD) is slowly developing neurodegenerative disorder associated with gradual decline in cerebration and laboriousness to perform routine piece of work. PD imposed a social burden on society through higher medical cost and by loss of social productivity in current era. The available treatment options are expensive and associated with serious adverse effect after long term use. Therefore, there is a critical clinical need to develop alternative pharmacotherapies from natural sources to prevent and cure the pathological hall marks of PD with minimal cost. Our study aimed to scrutinize the antiparkinsonian potential of curcuminoids-rich extract and its binary and ternary inclusion complexes. In healthy rats, 1 mg/kg haloperidol daily intraperitoneally, for 3 weeks was used to provoke Parkinsonism like symptoms except control group. Curcuminoids rich extract, binary and ternary inclusion complexes formulations 15-30 mg/kg, L-dopa and carbidopa (100 + 25 mg/kg) were orally administered on each day for 3 weeks. Biochemical, histopathological and RT-qPCR analyses were conducted after neurobehavioral observations. Findings of current study indicated that all curcuminoids formulations markedly mitigated the behavioral abnormalities, recovered the level of antioxidant enzymes, acetylcholinesterase inhibitory activity and neurotransmitters. Histological analysis revealed that curcuminoids supplements stabilized the neuronal loss, pigmentation and Lewy bodies' formation. The mRNA expressions of neuro-inflammatory and specific PD pathological biomarkers were downregulated by treatment with curcuminoids formulations. Therefore, it is suggested that these curcuminoids rich extract, binary and ternary supplements should be considered as promising therapeutic agents in development of modern anti-Parkinson's disease medications.

Curcuminoids-enriched extract and its cyclodextrin inclusion complexes ameliorates arthritis in complete Freund's adjuvant-induced arthritic mice via modulation of inflammatory biomarkers and suppression of oxidative stress markers.

Curcuma longa extract and its marker curcuminoids have potential use in inflammatory conditions. However, curcuminoids solubility and bioavailability are major hindrances to their bioactivity. The current study investigated green extraction-based curcuminoids-enriched extract (CRE) prepared from C. longa and its cyclodextrin inclusion complexes, i.e., binary inclusion complexes (BC) and ternary inclusion complexes (TC), in complete Freund's adjuvant (CFA)-induced mice for their comparative anti-arthritic efficacy. CRE, BC, and TC (2.5 and 5 mg/kg) with the standard drug diclofenac sodium (13.5 mg/kg) were orally administered to mice for 4 weeks. Variations in body weight, hematological and biochemical parameters, along with gene expression analysis of arthritis biomarkers, were studied in animals. The histopathological analysis and radiographic examination of joints were also performed. CRE, BC and TC treatment significantly restored the arthritic index, histopathology and body weight changes. The concentration of C-reactive protein, rheumatoid factor and other liver function parameters were significantly recovered by curcuminoids formulations. The pro-inflammatory cytokines (NF-κB, COX-2, IL-6, IL-1ß, and TNF-α) gene expression was considerably (p < 0.001) downregulated, while on the other side, the anti-inflammatory genes IL-4 and IL-10 were upregulated by the use of CRE and its complexes. The concentration of antioxidant enzymes was considerably (P < 0.001) recovered by CRE, BC and TC with marked decrease in lipid peroxidation, erosion of bone, inflammation of joints and pannus formation in comparison to arthritic control animals. Therefore, it is concluded that green CRE and its cyclodextrin formulations with enhanced solubility could be considered as an applicable therapeutic choice to treat chronic polyarthritis.

Investigation of anti-Parkinson activity of dicyclomine.

BACKGROUND: Parkinson's disease (PD) is a progressive neurodegenerative disorder. The major causative factors that progress the PD are age, genetic abnormalities, environmental factors and degeneration of dopamine neurons in substantia nigra. PD normally exerts a tonic inhibitory effect on striatal cholinergic interneurons. Anticholinergics act by normalizing the disequilibrium between striatal dopamine and acetylcholine-resulted reduction in tremors. OBJECTIVE: This study sought to evaluate the anti-Parkinson potential of dicyclomine in haloperidol (HAL)- and paraquat (PQT)-induced Parkinsonism models in mice. MATERIALS AND METHODS: Sixty albino mice were divided into six groups (n = 10) for each model. Group I: received distilled water 1 mL/kg, Group II: diseased group received HAL (1 mg/kg) for consecutive 21 days and PQT (2 mg/kg) every three days for three weeks, Group III: treated with sinemet (20 mg/kg), Group IV-VI: received 40, 80 and 160 mg/kg dose of dicyclomine, respectively, for consecutive 21 days. The effect of treatments on spontaneous locomotor activity and motor co-ordination was evaluated by using open field, rotarod, actophotometer and light and dark box tests. Cataleptic behavior was estimated by the block method and triple horizontal bar apparatus. Biochemical markers of oxidative stress and levels of neurotransmitters were estimated. RESULTS: Findings from this study showed that dicyclomine at highest dose level of 160 mg/kg prevented HAL- and PQT-induced PD through enhancement of antioxidant defense system. CONCLUSION: The study concluded that dicyclomine could be the potential drug in the management of Parkinsonism.

Sarcococca saligna extract attenuates formaldehyde-induced arthritis in Wistar rats via modulation of pro-inflammatory and inflammatory biomarkers.

Sarcococca saligna plant is commonly used as traditional therapy for arthritis especially in Asian countries. The current study is designed to explore the anti-arthritic potential of S. saligna aqueous methanolic extract (SSME). Preliminary proximate study and HPLC analysis were performed to investigate the phytochemical characterization and quality control. The safety of the SSME was evaluated by performing an acute oral toxicity study (OECD guidelines 425). The anti-arthritic potential of SSME was explored by in vivo formaldehyde-induced arthritis model. The antiarthritic effect of the SSME was determined through paw diameter, arthritic index, body weight, biochemical and haematological parameters. Radiographic and histopathological studies were also carried out to evaluate the results. qRT-PCR was performed to determine the upregulation and downregulation of anti- and pro-inflammatory cytokines in rats while ELISA was done to determine the concentration of HSP-70, IL-6 and TNF-α in the serum. Results of acute oral toxicity showed no abnormality and mortality. There was no noticeable change in haematological and biochemical parameters. Histopathological examination exhibited the normal structure of vital organs. So, SSME might be safe at a 2000 mg/kg dose, proposing that LD50 was higher than 2000 mg/kg body weight. Gallic acid, catechin, hydroxyl benzoic acid, sinapic acid, caffeic acid, ferulic acid and p-cumaric acid were identified by HPLC. The outcomes of in vivo formaldehyde-induced arthritic model showed that SSME significantly reduced paw inflammation and arthritic index and improved haematological and biochemical parameters. Moreover, the SSME influentially down-regulated the gene expression of IL-1ß, IL-6, COX-2, PGE2, TNF-α and NF-κB, and up-regulated the expression of IL-4, and IL-10. The results of the undertaken study suggest that S. saligna have strong anti-arthritic activity supporting its conventional application as the remedy of rheumatoid arthritis.

Pathogenic role of cytokines in COVID-19, its association with contributing co-morbidities and possible therapeutic regimens.

The Covid-19, a threatening pandemic, was originated from China in December 2019 and spread quickly to all over the world. The pathogenesis of coronavirus is linked with the disproportionate response of the immune system. This involves the systemic inflammatory reaction which is characterized by marked pro-inflammatory cytokine release commonly known as cytokine release storm (CRS). The pro inflammatory cytokines are involved in cascade of pulmonary inflammation, hyper coagulation and thrombosis which may be lethal for the individual. That's why, it is very important to have understanding of pro inflammatory cytokines and their pathological role in SARS-CoV-2. The pathogenesis of Covid is not the same in every individual, it can vary due to the presence of pre-existing comorbidities like suffering from already an inflammatory disease such as rheumatoid arthritis (RA), inflammatory bowel disease (IBD), chronic obstructive pulmonary disease (COPD), an immune-compromised patients suffering from Diabetes Mellitus (DM) and Tuberculosis (TB) are more vulnerable morbidity and complications following COVID-19. This review is particularly related to COVID-19 patients having comorbidity of other inflammatory diseases. We have discussed the brief pathogenesis of COVID-19 and cytokines release storm with reference to other co-morbidities including RA, IBD, COPD, DM and TB. The available therapeutic regimens for COVID-19 including cytokine inhibitors, anti-viral, anti-biotic, bronchodilators, JAK- inhibitors, immunomodulators and anti-fibrotic agents have also been discussed briefly. Moreover, newly emerging medicines in the clinical trials have also been discussed which are found to be effective in treating Covid-19.

Uncovering the Anticancer Potential of Polydatin: A Mechanistic Insight.

Polydatin or 3-O-ß-d-resveratrol-glucopyranoside (PD), a stilbenoid component of Polygonum cuspicadum (Polygonaceae), has a variety of biological roles. In traditional Chinese medicine, P. cuspicadum extracts are used for the treatment of infections, inflammation, and cardiovascular disorders. Polydatin possesses a broad range of biological activities including antioxidant, anti-inflammatory, anticancer, and hepatoprotective, neuroprotective, and immunostimulatory effects. Currently, a major proportion of the population is victimized with cervical lung cancer, ovarian cancer and breast cancer. PD has been recognized as a potent anticancer agent. PD could effectively inhibit the migration and proliferation of ovarian cancer cells, as well as the expression of the PI3K protein. The malignancy of lung cancer cells was reduced after PD treatments via targeting caspase 3, arresting cancer cells at the S phase and inhibiting NLRP3 inflammasome by downregulation of the NF-κB pathway. This ceases cell cycle, inhibits VEGF, and counteracts ROS in breast cancer. It also prevents cervical cancer by regulating epithelial-to-mesenchymal transition (EMT), apoptosis, and the C-Myc gene. The objective of this review is thus to unveil the polydatin anticancer potential for the treatment of various tumors, as well as to examine the mechanisms of action of this compound.

Screening of Synthetic Isoxazolone Derivative Role in Alzheimer's Disease: Computational and Pharmacological Approach.

Alzheimer's disease (AD) is age-dependent neurological disorder with progressive loss of cognition and memory. This multifactorial disease is characterized by intracellular neurofibrillary tangles, beta amyloid plaques, neuroinflammation, and increased oxidative stress. The increased cellular manifestations of these markers play a critical role in neurodegeneration and pathogenesis of AD. Therefore, reducing neurodegeneration by decreasing one or more of these markers may provide a potential therapeutic roadmap for the treatment of AD. AD causes a devastating loss of cognition with no conclusive and effective treatment. Many synthetic compound containing isoxazolone nucleus have been reported as neuroprotective agents. The aim of this study was to explore the anti-Alzheimer's potential of a newly synthesized 3,4,5-trimethoxy isoxazolone derivative (TMI) that attenuated the beta amyloid (Aß1-42) and tau protein levels in streptozotocin (STZ) induced Alzheimer's disease mouse model. Molecular analysis revealed increased beta amyloid (Aß1-42) protein levels, increased tau protein levels, increased cellular oxidative stress and reduced antioxidant enzymes in STZ exposed mice brains. Furthermore, ELISA and PCR were used to validate the expression of Aß1-42. Pre-treatment with TMI significantly improved the memory and cognitive behavior along with ameliorated levels of Aß1-42 proteins. TMI treated mice further showed marked increase in GSH, CAT, SOD levels while decreased levels of acetylcholinesterase inhibitors (AChEI's) and MDA intermediate. The multidimensional nature of isoxazolone derivatives and its versatile affinity towards various targets highpoint its multistep targeting nature. These results indicated the neuroprotective potential of TMI which may be considered for the treatment of neurodegenerative disease specifically in AD.

Drotaverine Inhibitor of PDE4: Reverses the Streptozotocin Induced Alzheimer's Disease in Mice.

Alzheimer's disease (AD) is a progressive neurodegenerative disease associated with decline in memory and cognitive impairments. Phosphodiesterase IV (PDE4) protein, an intracellular cAMP levels regulator, when inhibited act as potent neuroprotective agents by virtue of ceasing the activity of Pro-inflammatory mediators. The complexity of AD etiology has ever since compelled the researchers to discover multifunctional compounds to combat the AD and neurodegeneration. The aim of this study was to probe into role of drotaverine a PDE4 inhibitor in the management of AD. Albino mice were divided into seven groups (n = 10). Group 1 control group received carboxy methyl cellulose (CMC 1 mL/kg), group II diseased group treated with streptozotocin (STZ 3 mg/kg) by intracerebroventricular (ICV) route, group III administered standard drug Piracetam 200 mg/kg and groups IV-VII were given drotaverine (10, 20, 40, and 80 mg/kg i/p respectively). Groups II-VII were given STZ (3 mg/kg, ICV) on 1st and 3rd day of treatment to induce AD. All the groups were given their respective treatments for 23 days. Improvement in learning and memory was evaluated by using behavioral tests like open field test, elevated plus maze test, Morris water maze test and passive avoidance test. Furthermore, brain levels of biochemical markers of oxidative stress, neurotransmitters, ß-amyloid and tau protein were also measured. Drotaverine showed statistically significant dose dependent improvement in behavioral and biochemical markers of AD: the maximum response was achieved at a dose level of 80 mg/kg. The Study concluded that drotaverine ameliorates cognitive impairment and as well as exhibited modulated the brain levels of neurotransmitters.

Neuroprotective potential of Malva neglecta is mediated via down-regulation of cholinesterase and modulation of oxidative stress markers.

Alzheimer's disease affects daily routine due to loss of memory and decline in cognition. In vitro data showed acetylcholine esterase inhibition activity of Malva neglecta but no in vivo evidence is available. The current study aims to investigate the anti-Alzheimer's activity of Malva neglecta methanolic extract in the AlCl3-induced Alzheimer disease rats' model. Thirty Wistar rats were divided into six groups and respective doses were given orally for 21 days. Behavioural observations were recorded and biochemical analysis was performed on brain homogenate. Improvement in memory and cognition was noted in treated rats as compared to disease control. A dose-dependent decrease (0.530 ± 0.009 at 200 mg/kg, 0.212 ± 0.007 at 400 mg/kg, 0.173 ± 0.005 at 600 mg/kg) in AChE activity was noted in the treatment groups with reference to disease control value (1.572 ± 0.013). This decrease in AChE activity is linked with an increase in acetylcholine in the brain which plays a key role in retaining memory. Oxidative stress biomarkers; GSH (66.77 ± 0.01 at 600 mg/kg), SOD (26.60 ± 0.10 at 600 mg/kg), CAT (21.46 ± 0.01 at 600 mg/kg) levels were increased with a decrease in MDA (103.33 ±0.49 at 600 mg/kg) level in a dose-dependently manner in the treatment groups as compared to disease control respective values. It is concluded that Malva neglecta could ameliorate Alzheimer's symptoms possibly by decreasing AChE activity and oxidative stress.

Antiparkinsonian activity of Cucurbita pepo seeds along with possible underlying mechanism.

Cucurbita pepo is used as a vegetable in Pakistan and its seeds are also rich in tocopherol. Data showed the pivotal role of tocopherol in the treatment of Parkinson's disease (PD). The current study was designed to probe into the antiparkinson activity of methanolic extract of C. pepo (MECP) seeds in the haloperidol-induced Parkinson rat model. Behavioral studies showed improvement in motor functions. The increase in catalase, superoxide dismutase, glutathione levels whereas the decreases in the malondialdehyde and nitrite levels were noted in a dose-dependent manner. Acetylcholine-esterase (AchE) activity was increased. Molecular docking results revealed significant binding interaction of selected phytoconstituents within an active site of target protein AchE (PDB ID: 4EY7). Furthermore, α-synuclein was up regulated with down regulation of TNF-α and IL-1ß in the qRT-PCR study. Subsequently, ADMET results on the basis of structure to activity predictions in terms of pharmacokinetics and toxicity estimations show that selected phytochemicals exhibited moderately acceptable properties. These properties add knowledge towards the structural features which could improve the bioavailability of selected phytochemicals before moving towards the initial phase of the drug development. Our integrated drug discovery scheme concluded that C. pepo seeds could ameliorate symptoms of PD and may prove a lead remedy for the treatment of PD.

Aloe vera and artemisia vulgaris hydrogels: exploring the toxic effects of structural transformation of the biocompatible materials.

OBJECTIVES: This study was aimed to evaluate the toxicity profile of hydrogels of plant-derived mucilage from Aloe vera and Artemisia vulgaris used for various drug delivery applications, yet no such toxicity study has been reported for the toxicity evaluation of 3 D structures. New Drug carriers should be harmless for drug delivery applications. METHODS: Acute and sub-acute (repeated dose) oral toxicity studies were conducted following OECD 407 and 425 guidelines. In vitro toxicity through hemolysis and MTT assay were checked against RBC's and human macrophages respectively. RESULTS: The hemolysis and MTT assay showed good compatibility of hydrogels with blood components. Mutagenicity testing showed no genotoxic effects of hydrogels. In vivo toxicity evaluation was done in female albino rats and rabbits. General behavior, adverse effects, clinical signs and symptoms, and mortality were recorded for 14 days post-treatment which showed no significant (p < 005) abnormality. Hematological and biochemical parameters including LFTs and RFTs appeared to be normal with slight variations in the treated groups. The normal architecture of kidney, liver, heart and intestine was evident upon histopathological analyses. CONCLUSION: Hence, the results suggested that the 3 D structure of Aloe vera and Artemisia vulgaris based hydrogels are safe upon ingestion and can be used for drug delivery science being cheap, natural and biocompatible.

A comparison of intravenous midazolam and diazepam in management of status epilepticus in children.

OBJECTIVE: To compare the efficacy of intravenous midazolam and diazepam in the management of status epilepticus seizures in children. METHODS: The comparative study was conducted in the paediatric neurological emergency unit of The Children's Hospital and the Institute of Child Health, Multan, Pakistan, from December 15, 2018, to May 14, 2019, and comprised paediatric patients of status epilepticus seizures which were divided into Diazepam and Midazolam groups. Data was analysed using Graph-Pad Prism 5. RESULTS: Of the 164 patients, 82(50%) were in each of the two groups. There was no significant difference between the groups in terms of weight, age, residence area of patients and mean duration of seizures (p>0.05). Status epilepticus seizures subsided after intravenous midazolam administration in 77(93.90%) cases, while success in the diazepam group 64(78.05%) (p<0.05). Mean time taken by midazolam to halt seizures was significantly shorter than diazepam (p<0.05) and less cases of treatment failure were observed with intravenous midazolam (p<0.05). Somnolence was observed after diazepam administration in 47(57.3%) cases (p=0.0001). CONCLUSION: Intravenous midazolam was found to be superior in efficacy than intravenous diazepam in controlling status epilepticus seizures.

Role of Oxidative Stress and Antioxidant Defense Biomarkers in Neurodegenerative Diseases.

Oxidative stress is caused by an imbalance in a redox system. It may involve either excessive production of reactive oxygen species or dysfunction of the antioxidant defense system. Unlike other viscera, the brain is especially highly susceptible to oxidative damage because of it requires a high oxygen level and contains an abundance of peroxida-tion-susceptible lipid cells. Oxidative stress is among the common etiological factors involved in neurodegeneration. To measure The extent of oxidative stress is measured with several indicators or biomarkers that are known to arise from oxidation of major biomolecules, including lipids, proteins, carbohydrates, and nucleic acids. In this review, we will discuss oxidative stress biomarkers associated with neurodegenerative diseases, for instance, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease. We will also highlight the biomarkers of antioxidant defense mechanisms that are impaired in these diseases.

Exploring the Therapeutic Potentials of Highly Selective Oxygenated Chalcone Based MAO-B Inhibitors in a Haloperidol-Induced Murine Model of Parkinson's Disease.

Parkinson's disease (PD) is a neurodegenerative disorder of dopaminergic, noradrenergic, and serotonergic systems, in which dopamine, noradrenaline, and serotonin levels are depleted and lead to the development of motor and non-motor symptoms such as tremor, bradykinesia, weight changes, fatigue, depression, and visual hallucinations. Therapeutic strategies place much focus on dopamine replacement and the inhibition of dopamine metabolism. The present study was based on the known abilities of chalcones to act as molecular scaffolds that selectively inhibit MAO-B with the added advantage of binding reversibly. Recently, we synthesized a series of 26 chalcone compounds, amongst which (2E)-1-(2H-1,3-benzodioxol-5-yl)-3-(4-fluorophenyl)prop-2-en-1-one (O10) and (2E)-1-(2,3-dihydro-1,4-benzodioxin-6-yl)-3-(4-fluorophenyl)prop-2-en-1-one (O23) most inhibited MAO-B. Hence, the present study was performed to explore the molecular mechanisms responsible for the neuroprotective effect of O10 and O23 at varying doses such as 10, 20, and 30 mg/kg each in a haloperidol-induced murine model of PD. Both compounds were effective (though O23 was the more effective) at ameliorating extrapyramidal and non-motor symptoms in the model and improved locomotory and exploratory behaviors, reduced oxidative stress markers, and enhanced antioxidant marker and neurotransmitter levels. Furthermore, histopathological studies showed O10 and O23 both reduced neurofibrillary tangles and plaques to almost normal control levels.