Efficacy assessment of novel methanimine derivatives in chronic constriction injury-induced neuropathic model: An in-vivo, ex-vivo and In-Silico approach.

The multicomponent etiology, complex clinical implications, dose-based side effect and degree of pain mitigation associated with the current pharmacological therapy is incapable in complete resolution of chronic neuropathic pain patients which necessitates the perpetual requirement of novel medication therapy. Therefore, this study explored the ameliorative aptitude of two novel methanimine imitative like (E)-N-(4-nitrobenzylidene)-4­chloro-2-iodobenzamine (KB 09) and (E)-N-(4-methylbenzylidene)-4­chloro-2-iodobenzamine (KB 10) in chronic constriction injury (CCI) of sciatic nerve induced neuropathic pain in rat model. Standard behavioral tests like dynamic and static allodynia, cold, thermal and mechanical hyperalgesia along with rotarod activity were performed at various experimental days like 0, 3, 7, 14 and 21. Enzyme linked immunosorbent assay (ELISA) on spinal tissue and antioxidant assays on sciatic nerve were executed accompanied by molecular docking and simulation studies. Prolonged ligation of sciatic nerve expressively induced hyperalgesia as well as allodynia in rats. KB 09 and KB 10 substantially attenuated the CCI elicited hyperalgesia and allodynia. They significantly reduced the biomarkers of pain and inflammation like Interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) in ELISA and while enhanced the GSH, SOD and CAT and diminished the MDA levels during antioxidant assays. KB 09 displayed -9.62 kcal/mol with TNF-α and -7.68 kcal/mol binding energy with IL-6 whereas KB 10 exhibited binding energy of -8.20 kcal/mol with IL-6 while -11.68 kcal/mol with TNF-α and hence both trial compounds ensured stable interaction with IL-6 and TNF-α during computational analysis. The results advocated that both methanimine derivatives might be novel candidates for attenuation of CCI-induced neuropathic pain prospects via anti-nociceptive, anti-inflammatory and antioxidant mechanisms.

In vivo effects of a selected thiourea derivative 1-(2-chlorobenzoyl)-3-(2,3-dichlorophenyl) against nociception, inflammation and gastric ulcerogenicity: Biochemical, histopathological and in silico approaches.

The current study was designed to investigate the potential of a synthetic therapeutic agent for better management of pain and inflammation, exhibiting minimal to non-existent ulcerogenic effects. The effect of 1-(2-chlorobenzoyl)-3-(2,3-dichlorophenyl) thiourea was assessed through model systems of nociception and anti-inflammatory activities in mice. In addition, the ulcerogenic potential was evaluated in rats using the NSAID-induced pyloric ligation model, followed by histopathological and biochemical analysis. The test was conducted on eight groups of albino rats, comprising of group I (normal saline), groups II and III (aspirin® at doses of 100 mg/kg and 150 mg/kg, respectively), groups IV and V (indomethacin at doses of 100 mg/kg and 150 mg/kg, respectively), and groups VI, VII, and VIII (lead-compound at 15 mg/kg, 30 mg/kg and 45 mg/kg doses, respectively). Furthermore, molecular docking analyses were performed to predict potential molecular target site interactions. The results showed that the lead-compound, administered at doses of 15, 30, and 45 mg/kg, yielded significant reductions in chemically and thermally induced nociceptive pain, aligning with the levels observed for aspirin® and tramadol. The compound also effectively suppressed inflammatory response in the carrageenan-induced paw edema model. As for the ulcerogenic effects, the compound groups displayed no considerable alterations compared to the aspirin® and indomethacin groups, which displayed substantial increases in ulcer scores, total acidity, free acidity, and gastric juice volume, and a decrease in gastric juice pH. In conclusion, these findings suggest that our test compound exhibits potent antinociceptive, anti-inflammatory properties and is devoid of ulcerogenic effects.

Phytochemical analysis, radical scavenging and glioblastoma U87 cells toxicity studies of stem bark of buckthorn (Rhamnus pentapomica R. Parker).

BACKGROUND: During the past two decades, the correlation between oxidative stress and a variety of serious illnesses such as atherosclerosis, chronic obstructive pulmonary disease (COPD), Alzheimer disease (AD) and cancer has been established. Medicinal plants and their derived phytochemicals have proven efficacy against free radicals and their associated diseases. The current work was aimed to evaluate the phytochemical constituents of Rhamnus pentapomica R. Parker via Gas Chromatography-Mass Spectrometry (GC-MS) and its antioxidant and anti-glioblastoma potentials. METHODS: The bioactive compounds were analysed in Rhamnus pentapomica R. Parker stem bark extracts by GC-MS analysis, and to evaluate their antioxidant and anti-glioblastoma effects following standard procedures. The stem bark was extracted with 80% methanol for 14 days to get crude methanolic extract (Rp.Cme) followed by polarity directed fractionation using solvents including ethyl acetate, chloroform, butanol to get ethyl acetate fraction (Rp.EtAc), chloroform fraction (Rp.Chf) and butanol fraction (Rp.Bt) respectively. Antioxidant assay was performed using DPPH free radicals and cell viability assay against U87 glioblastoma cancer cell lines was performed via MTT assay. RESULTS: In GC-MS analysis, thirty-one compounds were detected in Rp.Cme, 22 in Rp.Chf, 24 in Rp.EtAc and 18 compounds were detected in Rp.Bt. Among the identified compounds in Rp.Cme, 9-Octadecenoic acid (Z)-methyl ester (7.73%), Octasiloxane (5.13%) and Heptasiloxane (5.13%), Hexadecanoic acid, methyl ester (3.76%) and Pentadecanoic acid, 14-methyl-, methyl Ester (3.76%) were highly abundant.. In Rp.Chf, Benzene, 1,3-dimethyl- (3.24%) and in Rp.EtAc Benzene, 1,3-dimethyl-(11.29%) were highly abundant compounds. Antioxidant studies revealed that Rp.Cme and Rp.EtAc exhibit considerable antioxidant potentials with IC50 values of 153.53 µg/ml and 169.62 µg/ml respectively. Both fractions were also highly effective against glioblastoma cells with IC50 of 147.64 µg/ml and 76.41ug/ml respectively. CONCLUSION: Phytochemical analysis revealed the presence of important metabolites which might be active against free radicals and glioblastoma cells. Various samples of the plant exhibited considerable antioxidant and anti-glioblastoma potentials warranting further detailed studies.

2-Hydroxybenzohydrazide as a novel potential candidate against nociception, inflammation, and pyrexia: in vitro, in vivo, and computational approaches.

The current study was designed to evaluate the 2-hydroxybenzohydrazide (HBH) as a drug having efficacy against pyrexia, inflammation, and nociception. Besides, the therapeutic effects of HBH on oxidative stress and C-reactive proteins were also evaluated. The pharmacological studies on HBH (20-60 mg/kg) were conducted using nociception, inflammation, and pyrexia standard models. Naloxone antagonism was performed to assess the possible involvement of opioidergic mechanisms. The antioxidant study was conducted on ABTS and DPPH assays using gallic acid as a standard. Moreover, the binding capability of HBH with enzymes cyclooxygenase-I/II (COX-I/II) was determined using molecular modeling analysis. The findings indicated that the HBH dose-dependently inhibited pain, inflammation, and pyrexia. The HBH has significant anti-nociceptive and anti-inflammatory activities at 60 mg/kg (***p < 0.001), similar to the lower doses of diclofenac sodium (50 mg/kg) and tramadol (30 mg/kg). The HBH at 60 mg/kg reduced pyrexia as paracetamol (150 mg/kg). The HBH at 20-60 mg/kg doses declined the plasma C-reactive protein concentration. The mechanistic studies showed that the anti-nociceptive effect of HBH was antagonized by naloxone, indicating that the opioidergic mechanisms are involved. Furthermore, computational studies showed that the HBH exhibited an affinity for COX-I/II target receptors. The HBH significantly inhibited ABTS and DPPH radicals (IC50 = 33.81 and 26.74 µg/ml). These results proposed that the HBH has significant antipyretic, anti-inflammatory, and anti-nociceptive activities involving opioidergic mechanism.

Neuroprotective evaluation of diospyrin against drug-induced Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disease linked to memory impairment. A current investigation was performed to assess the neuroprotective effect of Diospyrin, a novel therapeutic agent, for the curing of Alzheimer's disease. For this purpose, in-vitro acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory assays and antioxidant studies were conducted, whereas in-vivo studies involved different behavioral animal models tests such as elevated plus maze (EPM), morris water maze (MWM) and paddling Y-maze test. Results of the in-vitro analysis showed IC50 values of 95 µg/mL for AChE and 110 µg/mL for BChE as compared to the standard drug donepezil (IC50: 95 & 85 µg/mL, respectively). DPPH antioxidant assay showed a maximum of 72.85% inhibition (IC50: 139.74 µg/mL) of DPPH-free radicals at the highest concentration of 1000 µg/mL as compared to the ascorbic acid (IC50: 13.72 µg/mL). Moreover, the in-vivo analysis revealed that diospyrin treatment demonstrated gradual betterment in memory and enhanced motor functionality. On the other hand, the computational analysis also showed that the diospyrin had exceptional binding affinities for both AChE and BChE enzymes. In the net shell, it may be deduced that our compound diospyrin could be a valuable drug candidate in managing neurodegenerative disorders like AD.

Diosgenin normalization of disrupted behavioral and central neurochemical activity after single prolonged stress.

Introduction: Post-traumatic stress disorder (PTSD) is a chronic mental illness triggered by traumatic experiences such as wars, natural disasters, or catastrophes, and it is characterized by anxiety, depression and cognitive impairment. Diosgenin is a steroidal sapogenin with known neuroprotective and antioxidant properties. This study aimed to assess the pharmacological potential of diosgenin in a single prolonged stress (SPS) model of PTSD, plus other behavioral models along with any consequent alterations in brain neurochemistry in male mice. Methodology: SPS was induced by restraining animals for 2 h, followed by 20 min of forced swim, recuperation for 15 min, and finally, exposure to ether to induce anesthesia. The SPS-exposed animals were treated with diosgenin (20, 40, and 60 mg/kg) and compared with the positive controls, fluoxetine or donepezil, then they were observed for any changes in anxiety/depression-like behaviors, and cognitive impairment. After behavioral screening, postmortem serotonin, noradrenaline, dopamine, vitamin C, adenosine and its metabolites inosine and hypoxanthine were quantified in the frontal cortex, hippocampus, and striatum by high-performance liquid chromatography. Additionally, animal serum was screened for changes in corticosterone levels. Results: The results showed that diosgenin reversed anxiety- and depression-like behaviors, and ameliorated cognitive impairment in a dose-dependent manner. Additionally, diosgenin restored monoamine and vitamin C levels dose-dependently and modulated adenosine and its metabolites in the brain regions. Diosgenin also reinstated otherwise increased serum corticosterone levels in SPS mice. Conclusion: The findings suggest that diosgenin may be a potential candidate for improving symptoms of PTSD.

Involvement of the Opioidergic Mechanism in the Analgesic Potential of a Novel Indazolone Derivative: Efficacy in the Management of Pain, Neuropathy, and Inflammation Using In Vivo and In Silico Approaches.

Indazolones possess interesting pharmacological activities. The search for indazole and indazolone-containing nuclei as drugs is an important research area of medicinal chemistry. The current work aims to evaluate a novel indazolone derivative against in vivo and in silico targets of pain, neuropathy, and inflammation. An indazolone derivative (ID) was synthesized and characterized using advanced spectroscopic techniques. Well-established animal models of abdominal constriction, hot plate, tail immersion, carrageenan paw edema, and Brewer's yeast-induced pyrexia were employed for evaluating the potential of the ID at different doses (20-60 mg kg-1). Nonselective GABA antagonists, opioid antagonist naloxone (NLX) and pentylenetetrazole (PTZ), were employed to assess the potential role of GABAergic and opioidergic processes. The antineuropathic potential of the drug was evaluated using a vincristine-induced neuropathic pain model. In silico studies were performed to assess any possible interactions of the ID with pain target sites like cyclooxygenases (COX-I/II), GABAA, and opioid receptors. This study revealed that the selected ID (doses of 20-60 mg kg-1) efficiently hampered chemically and thermally induced nociceptive responses, producing significant anti-inflammatory and antipyretic effects. These effects produced by the ID were dose-dependent (i.e., 20-60 mg kg-1 and p range of 0.001-0.01) and significant in comparison to standards (p < 0.001). Antagonistic studies with NLX (1.0 mg kg-1) and PTZ (15.0 mg kg-1) revealed the involvement of the opioidergic mechanism rather than the GABAergic mechanism. The ID showed promising anti-static allodynia effects as well. In silico studies revealed preferential binding interactions of the ID with cyclooxygenases (COX-I/II), GABAA, and opioid receptors. According to the results of the current investigation, the ID may serve in the future as a therapeutic agent for the treatment of pyrexia, chemotherapy-induced neuropathic pain, and nociceptive inflammatory pain.

Effect of Gabapentin-Fluoxetine Derivative GBP1F in a Murine Model of Depression, Anxiety and Cognition.

Background and Objective: Gabapentin is a commonly prescribed antiepileptic agent for seizures, which is also used for pain and addiction management. Due to growing evidence of its abuse liability, there has been an incentive to synthesise potentially useful gabapentin derivatives devoid of adverse effects. A gabapentin adduct with a fluoxetine moiety, GBP1F, was assessed for any sedative, cognitive, anxiolytic, or antidepressant-like actions in murine behavioral models. Materials and Methods: Selected groups of mice were used for each behavioral paradigm, and the effect of GBP1F (5, 10, and 15 mg/kg) was assessed using spontaneous locomotor activity, the tail suspension test, elevated plus maze test, and the Y maze test models. Immediately following behavioral experiments, postmortem striatal and hippocampal tissues were evaluated for the effect of GBP1F on concentrations of dopamine, DOPAC, HVA, serotonin, 5-HIAA, vitamin C, and noradrenaline using high performance liquid chromatography with electrochemical detection. Results: GBP1F induced a mild suppression of locomotor activity, ameliorated anxiety and depression-like behavior, did not alter cognitive behavior, and raised serotonin and 5-HIAA concentrations in the hippocampus and striatum. GBP1F also positively enhanced dopamine and vitamin C tissue levels in the striatum. Thus, GBP1F represents a compound with anxiolytic- and antidepressant-like effects though further studies are warranted at the molecular level to focus on the precise mechanism(s) of action.

Thiadiazine-thione derivatives ameliorate STZ-induced diabetic neuropathy by regulating insulin and neuroinflammatory signaling.

Diabetes Mellitus is accompanied by chronic hyperglycemia, inflammation, and related molecular processes, which leads to diabetic neuropathy. In this work, we tested Thiadiazine-thione (TDT) synthetic derivatives TDT1 and TDT2 against streptozotocin (STZ)-induced diabetic neuropathy. Sprague Dawley's rats, SH-SY5Y neuronal and BV2 microglial cells were employed in this work, followed by behavioral, biochemical, and morphological studies utilizing RT-qPCR, ELISA, Immunoblotting, immunohistochemistry, Immunofluorescence, and in silico analyses. TDT1 and TDT2 abolished STZ-induced allodynia and hyperalgesia. Next, we examined IRS1/PI3K/AKT signaling to assess TDT1 and TDT2's impact on diabetic neuropathy. STZ downregulated IRS1, PI3K, AKT mRNA and protein expression in rat spinal cord and SH-SY5Y neuronal cells. TDT1 and TDT2 improved IRS1, PI3k, and AKT mRNA and protein expression. STZ elevated GSK3ß mRNA and protein expression in vivo and in vitro, whereas TDT1 and TDT2 mitigated it. STZ increased the expression of inflammatory mediators such as p-NF-κB, TNF-α, and COX-2 in rat spinal cord lysates. TDT1 and TDT2 co-treatment with STZ decreased inflammatory cytokine expression by ameliorating astrocytosis (revealed by increased GFAP) and microgliosis (indicated by increased Iba1). TDT1 and TDT2 reduced STZ-induced JNK, Iba1, and COX-2 upregulation in BV2 microglial cells validating our in vivo findings. In silico molecular docking and MD simulations analyses suggested that TDT1 and TDT2 have IRS binding affinity, however, both compounds had an identical binding affinity, but distinct interaction pattern with IRS protein residues. Overall, these findings demonstrate that TDT derivatives mitigated STZ-induced neuropathy through modulating the insulin and inflammatory signaling pathways.

Viral metatranscriptomic approach to study the diversity of virus(es) associated with Common Bean (Phaseolus vulgaris L.) in the North-Western Himalayan region of India.

Plant viruses are a major threat to legume production worldwide. In recent years, new virus strains have emerged with increasing frequencies in various legume cropping systems, which demands the development of cutting-edge virus surveillance techniques. In this study, we surveyed the common bean fields of Kashmir valley for virus infection using a total of 140 symptomatic and non-symptomatic leaf samples collected from different locations. The genetic diversity of viruses was examined by high-throughput sequencing (HTS) with three viruses being identified, namely, Bean Common Mosaic Virus (BCMV), Bean Common Mosaic Necrosis Virus (BCMNV), and Clover Yellow Vein Virus (ClYVV). BCMNV and ClYVV are new reports from India. De novo assembly of transcriptome constructed near-complete genomes of these viruses. RT-PCR results confirmed the presence of these viruses with an emerge incidence of 56. 4% for BCMV, 27.1% for BCMNV and 16.4 for ClYVV in the valley. Several samples were found to contain multiple virus infections with BCMV being the most predominant. Recombination events were detected in the genomes of BCMV and ClYVV, but not BCMNV. Phylogenetic and pairwise identity matrix evidence suggests viral import from multiple countries. Our results demonstrate that HTS followed by multiplex PCR assay is a simple, rapid, and reliable approach for simultaneous diagnosis of plant viruses.

Efficacy of 2-Hydroxyflavanone in Rodent Models of Pain and Inflammation: Involvement of Opioidergic and GABAergic Anti-Nociceptive Mechanisms.

The current work examined the pharmacological potential of a selected flavanone derivative 2-hydroxyflavanone as a promising remedy for the treatment and management of pain. The selected flavanone derivative (2-HF) was evaluated for its analgesic and anti-inflammatory potentials following standard pharmacological protocols including hot plate, acetic acid-induced writhing and tail immersion tests. Naloxone and pentylenetetrazol were used to evaluate the potential implication of GABAergic and opioidergic mechanisms. The anti-inflammatory potential of 2-HF was confirmed using carrageenan-, serotonin- and histamine-induced paw edema models as well as a xylene-induced ear edema model. Furthermore, the anti-neuropathic potential of 2-HF was tested using a cisplatin-induced neuropathic pain model. Our sample, at the tested concentrations of 15, 30 and 45 mg kg-1, showed considerable analgesic, anti-inflammatory effects, as well as efficacy against neuropathic pain. Naloxone and pentylenetetrazol at 1 and 15 mg kg-1 antagonized the anti-nociceptive activities of 2-hydroxyflavanone indicating the involvement of opioidergic and GABAergic mechanisms. In the static allodynia model, combination of gabapentin 75 mg kg-1 with 2-HF at 15, 30, 45 mg kg-1 doses exhibited considerable efficacy. In cold allodynia, 2-hydroxyflavanone, at doses of 15, 30 and 45 mg kg-1 and in combination with gabapentin (75 mg kg-1), demonstrated prominent anti-allodynic effects. The paw withdrawal latency was considerably increased in gabapentin + cisplatin treated groups. Moreover, cisplatin + 2-hydroxyflavanone 15, 30, 45 mg kg-1 showed increases in paw withdrawal latency. Likewise, considerable efficacy was observed for 2-hydroxyflavanone in thermal hyperalgesia and dynamic allodynia models. Our findings suggest that 2-hydroxyflavanone is a potential remedy for pain syndrome, possibly mediated through opioidergic and GABAergic mechanisms.

Mechanistic efficacy assessment of selected novel methanimine derivatives against vincristine induced Neuropathy: In-vivo, Ex-vivo and In-silico correlates.

Vincristine induced peripheral neuropathy (VIPN) is a serious untoward side effect suffered by cancer patients, which still lacks an adequate therapeutic approach. This study examined the alleviating potential of novel methanimine derivatives i.e. (E)-N-(4-nitrobenzylidene)-4-chloro-2-iodobenzamine (KB 9) and (E)-N-(2-methylbenzylidene)-4-chloro-2-iodobenzamine (KB 10) in VIPN. Vincristine was injected in BALB/c mice for 10 days to instigate nociceptive neuropathy. Dynamic and static allodynia, thermal (hot and cold) hyperalgesia were evaluated at 0, 5, 10 and 14 days using cotton brush, Von Frey filament application, hot plate test, acetone drop and cold water respectively. Tumour necrosis factor alpha (TNF-α), interleukin-1ß (IL-1ß), lipid peroxide (LPO), glutathione-S-transferase (GST), catalase (CAT), superoxide dismutase (SOD) and reactive oxygen species (ROS) assays were performed to assess the efficacy of KB9 and KB10 against neuroinflammation and oxidative stress utilizing ELISA, immunohistochemistry and western blot analysis in brain and sciatic nerve tissues. Computational studies were executed to determine the stable binding conformation of both compounds with respect to COX-2 and NF-κB. Interestingly, both compounds substantially reduced protein expression related to neuroinflammation, oxidative stress (LPO, GST, SOD, CAT) and pain (NF-κB, COX-2, IL-1ß and TNF-α). This molecular analysis suggested that the neuroprotective effect of KB9 and KB10 was mediated via regulation of inflammatory signaling pathways. Overall, this study demonstrated that KB9 and KB10 ameliorated vincristine induced neuropathy, through anti-inflammatory, anti-nociceptive and antioxidant mechanisms.

The Neuroprotective Propensity of Organic Extracts of Acacia stenophylla Bark and Their Effectiveness Against Scopolamine-/Diazepam-Induced Amnesia in Mice.

Background: Alzheimer's disease (AD) is a neurodegenerative disorder that is more prevalent in the elderly. There is extensive literature on using Acacia species against central nervous system disorders, although Acacia stenophylla has not been investigated for any neuroprotective potential. The purpose of the study was to elucidate the ameliorative effect of ethyl acetate (ASEE) and butanol (ASB) extracts from the bark of A. stenophylla on memory deficits and cognitive dysfunction in scopolamine- or diazepam-induced amnesia in mice. Methods: The phytochemical constituents of the extracts of A. stenophylla were determined by GC-MS and the in vitro anticholinesterase plus antioxidant activities were also evaluated. Anti-amnesic effects were determined employing the open field test, elevated plus maze (EPM), Morris water maze (MWM), and Y-maze paradigms. Results: The in vitro cholinesterase assays disclosed a concentration-dependent inhibition of both AChE and BuChE with IC50 values of 28.48 and 44.86 µg/mL for the ASEE extract and 32.04 and 50.26 µg/mL for the ASB extract against AChE and BuChE respectively. DPPH and H2O2 antioxidant assays revealed respective IC50 values for the ASEE extract of 28.04 and 59.84 µg/mL, plus 32.77 and 64.65 µg/mL for ASB extract. The findings revealed that both extracts possessed substantial antioxidant properties. Furthermore, these fractions restored scopolamine- and diazepam-induced memory deficits in a dose-dependent manner, as observed by a significant decrease in the transfer latency in EPM, reduction in escape latency, added time spent in the target quadrant in the MWM, and elevated spontaneous alternation behavior (SAB) in the Y-maze test. Conclusion: The ameliorative effect of A. stenophylla on scopolamine- and diazepam-induced amnesia can be attributed to antioxidant and anticholinesterase activity. Consequently, the use of A. stenophylla might be exploited in the alleviation of oxidative stress and the management of AD.

Tannic acid inhibits lipopolysaccharide-induced cognitive impairment in adult mice by targeting multiple pathological features.

Tannic acid (TA) is a natural compound present abundantly in fruit such as grapes and green tea. In this study, we have evaluated the therapeutic efficacy of TA against Lipopolysaccharide (LPS)-induced oxidative stress-mediated memory impairment, neuroinflammation, insulin signaling impairment, and Amyloid Beta (Aß) deposition in adult male mice. The LPS was administered once per week and TA twice a week to adult male mice for three months consecutively. Behavioral studies were performed using different behavioral models such as balance beam, novel object recognition (NOR), Morris water maze (MWM), and Y-maze tests. The protein expression of different mediators such as TNF-α, p-JNK, pIRS636, BACE1, APP, and Aß was evaluated through western blot and immunofluorescence staining techniques. Biochemical assays were carried out to assess the antioxidant activities of TA. The computational study was conducted to predict the binding mode of TA with target sites of TNF-α. Behavioral studies showed that the TA-treated mice exhibited gradual memory improvement. TA significantly inhibited BACE1 activity and reduced production and accumulation of Aß in the hippocampus of mice brains. Moreover, the TA significantly inhibited LPS-induced ROS production and enhanced the glutathione levels. Furthermore, we have shown via the computational method for the first time that TA inhibits LPS-triggered TNF-á½° and its downstream signaling to reduce AD pathology including memory impairment, neuroinflammation, insulin signaling impairment, and Aß deposition in adult mice. Taken together our current study demonstrates that TA is a potential candidate for the abrogation of LPS-induced neurotoxicity and AD pathology in rodent's models.

Coagulansin-A improves spatial memory in 5xFAD Tg mice by targeting Nrf-2/NF-κB and Bcl-2 pathway.

The present study was designed to investigate the underlying molecular signaling of Coagulansin-A (Coag-A) as a therapeutic agent against Alzheimer's disease (AD). Preliminarily, it exhibited a neuroprotective effect against H2O2-induced oxidative stress in HT-22 cells. The in vivo studies were performed by administering Coag-A (0.1, 1, and 10 mg/kg) intraperitoneally to 5xFAD transgenic (Tg) mouse model. Coag-A (10 mg/kg) significantly attenuated the cognitive decline compared to Tg mice group in the shallow water maze (SWM) and Y-maze test paradigms. The anti-aggregation potential of Coag-A was determined by performing Fourier transform-infrared (FT-IR) spectroscopy and differential scanning calorimeter (DSC) analysis in the prefrontal cortex (PFC) and hippocampal (HC) regions of mice brain. The FT-IR spectra demonstrated the inhibition of amyloid beta (Aß) through a decrease in ß-sheet aggregation, along with the inhibition of changes in the lipids, proteins, and phospholipids. The DSC analysis displayed a low-temperature exotherm associated with the reversible process of aggregation of soluble protein fractions prior to denaturation. Furthermore, Coag-A treatment displayed a regular density of granule cells in H&E stained sections, along with a reduced amyloid load and PAS-positive granules in all the regions of interest in mice brain. The real-time polymerase chain reaction (q-PCR), western blot and immunohistochemical (IHC) analysis demonstrated antioxidant, anti-inflammatory, and anti-apoptotic effect of Coag-A by enhancing the expression of nuclear factor erythroid-2-related factor (Nrf-2) and reducing nuclear factor kappa B (NF-κB) and Bax protein expression. In addition, Coag-A significantly increased the antioxidant enzymes and proteins level, along with a reduced pro-inflammatory cytokines production.

Analagesic and Anti-Inflammatory Potentials of a Less Ulcerogenic Thiadiazinethione Derivative in Animal Models: Biochemical and Histochemical Correlates.

Purpose: Gastric ulcer induced by NSAIDs is the major medical concern and researchers are utilizing several approaches to combat this medical issue. In the current study, we investigated the efficacy of thiadiazinethione derivative (2,2'(2-thioxo-1,3,5-thiadiazinane-3,5-diyl) diacetic acid, as new less ulcerogenic compound. Methods: 2,2'(2-thioxo-1,3,5-thiadiazinane-3,5-diyl) diacetic acid was evaluated using standard animal models including hot plate, writhing test and formalin induced nociceptive models. Anti-inflammatory activity was assessed via carrageenan-induced paw oedema model. Involvement of opioidergic nociceptive mechanism was confirmed via naloxone administration in hot plat assay. The gastro-ulcerogenic potential of test and standard compounds were evaluated via NSAID-induced pyloric ligation model followed by standard histopathological and biochemical analysis. Results: In acetic acid-induced writhing test, our compound significantly reduced abdominal constrictions at the tested doses of 15 (p < 0.05), 30 (p < 0.01) and 45 mg kg-1 (p < 0.001) as compared to control (p < 0.001). In hot plate test, after 30 min of administration, our test compound showed significant anti-nociceptive potential (p < 0.05 at 15 and 30 mg kg-1 and p < 0.01 at 45 mg kg-1) and tramadol (p ˂ 0.001) at 30 mg kg-1 dose. After 60 min tramadol (30 kg-1) and test sample (30, 45 mg kg-1) exhibited significant anti-nociceptive activity p < 0.001. In Formalin-induced nociceptive response, a significant decline (p ˂ 0.001) was observed for aspirin and test compound during acute and chronic phases. Decline in the anti-nociceptive potential of tramadol and test sample via administration of naloxone indicate the involvement of opioidergic mechanism. Our compound exhibited significant anti-inflammatory activity in second phase of carrageenan induced paw oedema model. Histological and biochemical parameters exhibited less ulcerogenic potential as compared to aspirin. Conclusion: Our findings suggests that our test compound has desirable anti-nociceptive and anti-inflammatory potentials with less propensity to cause gastric ulcer.

Cassia artemisiodes attenuates nociceptive and diabetes-induced neuropathic pain modalities apropos antioxidant and anti-inflammatory mechanisms.

Cassia plants have a considerable position in conventional systems of medicine. The possible anti-nociceptive, anti-inflammatory, and anti-neuropathic properties of Cassia artemisiodes (CAD) extract were tested using the standard animal models. In this study, in vitro antioxidant, cyclooxygenase (COX-1 and 2), and 5-lipoxygenase (5-LOX) inhibitory assays were performed. The anti-inflammatory activity was evaluated using carrageenan, histamine, and serotonin-induced paw edema models. Antipyretic activity, thermally and chemically-induced nociception, and naloxone antagonistic activities were carried out. The CAD extract was tested for anti-neuropathic activity in the streptozotocin-induced diabetic neuropathy model. Suppressing the effect of CAD extract on the mRNA level of inducible nitric oxide synthase (iNOS), COX-2, and pro-inflammatory cytokines (TNF-α, IL-1ß, IL-6) was determined by performing RT-PCR. The CAD extract inhibited COX-2 and 5-LOX enzymes, paw inflammation, and reduced nociceptive behaviors. The mRNA gene expression of iNOS, COX-2, and inflammatory cytokines was reduced significantly with increased DPPH scavenging activity. The extract significantly reduced the diabetes-induced neuropathic pain. In a nutshell, these results recommended that the CAD extract has anti-nociceptive and anti-neuropathic activities due to inhibition of inflammatory and oxidative signaling.

The 7-Hydroxyflavone attenuates chemotherapy-induced neuropathic pain by targeting inflammatory pathway.

Vincristine and paclitaxel are widely used chemotherapeutic drugs for the treatment of brain tumors, breast cancer, leukemia, lymphomas, and malignant solid tumors. Though, these drugs are associated with some severe adverse effects including peripheral neuropathic pain. The anti-nociceptive and anti-inflammatory properties of the 7-Hydroxyflavone (7HF) were evaluated in the mice using thermally- and chemically-induced nociception, naloxone antagonistic test, and carrageenan-induced paw edema models. Initially, the in-vitro cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX) inhibitory assays were carried out. Peripheral neuropathic pain was induced in the Sprague Dawley (SD) rats by administration of paclitaxel (4 mg/kg) and vincristine (200 µg/kg) on days 1, 3, 5, 7, and 9, respectively. The protective effect of 7HF was assessed against the chemotherapy-induced peripheral neuropathy in the rats. Moreover, the expression of the inflammatory mediators in the spinal cord was investigated through RT-PCR. In addition, a computational study was performed to find the potential therapeutic targets and the binding mechanism of 7HF. The 7HF caused concentration-dependent inhibition of COX-2 and 5-LOX, it attenuated the nociceptive pain, carrageenan-induced paw edema, and the development of mechanical and cold allodynia, and hyperalgesia dose-dependently without causing motor coordination deficit. Likewise, the 7HF decreased the vincristine-induced increased expression of different inflammatory mediators including COX-2, tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-1ß (IL-1ß), and nuclear factor-kappa B (NF-κB). The computational study showed the effective interactions of 7HF with the binding sites of NF-κB, COX-2, and 5-LOX, exert its inhibitory activities. These findings reveal that the 7HF has anti-nociceptive, anti-inflammatory, and anti-neuropathic potentials.

Distribution and molecular characterization of potato virus Y (PVY) strains infecting potato (Solanum tuberosum) crop in Kashmir (India).

For breeding resistant cultivars, understanding the nature and distribution of PVY strains is indispensable. In present study, during the course of survey two hundred potato samples showing symptoms of vein clearing, mosaic, stunting, mottling, curling and vein banding were collected from 4 major potato growing districts of Kashmir valley. The disease incidence ranged from 16 to 27.33% with maximum in district Srinagar (27.33%). All the samples were serologically tested for PVY infection using DAS-ELISA and 74 tested positive for PVY infection. Out of 74 positive samples forty samples were re-confirmed by RT-PCR by amplifying 900 bp using coat protein (CP) gene specific primers. The PCR-positive samples were further characterized into different strains using strain specific primers. The strains NTN, N and O were reported and among them NTN strain was found to be most prevalent throughout the valley. The phylogenetic analysis of selected isolates carried out with known PVY strains also confirmed that the isolates belong to the N, NTN and O strains of PVY. The study will help in developing point of care strain specific diagnostics and also in devising the strategy for developing PVY resistant varieties, because when we have the complete information about the virus and its strains it will help us in screening the germplasm against each strain and, therefore, eventually development of a multi-strain resistant variety. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13337-021-00722-2.