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Chlorpyrifos (CPF), methyl parathion (MPT), and malathion (MLT) are among the most extensively used organophosphate (OP) pesticides in India. DNA protein cross-links (DPC) and DNA strand breaks are toxic lesions associated with the mechanism(s) of toxicity of carcinogenic compounds. In the present study, we examined the hypothesis that individual and interactive genotoxic effects of CPF, MPT, and MLT are involved in the formation of DPC and DNA strand break. The DNA strand break was measured by comet assay and expressed as DNA damage index, while DPC estimation was carried out by fluorescence emission assay. The results showed that exposure of rat lymphocytes with CPF, MPT, and MLT caused significantly marked increase in DNA damage and DPC formation in time-dependent manner. MPT caused the highest damage, and these pesticides do not potentiate the toxicity of each other. [ABSTRACT FROM AUTHOR]

Summary 1. Centella asiatica , an Indian medicinal plant, has been described as possessing central nervous system activity, such as improving intelligence. In addition, we have demonstrated that C. asiatica has cognitive-enhancing and anti-oxidant properties in normal rats. Oxidative stress or an impaired endogenous anti-oxidant mechanism is an important factor that has been implicated in Alzheimer's disease (AD) and cognitive deficits seen in the elderly. 2. Intracerebroventricular (i.c.v.) streptozotocin (STZ) in rats has been likened to sporadic AD in humans and the cognitive impairment is associated with free radical generation in this model. Therefore, in the present study, the effect of an aqueous extract of C. asiatica (100, 200 and 300 mg/kg for 21 days) was evaluated in i.c.v. STZ-induced cognitive impairment and oxidative stress in rats. 3. Male Wistar rats were injected with STZ (3 mg/kg, i.c.v.) bilaterally on the days 1 and 3. Cognitive behaviour was assessed using passive avoidance and elevated plus-maze paradigms on the days 13, 14 and 21. Rats were killed on the day 21 for estimation of oxidative stress parameters (malondialdehyde (MDA), glutathione, superoxide dismutase and catalase) in the whole brain upon completion of the behavioural task. 4. Rats treated with C. asiatica showed a dose-dependent increase in cognitive behaviour in both paradigms. A significant decrease in MDA and an increase in glutathione and catalase levels were observed only in rats treated with 200 and 300 mg/kg C. asiatica . 5. The present findings indicate that an aqueous extract of C. asiatica is effective in preventing the cognitive deficits, as well as the oxidative stress, caused by i.c.v. STZ in rats. [ABSTRACT FROM AUTHOR]

In this study we have identified POLθ-S6K-p62 as a novel druggable regulator of radiation response in prostate cancer. Despite significant advances in delivery, radiotherapy continues to negatively affect treatment outcomes and quality of life due to resistance and late toxic effects to the surrounding normal tissues such as bladder and rectum. It is essential to develop new and effective strategies to achieve better control of tumor. We found that ribosomal protein S6K (RPS6KB1) is elevated in human prostate tumors, and contributes to resistance to radiation. As a downstream effector of mTOR signaling, S6K is known to be involved in growth regulation. However, the impact of S6K signaling on radiation response has not been fully explored. Here we show that loss of S6K led to formation of smaller tumors with less metastatic ability in mice. Mechanistically we found that S6K depletion reduced NFκB and SQSTM1 (p62) reporter activity and DNA polymerase θ (POLθ) that is involved in alternate end-joining repair. We further show that the natural compound berberine interacts with S6K in a in a hitherto unreported novel mode and that pharmacological inhibition of S6K with berberine reduces Polθ and downregulates p62 transcriptional activity via NFκB. Loss of S6K or pre-treatment with berberine improved response to radiation in prostate cancer cells and prevented radiation-mediated resurgence of PSA in animals implanted with prostate cancer cells. Notably, silencing POLQ in S6K overexpressing cells enhanced response to radiation suggesting S6K sensitizes prostate cancer cells to radiation via POLQ. Additionally, inhibition of autophagy with CQ potentiated growth inhibition induced by berberine plus radiation. These observations suggest that pharmacological inhibition of S6K with berberine not only downregulates NFκB/p62 signaling to disrupt autophagic flux but also decreases Polθ. Therefore, combination treatment with radiation and berberine inhibits autophagy and alternate end-joining DNA repair, two processes associated with radioresistance leading to increased radiation sensitivity., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Introduction: The safety and therapeutic effects of Gingko biloba extract EGb 761® to treat cognitive decline have been demonstrated in numerous clinical trials. However, trials in Indian populations have been lacking., Methods: This open-label, multicenter, single-arm, phase IV trial enrolled 150 patients aged ≥50 years with major neurocognitive disorder due to Alzheimer's disease, major vascular neurocognitive disorder, or mixed forms of both according to the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5) criteria and a Mini-Mental State Examination (MMSE) score of 12-24. Patients took 120 mg EGb 761® twice daily for 18 weeks. Therapeutic effects were assessed by CERAD constructional praxis and recall of constructional praxis (CERAD CP, CERAD recall of CP), Trail-Making Test (TMT), Behavioral Pathology in Alzheimer's Disease (BEHAVE-AD), Clinical Global Impressions (CGI) scale, and 11-point box scales for tinnitus and vertigo. Safety assessment was based on the occurrence of adverse events as well as changes in clinical, laboratory, and functional parameters., Results: After 18 weeks, significant improvements compared to baseline were found in constructional praxis (CERAD CP, p < 0.0001), memory (CERAD recall of CP, p < 0.0001), speed and executive functioning (TMT A, p < 0.0001; TMT B, p < 0.0001), and behavioral symptoms (BEHAVE-AD, p < 0.0001). Forty-five adverse events were reported in 33 (22.0%) patients in total, including ten presumed adverse drug reactions in 9 (6.0%) patients. Headache and diarrhea of mild-to-moderate severity were the most frequent events. Two serious adverse events, both considered unrelated to the study drug, occurred in 2 (1.3%) patients., Conclusion: This study confirmed the favorable safety profile and suggested therapeutic benefits of EGb 761® in Indian patients with major neurocognitive disorder., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

The mechanism by which interferon regulatory factor 8 (IRF8) mutation contributes to lymphomagenesis is unknown. We modeled IRF8 variants in B cell lymphomas and found that they affected the expression of regulators of antigen presentation. Expression of IRF8 mutants in murine B cell lymphomas suppressed CD4, but not CD8, activation elicited by antigen presentation and downmodulated CD74 and human leukocyte antigen (HLA) DM, intracellular regulators of antigen peptide processing/loading in the major histocompatibility complex (MHC) II. Concordantly, mutant IRF8 bound less efficiently to the promoters of these genes. Mice harboring IRF8 mutant lymphomas displayed higher tumor burden and remodeling of the tumor microenvironment, typified by depletion of CD4, CD8, and natural killer cells, increase in regulatory T cells and T follicular helper cells. Deconvolution of bulk RNA sequencing data from IRF8-mutant human diffuse large B cell lymphoma (DLBCL) recapitulated part of the immune remodeling detected in mice. We concluded that IRF8 mutations contribute to DLBCL biology by facilitating immune escape.

Introduction: Intravenous corticosteroids are the mainstay of treatment of patients hospitalized with acute severe ulcerative colitis (ASUC). However, 30%-40% of the patients are refractory to corticosteroids. We investigated whether addition of tofacitinib to corticosteroids improved the treatment responsiveness in patients with ASUC., Methods: This single-center, double-blind, placebo-controlled trial randomized adult patients with ASUC (defined by the Truelove Witts severity criteria) to receive either tofacitinib (10 mg thrice daily) or a matching placebo for 7 days while continuing intravenous corticosteroids (hydrocortisone 100 mg every 6 hours). The primary end point was response to treatment (decline in the Lichtiger index by >3 points and an absolute score <10 for 2 consecutive days without the need for rescue therapy) by day 7. The key secondary outcome was the cumulative probability of requiring initiation of infliximab or undergoing colectomy within 90 days following randomization. All analyses were performed in the intention-to-treat population., Results: A total of 104 patients were randomly assigned to a treatment group (53 to tofacitinib and 51 to placebo). At day 7, response to treatment was achieved in 44/53 (83.01%) patients receiving tofacitinib vs 30/51 (58.82%) patients receiving placebo (odds ratio 3.42, 95% confidence interval 1.37-8.48, P = 0.007). The need for rescue therapy by day 7 was lower in the tofacitinib arm (odds ratio 0.27, 95% confidence interval 0.09-0.78, P = 0.01). The cumulative probability of need for rescue therapy at day 90 was 0.13 in patients who received tofacitinib vs 0.38 in patients receiving placebo (log-rank P = 0.003). Most of the treatment-related adverse effects were mild. One patient, receiving tofacitinib, developed dural venous sinus thrombosis., Discussion: In patients with ASUC, combination of tofacitinib and corticosteroids improved treatment responsiveness and decreased the need for rescue therapy., (Copyright © 2024 by The American College of Gastroenterology.)

Background: Bortezomib, a commonly used anti-myeloma drug, is metabolized by liver microsomal enzymes which may be polymorphic and responsible for lack of response in 30% patients. Hence, the association of CYP2C19 polymorphism with treatment response was explored in this study., Methods: Treatment naive multiple myeloma (MM) patients, eligible for bortezomib-based induction treatment, were recruited as per the inclusion - exclusion criteria. The genotyping of CYP2C19 was done using polymerase chain reaction-restriction fragment length polymorphism for *2, *3 and *17 alleles. The incidence and severity of peripheral neuropathy were noted at follow-up visits and graded as per CTCAE criteria ver 5.0., Results: Total 220 patients were recruited from August 2016 till May 2021; with a mean age of 55.6 (9.5) years and 65.9% males. Bortezomib+cyclophosphamide+dexamethasone (41.8%) and bortezomib+lenalidomide+dexamethasone (38.2%) were the most prescribed regimens. The CYP2C19 was polymorphic in 38.6%, 2.3% and 23.7% patients for *2, *3 and *17 allele respectively. There were 195 treatment responders and 25 non-responders, and CYP2C19*2 allele was different between responders and non-responders (p = 0.02). All extensive metabolisers (n = 54) were noted to be treatment responders. Peripheral neuropathy was reported by 23.2% patients. The frequency of peripheral neuropathy was somewhat lower in patients having either *2/*2 or *3/*3 allele pattern for CYP2C19 (p = 0.44)., Conclusions: Polymorphism in CYP2C19 enzyme is likely to have an impact on bortezomib treatment response and peripheral neuropathy. The study suggests the role of pharmacogenetics in personalised treatment of MM., Competing Interests: Declaration of competing interest The authors have no relevant financial or non-financial interests to disclose., (Copyright © 2024 Southern Society for Clinical Investigation. Published by Elsevier Inc. All rights reserved.)

Well conducted clinical trials are the mainstay for generating evidence on preferred treatments. In order to adequately protect the interests of the trial participants, the Central Licensing Authority of India has formulated guidelines to determine the quantum of compensation in cases of regulatory clinical trial related injury or death. However, these guidelines do not address the nuances of trials recruiting children aged under 16 years, within which, neonates are the most vulnerable population. Thus, there is a need for addressing this lacuna in the current guidelines. This article examines the challenges in determining the quantum of compensation in neonatal clinical trials using the current formula, which is a corollary to the challenges faced by the authors in procuring clinical trial insurance for the Probiotic supplementation for Prevention of Neonatal Sepsis (ProSPoNS) trial. Further, it suggests a template for a differential formula using birthweight of infants, which is one of the many important factors impacting neonatal mortality.

The move toward early detection and treatment of cancer presents challenges for value assessment using traditional endpoints. Current cancer management rarely considers the full economic and societal benefits of therapies. Our study used a modified Delphi process to develop principles for defining and assessing value of cancer therapies that aligns with the current trajectory of oncology research and reflects broader notions of value. 24 experts participated in consensus-building activities across 5 months (16 took part in structured interactions, including a survey, plenary sessions, interviews, and off-line discussions, while 8 participated in interviews). Discussion focused on: 1) which oncology-relevant endpoints should be used for assessing treatments for early-stage cancer and access decisions for early-stage treatments, and 2) the importance of additional value components and how these can be integrated in value assessments. The expert group reached consensus on 4 principles in relation to the first area (consider oncology-relevant endpoints other than overall survival; build evidence for endpoints that provide earlier indication of efficacy; develop evidence for the next generation of predictive measures; use managed entry agreements supported by ongoing evidence collection to address decision-maker evidence needs) and 3 principles in relation to the second (routinely use patient reported outcomes in value assessments; assess broad economic impact of new medicines; consider other value aspects of relevance to patients and society)., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Plant nucleotide-binding leucine-rich repeat (NLRs) immune receptors directly or indirectly recognize pathogen-secreted effector molecules to initiate plant defense. Recognition of multiple pathogens by a single NLR is rare and usually occurs via monitoring for changes to host proteins; few characterized NLRs have been shown to recognize multiple effectors. The barley (Hordeum vulgare) NLR gene Mildew locus a (Mla) has undergone functional diversification, and the proteins encoded by different Mla alleles recognize host-adapted isolates of barley powdery mildew (Blumeria graminis f. sp. hordei [Bgh]). Here, we show that Mla3 also confers resistance to the rice blast fungus Magnaporthe oryzae in a dosage-dependent manner. Using a forward genetic screen, we discovered that the recognized effector from M. oryzae is Pathogenicity toward Weeping Lovegrass 2 (Pwl2), a host range determinant factor that prevents M. oryzae from infecting weeping lovegrass (Eragrostis curvula). Mla3 has therefore convergently evolved the capacity to recognize effectors from diverse pathogens., Competing Interests: Conflict of interest statement. None declared., (Published by Oxford University Press on behalf of American Society of Plant Biologists 2023.)

Antibiotics have substantially improved life expectancy in past decades through direct control or prevention of infections. However, emerging antibiotic resistance and lack of access to effective antibiotics have significantly increased the death toll from infectious diseases, making it one of the biggest threats to global health. Addressing the antibiotic crisis to meet future needs require considerable investment in both research and development along with ensuring a viable marketplace to encourage innovation. Fortunately, there has been some improvement in the number of antibiotics approved or in different phases of development through collective global efforts. However, the universal access to these essential novel and generic antibiotics, especially in low- and middle-income countries (LMICs), is challenged by poor economic incentives, regulatory hurdles and poor health infrastructure. Recently, the agenda of securing and expanding access has gained global attention. Several mechanisms are now being proposed and implemented to improve access to essential antibiotics. This review provides an insight into the major barriers to antibiotic access as well as the models proposed and implemented to mitigate accessibility issues. These models include but are not limited to market entry rewards, subscription models and transferable exclusivity vouchers. Further, global access programmes including, Global Antibiotic Research and Development Partnership, Antimicrobial Resistance Action Fund and SECURE Platform are discussed. We also propose the way forward for improving access in LMICs with suggested measures to improve access to generic and novel antibiotics., (© The Author(s) 2023. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

BRCA1-deficient cells have increased IRE1 RNase, which degrades multiple microRNAs. Reconstituting expression of one of these, miR-4638-5p, resulted in synthetic lethality in BRCA1-deficient cancer cells. We found that miR-4638-5p represses expression of TATDN2, a poorly characterized member of the TATD nuclease family. We discovered that human TATDN2 has RNA 3' exonuclease and endonuclease activity on double-stranded hairpin RNA structures. Given the cleavage of hairpin RNA by TATDN2, and that BRCA1-deficient cells have difficulty resolving R-loops, we tested whether TATDN2 could resolve R-loops. Using in vitro biochemical reconstitution assays, we found TATDN2 bound to R-loops and degraded the RNA strand but not DNA of multiple forms of R-loops in vitro in a Mg2+-dependent manner. Mutations in amino acids E593 and E705 predicted by Alphafold-2 to chelate an essential Mg2+ cation completely abrogated this R-loop resolution activity. Depleting TATDN2 increased cellular R-loops, DNA damage and chromosomal instability. Loss of TATDN2 resulted in poor replication fork progression in the presence of increased R-loops. Significantly, we found that TATDN2 is essential for survival of BRCA1-deficient cancer cells, but much less so for cognate BRCA1-repleted cancer cells. Thus, we propose that TATDN2 is a novel target for therapy of BRCA1-deficient cancers., (© The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research.)

A common mRNA modification is 5-methylcytosine (m 5 C), whose role in gene-transcript processing and cancer remains unclear. Here, we identify serine/arginine-rich splicing factor 2 (SRSF2) as a reader of m 5 C and impaired SRSF2 m 5 C binding as a potential contributor to leukemogenesis. Structurally, we identify residues involved in m 5 C recognition and the impact of the prevalent leukemia-associated mutation SRSF2 P95H . We show that SRSF2 binding and m 5 C colocalize within transcripts. Furthermore, knocking down the m 5 C writer NSUN2 decreases mRNA m 5 C, reduces SRSF2 binding, and alters RNA splicing. We also show that the SRSF2 P95H mutation impairs the ability of the protein to read m 5 C-marked mRNA, notably reducing its binding to key leukemia-related transcripts in leukemic cells. In leukemia patients, low NSUN2 expression leads to mRNA m 5 C hypomethylation and, combined with SRSF2 P95H , predicts poor outcomes. Altogether, we highlight an unrecognized mechanistic link between epitranscriptomics and a key oncogenesis driver., Competing Interests: Declaration of interests F.F. is a co-founder of Epics Therapeutics (Gosselies, Belgium)., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Monkeypox virus (MPXV) infections in humans have historically been restricted to regions of endemicity in Africa. However, in 2022, an alarming number of MPXV cases were reported globally, with evidence of person-to-person transmission. Because of this, the World Health Organization (WHO) declared the MPXV outbreak a public health emergency of international concern. The supply of MPXV vaccines is limited, and only two antivirals, tecovirimat and brincidofovir, approved by the U.S. Food and Drug Administration (FDA) for the treatment of smallpox, are currently available for the treatment of MPXV infection. Here, we evaluated 19 compounds previously shown to inhibit different RNA viruses for their ability to inhibit orthopoxvirus infections. We first used recombinant vaccinia virus (rVACV) expressing fluorescence (mScarlet or green fluorescent protein [GFP]) and luciferase (Nluc) reporter genes to identify compounds with antiorthopoxvirus activity. Seven compounds from the ReFRAME library (antimycin A, mycophenolic acid, AVN-944, pyrazofurin, mycophenolate mofetil, azaribine, and brequinar) and six compounds from the NPC library (buparvaquone, valinomycin, narasin, monensin, rotenone, and mubritinib) showed inhibitory activity against rVACV. Notably, the anti-VACV activity of some of the compounds in the ReFRAME library (antimycin A, mycophenolic acid, AVN-944, mycophenolate mofetil, and brequinar) and all the compounds from the NPC library (buparvaquone, valinomycin, narasin, monensin, rotenone, and mubritinib) were confirmed with MPXV, demonstrating their inhibitory activity in vitro against two orthopoxviruses. IMPORTANCE Despite the eradication of smallpox, some orthopoxviruses remain important human pathogens, as exemplified by the recent 2022 monkeypox virus (MPXV) outbreak. Although smallpox vaccines are effective against MPXV, access to those vaccines is limited. In addition, current antiviral treatment against MPXV infections is limited to the use of the FDA-approved drugs tecovirimat and brincidofovir. Thus, there is an urgent need to identify novel antivirals for the treatment of MPXV infection and other potentially zoonotic orthopoxvirus infections. Here, we show that 13 compounds, derived from two different libraries, previously found to inhibit several RNA viruses, also inhibit VACV. Notably, 11 compounds also displayed inhibitory activity against MPXV., Competing Interests: The authors declare no conflict of interest.

Background/aims: The inflammatory bowel disease (IBD)-disk is a validated, visual, 10-item, self-administered questionnaire used to evaluate IBD-related disability. The present study aimed to evaluate IBD-disk in assessment of IBD daily life burden and its relation with disease activity., Methods: A cross-sectional study was conducted between June 2021 and December 2021. Patients with IBD were asked to complete the IBD-disk and a visual analogue scale of IBD daily-life burden (scored from 0-10, score >5 indicative of high burden). The internal consistency of IBD-disk, correlation with IBD daily life burden and disease activity (assessed by partial Mayo score and Harvey Bradshaw Index in patients with ulcerative colitis [UC] and Crohn's disease [CD], respectively) and diagnostic performance of IBD-disk to detect high burden were analyzed., Results: Out of the 546 patients (mean age 40.33±13.74 years, 282 [51.6%] males) who completed the IBD-disk, 464 (84.98%) had UC and the remaining (n=82, 15.02%) had CD. A total of 311 patients (291 UC and 20 CD; 56.95%) had active disease. The mean IBD-disk total score and IBD daily life burden were 18.39±15.23 and 2.45±2.02, respectively. The IBD-disk total score correlated strongly with the IBD daily life burden (ρ=0.94, P<0.001), moderately with partial Mayo score (ρ=0.50) and weakly with Harvey Bradshaw Index (ρ=0.34). The IBD-disk total score >30 predicted high IBD daily-life burden., Conclusions: The IBD-disk accurately predicts the daily life burden and parallels disease activity in patients with IBD and can be applied in clinical practice. (Intest Res, Published online).

The global economy has suffered losses as a result of the COVID-19 epidemic. Accurate and effective predictive models are necessary for the governance and readiness of the healthcare system and its resources and, ultimately, for the prevention of the spread of illness. The primary objective of the project is to build a robust, universal method for predicting COVID-19-positive cases. Collaborators will benefit from this while developing and revising their pandemic response plans. For accurate prediction of the spread of COVID-19, the research recommends an adaptive gradient LSTM model (AGLSTM) using multivariate time series data. RNN, LSTM, LASSO regression, Ada-Boost, Light Gradient Boosting and KNN models are also used in the research, which accurately and reliably predict the course of this unpleasant disease. The proposed technique is evaluated under two different experimental conditions. The former uses case studies from India to validate the methodology, while the latter uses data fusion and transfer-learning techniques to reuse data and models to predict the onset of COVID-19. The model extracts important advanced features that influence the COVID-19 cases using a convolutional neural network and predicts the cases using adaptive LSTM after CNN processes the data. The experiment results show that the output of AGLSTM outperforms with an accuracy of 99.81% and requires only a short time for training and prediction.

Patients from countries, endemic with tuberculosis, who present with febrile lymphadenopathy refractory to first line antibiotics are often empirically treated for extra-pulmonary tuberculosis. However, Kikuchi-Fujimoto Disease (KFD) or histiocytic necrotizing lymphadenitis, a self-limiting and benign condition, presents with similar clinical symptoms. We present an adolescent with febrile lymphadenopathy, who was initially treated for tubercular lymphadenopathy, before a diagnosis of KFD was made.

Background/aims: Inflammatory bowel disease (IBD) is increasingly being recognized in elderly patients. Data on clinical spectrum of elderly-onset IBD patients is lacking from India., Methods: A cross-sectional retrospective analysis of a prospectively maintained database of patients diagnosed with IBD was conducted at 2 centers in India. The clinical spectrum of elderly-onset IBD including demographic profile (age and sex), clinical presentation, disease characteristics (disease behavior and severity, extent of disease), and treatment were recorded and compared with adult-onset IBD., Results: During the study period, 3,922 (3,172 ulcerative colitis [UC] and 750 Crohn's disease [CD]) patients with IBD were recorded in the database. A total of 186 patients (4.74%; 116 males [62.36%]) had elderly-onset IBD (69.35% UC and 30.64% CD). Diarrhea, blood in stools, nocturnal frequency and pain abdomen were the commonest presentations for UC, whereas pain abdomen, weight loss and diarrhea were the most frequent symptoms in CD. For both elderly onset UC and CD, majority of the patients had moderately severe disease. Left-sided colitis was the commonest disease location in UC. Isolated ileal disease and inflammatory behavior were the most common disease location and behavior, respectively in CD. 5-Aminosalicylates were the commonest prescribed drug for both elderly onset UC and CD. Thiopurines and biologics were used infrequently. Prevalence of colorectal cancer was higher in elderly onset IBD., Conclusions: Elderly onset IBD is not uncommon in India. Both the elderly onset UC and CD were milder, with no significant differences in disease characteristics (disease extent, location and behavior) when compared to adult-onset IBD. Colorectal cancer was more common in elderly onset IBD.

With >7000 species the order of rust fungi has a disproportionately large impact on agriculture, horticulture, forestry and foreign ecosystems. The infectious spores are typically dikaryotic, a feature unique to fungi in which two haploid nuclei reside in the same cell. A key example is Phakopsora pachyrhizi, the causal agent of Asian soybean rust disease, one of the world's most economically damaging agricultural diseases. Despite P. pachyrhizi's impact, the exceptional size and complexity of its genome prevented generation of an accurate genome assembly. Here, we sequence three independent P. pachyrhizi genomes and uncover a genome up to 1.25 Gb comprising two haplotypes with a transposable element (TE) content of ~93%. We study the incursion and dominant impact of these TEs on the genome and show how they have a key impact on various processes such as host range adaptation, stress responses and genetic plasticity., (© 2023. The Author(s).)

A free space optical module is used in laser communication to transport a signal from the transmitter to the receiver. Free Space Optical Communication (FSOC) is a Line of Sight connectivity that sends a highly narrow beamwidth. FSOC provides high bandwidth and data rates greater than 10 Gbps. Although FSOC technology has several advantages, it is inefficient for long-distance transmission because of many constraints caused by atmospheric variables. In FSOC connections, turbulence-induced scintillation is a severe problem that significantly reduces link performance. Keeping this problem in mind, the objective of this study is to enhance FSOC performance in terms of energy efficiency, spectral efficiency and long-distance transmission. To achieve this, a study is employed using a hybrid combination of Higher-order Gaussian filter (HGF), post-amplification and a homodyne detection method. Precisely, the simulative study of 32-channel wavelength division multiplexing (WDM) FSOC has used channel model Gamma-Gamma with single-beam (SB), dual-beam (DB), four multiple-beam (MB4) and eight multiple-beam (MB8) techniques. The proposed framework has achieved a Channel capacity of more than 320 Gbps. The transmission range enhancement of 112% and reduction in transmitted power of 100% are achieved, which are considerably more significant compared with state-of-the-art literature studies. The OptiSystem platform is used to gather the outcomes. The performance is based on parametric analysis of bit error rate (BER), Quality (Q) factor and eye height., Competing Interests: The authors declare no conflict of interest., (© 2023 The Authors.)

The growing need for effective antibiotics is attributed to the intrinsic ability of bacteria to develop survival mechanisms. The speed at which pathogens develop resistance is at par or even faster than the discovery of newer agents. Due to the enormous cost of developing an antibiotic and poor return on investment, big pharmaceutical companies are stepping out of the antibiotic research field, and the world is now heading towards the silent pandemic of antibiotic resistance. Lack of investment in research has further led to the anemic antibiotic pipeline. To overcome these challenges, various organizations have come forward with push funding to financially assist antibiotic developers. Although push funding has somewhat reinvigorated the dwindled field of antibiotic development by bearing the financial risks of failure, the landscape is still large and staggered. Most of the funding is funneled towards the early stages; however, to carry the promising compounds forward, equal or more funding is required formid- and late-stage research. To some extent, the complexity associated with accessing the funding mechanisms has led to their underutilization. In the present review, we discuss several major push funding mechanisms, issues in their effective utilization, recent strategies adopted, and a way forward to streamline funding in antibiotic research.

GRP78 overexpression in myeloma cells has been associated with bortezomib resistance in multiple myeloma (MM). However, serum GRP78 as a maker of bortezomib-based treatment response remains unexplored. The objective of the study was to evaluate serum GRP78 levels in MM patients who underwent a bortezomib-based induction regimen. This cross-sectional study included adult MM patients (n=30) who completed at least four cycles of bortezomib-based induction therapy. Healthy volunteers (n=30) and newly diagnosed MM patients (n=19) were also recruited to identify the disease-associated change in GRP78 levels. Serum GRP78 was estimated by ELISA. Surface and intracellular expression of GRP78 in bone marrow plasma cells was evaluated in ten MM patients by flow cytometry. Among 30 MM patients [median (range): 52 (38-68) years; 20 males] who completed at least four cycles of bortezomib-based induction therapy, 20 were responders and 10 were non-responders. Serum GRP78 levels were not significantly different between responders [median (IQR): 5.2 (3.1, 8.0) μg/ml] and non-responders [median (IQR): 4.3 (0.1, 7.1) μg/ml] (p=0.4). Although non-significant (p=0.3), median serum GRP78 was higher in newly diagnosed patients when compared to healthy volunteers. Bone marrow plasma cells ranged from 0.2 to 57.8% in the analyzed samples. Intracellular GRP78 expression in bone marrow plasma cells was higher (1.6 to 5 times) when compared to surface expression. To conclude, serum GRP78 levels vary widely in different MM patient groups but did not correlate with response to a bortezomib-based induction regimen.

Insulin-resistant brain state is proposed to be the early sign of Alzheimer's disease (AD), which can be studied in the intracerebroventricular streptozotocin (ICV-STZ) rodent model. ICV-STZ is reported to induce sporadic AD with the majority of the disease hallmarks as phenotype. On the other hand, available experimental evidence has used varying doses of STZ (< 1 to 3 mg/kg) and studied its effect for different study durations, ranging from 14 to 270 days. Though these studies suggest 3 mg/kg of ICV-STZ to be the optimum dose for progressive pathogenesis, the reason for such is elusive. Here, we sought to investigate the mechanism of action of 3 mg/kg ICV-STZ on cognitive and non-cognitive aspects at a follow-up interval of 2 weeks for 2 months. On the 60th day, we examined the layer thickness, cell density, ventricular volume, spine density, protein expression related to brain metabolism, and mitochondrial function by histological examination. The findings suggest a progressive loss of a spatial, episodic, and avoidance memory with an increase in anxiety in a span of 2 months. Furthermore, hippocampal neurodegeneration, ventricular enlargement, diffused amyloid plaque deposition, loss of spine in the dentate gyrus, and imbalance in energy homeostasis were found on the 60th day post-injection. Interestingly, AD rats showed a uniform fraction of time spent in four quadrants of the water maze with a change in strategy when they were exposed to height. Our findings reveal that ICV-STZ injection at a dose of 3 mg/kg can cause cognitive and neuropsychiatric abnormalities due to structural loss both at the neuronal as well as the synaptic level, which is tightly associated with the change in neuronal metabolism., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: Morphine is widely used in patients and has been reported to alter seizure threshold, but its role in the development of epilepsy is unknown. In this study, role of morphine administration in the development of epilepsy using the status epilepticus (SE) model was determined in rats., Methods: Rats experiencing SE with lithium-pilocarpine (LiP) were randomized into four groups- saline, morphine low dose (5 mg/kg, s.c.), morphine high dose (5-20 mg/kg, s.c.), and naloxone (1 mg/kg, s.c.). Treatments were started 90 min after termination of SE and repeated twice daily for next three days. Rats were video monitored daily for 21 days to determine onset and frequency of spontaneous convulsive seizures (SS)., Results: Morphine in low doses increased frequency of SS (1.51 ± 0.15 vs LiP 0.60 ± 0.12 seizures/rat/day, p-value = 0.0026) and seizures occurred during handling (SDH) (0.08 ± 0.02 vs LiP control 0.01 ± 0.01) (p-value = 0.0018). In high doses, no significant change in SS and SDH was found as compared to LiP. No effect of morphine on the onset of SS and percentage of rats experienced SS was found. No effect of naloxone per se was found on SS., Conclusion: Morphine administration after SE does not affect epileptogenesis as no change in the onset of SS and percentage of rats experiencing SS was found. However, it might alter the susceptibility and frequency of SS. As no other study is available with a similar finding, it needs further evaluation., Competing Interests: Declaration of Competing Interest None., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Traditional drug development is a tedious process with involvement of enormous cost and a high attrition rate. Outsourcing drug development services to contract research organizations (CROs) has become an important strategy for cost and risk reduction, capacity building, and data generation. The therapeutic and operational expertise of these CROs has allowed pharmaceutical industry to reduce in-house infrastructure as well as research capacity. Working with specialized CROs has not only increased the rate of success but also the speed of drug discovery process. Small firms with promising molecules but limited resources and large firms interested in diversifying their dimensions are utilizing the services of efficient CROs. Globally, approximately one-third of the drug development processes are now being outsourced and the data generated by the independent third party are well appreciated during regulatory submissions. In this article, we discuss the international and national trends, outsourcing services and models, key considerations while selecting CRO, and benefits and challenges of outsourcing. Further, we discuss how the technical expertise of competent CROs was utilized when traditional ways of conducting clinical trials were disrupted by the COVID-19 pandemic. Taken together, the increasing health-care demands, COVID-19 pandemic or any other such upcoming health crisis, and recent advances in advanced technologies (machine learning and artificial intelligence, etc.) are likely to fuel global CRO market in the coming years., Competing Interests: None

Fungal interactions with plant roots, either beneficial or detrimental, have a crucial impact on agriculture and ecosystems. The cosmopolitan plant pathogen Fusarium oxysporum (Fo) provokes vascular wilts in more than a hundred different crops. Isolates of this fungus exhibit host-specific pathogenicity, which is conferred by lineage-specific Secreted In Xylem (SIX) effectors encoded on accessory genomic regions. However, such isolates also can colonize the roots of other plants asymptomatically as endophytes or even protect them against pathogenic strains. The molecular determinants of endophytic multihost compatibility are largely unknown. Here, we characterized a set of Fo candidate effectors from tomato (Solanum lycopersicum) root apoplastic fluid; these early root colonization (ERC) effectors are secreted during early biotrophic growth on main and alternative plant hosts. In contrast to SIX effectors, ERCs have homologs across the entire Fo species complex as well as in other plant-interacting fungi, suggesting a conserved role in fungus-plant associations. Targeted deletion of ERC genes in a pathogenic Fo isolate resulted in reduced virulence and rapid activation of plant immune responses, while ERC deletion in a nonpathogenic isolate led to impaired root colonization and biocontrol ability. Strikingly, some ERCs contribute to Fo infection on the nonvascular land plant Marchantia polymorpha, revealing an evolutionarily conserved mechanism for multihost colonization by root infecting fungi., (© American Society of Plant Biologists 2022. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

The major limitations of DNA-targeting chemotherapy drugs include life-threatening toxicity, acquired resistance and occurrence of secondary cancers. Here, we report a small molecule, Carbazole Blue (CB), that binds to DNA and inhibits cancer growth and metastasis by targeting DNA-related processes that tumor cells use but not the normal cells. We show that CB inhibits the expression of pro-tumorigenic genes that promote unchecked replication and aberrant DNA repair that cancer cells get addicted to survive. In contrast to chemotherapy drugs, systemic delivery of CB suppressed breast cancer growth and metastasis with no toxicity in pre-clinical mouse models. Using PDX and ex vivo explants from estrogen receptor (ER) positive, ER mutant and TNBC patients, we further demonstrated that CB effectively blocks therapy-sensitive and therapy-resistant breast cancer growth without affecting normal breast tissue. Our data provide a strong rationale to develop CB as a viable therapeutic for treating breast cancers., (© 2022. The Author(s).)

Background: Polypharmacy is principal cause of potentially inappropriate medications (PIMs) in elderly patients, which include over prescribing, under prescribing, and misprescribing., Methods: Elderly subjects (≥60 years), of either sex, receiving two or more medications for one or more chronic ailments, attending Geriatrics Outpatient Department (OPD), at All India Institute of Medical Sciences (AIIMS) New Delhi, were included. Their prescriptions were assessed for PIMs by using Beers criteria 2015 and were further followed up at least once in 6 months for adverse events, telephonically. The results were analyzed by using suitable regression models and correlation analysis., Results: Three hundred eighty patients average age of 65.4 ± 4.7 years were enrolled. Eighty-eight percent of the people were having greater than or equal to two ailments. Each patient was prescribed 6.7 ± 2.1 medications with 65% of prescriptions having one or more PIMs. Out of the total prescribed drugs, 15% were satisfying Beers criteria for PIMs. There were 63 adverse drug reactions (ADRs) reported. A statistically significant correlation was observed among comorbidities, number of prescribed medications, PIMs, and ADRs. Quality of life (QOL) of the elderly patients was negatively corelated with polypharmacy and female sex., Conclusion: A risk-benefit analysis of prescribed medications is part and parcel of prescribing, especially in elderly patients. In order to decrease further risks associated with inappropriate prescribing, there is need for indigenous guidelines and intensive training., Competing Interests: None., (© 2022 The Authors. Aging Medicine published by Beijing Hospital and John Wiley & Sons Australia, Ltd.)

Methyltransferase like-3 (METTL3) and METTL14 complex transfers a methyl group from S -adenosyl-L-methionine to N 6 amino group of adenosine bases in RNA (m 6 A) and DNA (m 6 dA). Emerging evidence highlights a role of METTL3-METTL14 in the chromatin context, especially in processes where DNA and RNA are held in close proximity. However, a mechanistic framework about specificity for substrate RNA/DNA and their interrelationship remain unclear. By systematically studying methylation activity and binding affinity to a number of DNA and RNA oligos with different propensities to form inter- or intra-molecular duplexes or single-stranded molecules in vitro, we uncover an inverse relationship for substrate binding and methylation and show that METTL3-METTL14 preferentially catalyzes the formation of m 6 dA in single-stranded DNA (ssDNA), despite weaker binding affinity to DNA. In contrast, it binds structured RNAs with high affinity, but methylates the target adenosine in RNA (m 6 A) much less efficiently than it does in ssDNA. We also show that METTL3-METTL14-mediated methylation of DNA is largely restricted by structured RNA elements prevalent in long noncoding and other cellular RNAs., Competing Interests: SQ, JM, JV, SA, MR No competing interests declared, SC, ND, IC is an employee of New England Biolabs, a manufacturer and vendor of molecular biology reagents, RH owns equity in Dialectic Therapeutics and Abfero, YG is founder of Atomic Therapeutics. None of these affiliations affect the authors' impartiality, adherence to journal standards and policies, or availability of data, (© 2022, Qi et al.)

Objectives: Antiepileptic-drug (AED) serum level and inflammatory biomarkers are primarily monitored/assessed during epilepsy treatment for effective seizure control; however, their correlation with seizure recurrence (SR) following AED-tapering has not been established, and this is being investigated in this study., Materials and Methods: This prospective observational study enrolled persons with epilepsy (PWE) on AED monotherapy and going to start tapering after being seizure-free for ≥2 years. Data regarding seizure episodes, AED-treatment, and adverse events (using Liverpool Adverse Event profile [LAEP]-score) were recorded. Serum AED levels using high-performance liquid chromatography and biomarkers levels through enzyme-linked immunosorbent assay kits were estimated at AED-tapering commencement and at 6 months/SR time., Results: Among 129 enrolled PWE (levetiracetam [n = 52], valproate [n = 34], carbamazepine [n = 29], and phenytoin [n = 14]), SR occurred in 23.3% during follow-up (range 12-44 months). PWE with subtherapeutic serum AED level at the onset of tapering had higher SR (P = 0.004) than those with therapeutic or higher levels. Levetiracetam-treated PWEs with SR have significantly low AED levels than PWE with no-SR (P < 0.001). PWE had significantly raised inflammatory biomarkers (interleukin [IL]-1 β, tumor necrosis factor [TNF]-α, IL-6, and high-mobility group box protein 1) and decreased IL-10 than healthy control subjects. SR and no-SR groups did not differ significantly in inflammatory markers except for higher IL-1 β and TNF-α levels in SR group (P = 0.001, 0.02, respectively). Improvement in LAEP score was observed in follow-up visits without any difference between SR and no-SR groups., Conclusion: Low serum AED levels (especially levetiracetam) and raised levels of TNF-α and IL-1 β during tapering commencement had a higher association with SR following AED-tapering., Competing Interests: None

Background: The use of plants and plant products in health care has shown an exponential increase in the past two decades., Introduction: In-spite of the availability of well-established pharmacotherapy for epilepsy, a large no of the population still explores alternative treatments due to refractory seizures, adverse effects of drugs, chronic treatment, inaccessibility of standard therapies in rural areas and the social stigma attached to the disease. Various studies on medicinal plants showed the protective effect of herbals in animal models of epilepsy., Methods: In the present review, a status analysis of the traditional use of various medicinal plants in epilepsy with a special focus on plats having anti-inflammatory potential is recorded., Result and Conclusion: The shortcomings of research on medicinal plants which need to be explored further in order to tackle the growing need for safer and effective drugs for epilepsy are discussed. Overall, there is a huge scope of herbal drugs in CNS disorders, especially epilepsy, either as an adjunct by reducing the dose and thus side effects of standard anti-epileptic drugs or as a standalone agent. Although, there is still an urgent need of well planned randomized controlled clinical trials to validate their efficacy and safety., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

During the ongoing COVID-19 Pandemic we have seen a surge in online transactions. The current wallet payment architecture requires online connectivity during transactions. It is observed that there is a possibility of not getting connected to the Internet due to various reasons. We are working on a solution to enable offline transactions due to any internet failure. We identify three main scenarios where fully offline transaction capability is considered to be beneficial for both merchants and consumers. It includes making purchases in locations without online connectivity, when a reliable connection is not guaranteed, and when it is cheaper to carry out offline transactions due to higher communication/payment processing costs involved in online approvals. Our work aims to address the challenge of providing secure offline transaction capability when there is no online connectivity keeping in mind to not compromise any security features in our M-Commerce offline wallet payment application., Competing Interests: Conflict of InterestThe authors declare that they have no conflict of interest., (© The Author(s), under exclusive licence to Springer Nature Singapore Pte Ltd 2021.)

Bacopa monnieri (L.) Wettst. (BM) has been traditionally used in Ayurveda for improving memory and cognitive deficits which is also evidenced through experimental and clinical studies. The neuropharmacological properties of BM are attributed to "bacosides", a complex mixture of saponin compounds. BM extracts enriched with bacosides offers commercial advantage due to perceived higher efficacy. However, there is no scientific data to support the same. In the present study, methanolic extract of BM (BME) was compared with bacosides enriched (BME-EF) vis a vis bacosides free fraction (BME-FF). Potential antioxidant and cholinesterase inhibitory activity has been evaluated using in vitro and in vivo methods. BME showed not only the highest anti-amnesic efficacy but also antioxidant and cholinesterase inhibitory activity, followed by either BME-FF or BME-EF. Interestingly, no significant differences were found in between the groups. These findings dispel the notion that bacosides enrichment enhances anti-amnesic efficacy and also suggests the contribution of other components.

Background: Candida auris has emerged globally as a multi-drug resistant yeast and is commonly associated with nosocomial outbreaks in ICUs. Methods: We conducted a retrospective observational multicentre study to determine the epidemiology of C. auris infections, its management strategies, patient outcomes, and infection prevention and control practices across 10 centres from five countries. Results: Significant risk factors for C. auris infection include the age group of 61-70 years (39%), recent history of ICU admission (63%), diabetes (63%), renal failure (52%), presence of CVC (91%) and previous history of antibiotic treatment (96%). C. auris was commonly isolated from blood (76%). Echinocandins were the most sensitive drugs. Most common antifungals used for treatment were caspofungin (40%), anidulafungin (28%) and micafungin (15%). The median duration of treatment was 20 days. Source removal was conductedin 74% patients. All-cause crude mortality rate after 30 days was 37%. Antifungal therapy was associated with a reduction in mortality (OR:0.27) and so was source removal (OR:0.74). Contact isolation precautions were followed in 87% patients. Conclusions: C. auris infection carries a high risk for associated mortality. The organism is mainly resistant to most azoles and even amphotericin-B. Targeted antifungal therapy, mainly an echinocandin, and source control are the prominent therapeutic approaches.

PrimPol is a human DNA polymerase-primase that localizes to mitochondria and nucleus and bypasses the major oxidative lesion 7,8-dihydro-8-oxoguanine (oxoG) via translesion synthesis, in mostly error-free manner. We present structures of PrimPol insertion complexes with a DNA template-primer and correct dCTP or erroneous dATP opposite the lesion, as well as extension complexes with C or A as a 3'-terminal primer base. We show that during the insertion of C and extension from it, the active site is unperturbed, reflecting the readiness of PrimPol to accommodate oxoG(anti). The misinsertion of A opposite oxoG(syn) also does not alter the active site, and is likely less favorable due to lower thermodynamic stability of the oxoG(syn)•A base-pair. During the extension step, oxoG(syn) induces an opening of its base-pair with A or misalignment of the 3'-A primer terminus. Together, the structures show how PrimPol accurately synthesizes DNA opposite oxidatively damaged DNA in human cells.

The SARS-CoV-2 nsp16/nsp10 enzyme complex modifies the 2'-OH of the first transcribed nucleotide of the viral mRNA by covalently attaching a methyl group to it. The 2'-O methylation of the first nucleotide converts the status of mRNA cap from Cap-0 to Cap-1, and thus, helps the virus evade immune surveillance in host cells. Here, we report two structures of nsp16/nsp10 representing pre- and post-release states of the RNA product (Cap-1). We observe overall widening of the enzyme upon product formation, and an inward twisting motion in the substrate binding region upon product release. These conformational changes reset the enzyme for the next round of catalysis. The structures also identify a unique binding mode and the importance of a divalent metal ion for 2'-O methylation. We also describe underlying structural basis for the perturbed enzymatic activity of a clinical variant of SARS-CoV-2, and a previous SARS-CoV outbreak strain.

Alzheimer's disease (AD) is a multifactorial neurological disorder associated with neuropathological and neurobehavioral changes, like cognition and memory loss. Pathological hallmarks of AD comprise oxidative stress, formation of insoluble β-amyloid (Aβ) plaques, intracellular neurofibrillary tangles constituted by hyperphosphorylated tau protein (P-tau), neurotransmitters dysbalanced (DA, NE, 5-HT, GABA and Glutamate) and metal deposition. Chronic exposure to metals like aluminium and copper causes accumulation of Aβ plaques, promotes oxidative stress, neuro-inflammation, and degeneration of cholinergic neurons results in AD-like symptoms. In the present study, rats were administered with aluminium chloride (200 mg/kg p.o) and copper sulfate (0.5 mg/kg p.o) alone and in combination for 28 days. Allicin (10 and 20 mg/kg i.p) was administered from day 7 to day 28. Spatial and recognition memory impairment analysis was performed using Morris water maze, Probe trial, and Novel Object Recognition test. Animals were sacrificed on day 29, brain tissue was isolated, and its homogenate was used for biochemical (lipid peroxidation, nitrite, and glutathione), neuro-inflammatory (IL-1β, IL-6 and TNF- α), neurotransmitters (DA, NE, 5-HT, GABA and Glutamate), Aβ (1-42) level, Al concentration estimation, and Na + /K + -ATPase activity. In the present study, aluminium chloride and copper sulfate administration increased oxidative stress, inflammatory cytokines release, imbalanced neurotransmitters' concentration, and promoted β-amyloid accumulation and Na + /K + -ATPase activity. Treatment with allicin dose-dependently attenuated these pathological events via restoration of antioxidants, neurotransmitters concentration, and inhibiting cytokine release and β-amyloid accumulation. Moreover, allicin exhibited the neuroprotective effect through antioxidant, anti-inflammatory, neurotransmitters restoration, attenuation of neuro-inflammation and β-amyloid-induced neurotoxicity.

Ethnopharmacological Relevance: Centella asiatica (CA) is commonly used herbal medicine for treatment of epilepsy. CA has CYP2C9, CYP2D6 and CYP3A4 enzymes inhibition property and used as an adjuvant therapy with conventional antiepileptic drugs (AEDs). That may be responsible for herb-drug interaction., Aim of the Study: The present study was planned to evaluate interactions profile of hydroalcoholic extract Centella asiatica (HECA) with antiepileptic drugs in experimental models of epilepsy in rats., Materials and Methods: Wistar rats (175-200 g) were used. In the pharmacodynamic interaction study, seizures were induced using pentylenetetrazole (PTZ) (60 mg/kg, i.p.) and maximal electroshock seizure (MES) (70 mA for 0.2 s). The therapeutic and sub-therapeutic doses of valproate (VPA) and phenytoin (PHT) were co-administrated with HECA in PTZ and MES model of seizures respectively. Behavioural parameters were assessed using elevated plus maze test and passive avoidance paradigm. Rat brain oxidative stress parameters were also assessed. In the pharmacokinetic interaction study, the serum levels of the VPA and PHT were estimated at different time intervals by HPLC and pharmacokinetic parameters were analyzed by WinNonlin software., Results: The VPA and PHT produced complete protection against seizures in their therapeutic doses but not with sub-therapeutic doses. However, co-administration of HECA with a sub-therapeutic dose of VPA and PHT enhanced the protection of seizures and significantly (p < 0.001) attenuated the seizure induced oxidative stress and cognitive impairment. It also significantly increased (p < 0.001) serum levels of VPA and PHT. The alterations in pharmacokinetic parameters (maximum serum concentration, area under the curve, clearance) of AEDs were also found with co-administration of HECA., Conclusion: The results suggested that co-administration of HECA could improve the therapeutic efficacy of VPA and PHT. But, alteration in pharmacokinetic parameters revel that needs critical medical supervision to avoid any toxic reactions., (Copyright © 2021. Published by Elsevier B.V.)