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Background: The microbiota-gut-brain axis (MGBA) is a central nexus that integrates higher cognitive and emotional centers of the central nervous system (CNS) within the intricate functioning of the intestine. Accumulating evidence suggests that dysbiosis in the taxonomic diversity of gut flora plays a salient role in the progression of epilepsy and comorbid secondary complications., Methods: In the current study, we investigated the impact of long-term oral bacteriotherapy (probiotics; 10 mL/kg; 10 9 colony-forming unit/ml) as an adjunctive treatment intervention with brivaracetam (BRV; 10 mg/kg) over 21 days on pentylenetetrazole (PTZ) induced augmented epileptic response and associated electrographical and behavioral perturbations in mice. Moreover, we also unveiled antioxidant capacity and histopathologic changes in treated versus non-treated animals., Results: Results revealed combination increases seizure threshold and prevented high ictal spiking. Additionally, it alleviated PTZ-induced neuropsychiatric disturbances such as anxiety and depressive-like phenotype along with cognitive deficits. Furthermore, dual therapy prompted physiological oxidant/antioxidant balance as evidenced by increased activity of antioxidant enzymes (SOD and catalase) and reduced levels of oxidative stressor (MDA). This therapeutic intervention with commensal species suppressed network-driven neuroinflammation and preserved normal cytoarchitecture with intact morphology in the pyramidal layers of cornu ammonis (CA1 and CA3)., Conclusion: Our study provides supporting evidence for the use of probiotics as adjunctive therapy with anti-seizure medications to modulate epileptogenic processes and related multimorbidities, particularly in individuals with drug-resistant seizures., (© 2024 The Author(s). CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

Background: Besides seizures, a myriad of overlapping neuropsychiatric and cognitive comorbidities occur in patients with epilepsy, which further debilitates their quality of life. This study provides an in-depth characterization of the impact of brivaracetam and rufinamide individually and in combination at 10 and 20 mg/kg doses, respectively, on corneal kindling-induced generalized seizures and behavioral alterations. Furthermore, observed convulsive frequency and behavioral changes were correlated to post-kindling-induced changes in the activity of markers of oxidative stress., Methods: Adult C57BL/6 mice were kindled via twice-daily transcorneal 50-Hz electrical stimulations (3 mA) for 3 s for 12 days until animals reached a fully kindled state. After the kindling procedure, animals were tested using a set of behavioral tests, and neurochemical alterations were assessed., Results: Corneal-kindled animals exhibited intense generalized convulsions, altered behavioral phenotypes typified by positive symptoms (hyperlocomotion), negative symptoms (anxiety and anhedonia), and deficits in semantic and working memory. BRV 10 + RFM 20 dual regime increased convulsive threshold and propensity toward the start of stage 4-5 seizures and improved phenotypical deficits, that is, anxiety, depression, and memory impairments. Moreover, this combination therapy mitigated kindling-induced redox impairments as evidenced by reduced malondialdehyde and acetylcholinesterase levels and increased glutathione antioxidant activity in the brain of animals subjected to repetitive brain insult., Conclusion: Based on our outcomes, this dual therapy provides supporting evidence in alleviating epilepsy-induced neurobehavioral comorbidities and changes in redox homeostasis., (© 2024 The Author(s). Animal Models and Experimental Medicine published by John Wiley & Sons Australia, Ltd on behalf of The Chinese Association for Laboratory Animal Sciences.)

Introduction: Enhanced recovery after surgery (ERAS) is a patient-centerd, evidence-based approach to improve postoperative outcomes. The protocol involves multidisciplinary collaboration and standardisation of perioperative interventions. ERAS has shown positive results in reducing hospitalisation and complications., Methods: The study conducted in the Department of Urology was a retro-prospective study. It included an ERAS cohort group of 47 patients, studied prospectively from May 2021 to May 2023. These patients were compared to a historical cohort of 47 consecutive patients who underwent radical cystectomy with traditional care before the ERAS pathway was implemented. The primary outcome was hospital length of stay (LOS). Secondary outcomes included perioperative management, time to recovery milestones and complications., Results: Implementation of ERAS pathway for radical cystectomy was associated with reduced hospital LOS (mean LOS 16.19 ± 2.53 days vs. 10.26 ± 3.33 days 7 days; p  < 0.0001), reduced time to key recovery milestones, including days to first flatus (3.17 vs. 2.68; p  = 0.013) and days to first solid food (5.19 vs. 3.45 p value < 0.0001), first stool (5.53 vs. 4.23; p  < 0.0001), reductions in some complications like postoperative ileus ( p value = 0.021) and need for total parental nutrition ( p value = 0.023)., Conclusion: In conclusion, the implementation of the integrated approach facilitates a more efficient recovery process, potentially reducing healthcare costs and enhancing patient comfort., Competing Interests: The authors declare no competing interests that could potentially influence the objectivity or interpretation of the reported findings., (© 2024 The Author(s). BJUI Compass published by John Wiley & Sons Ltd on behalf of BJU International Company.)

Introduction: Cefpodoxime, a third-generation cephalosporin, is a broad-spectrum antibiotic widely used to treat acute upper respiratory tract infections (RTI). This systematic review aims to present a comprehensive view of all the available pharmacokinetics (PK) data associated with the pharmacodynamics (PD) parameters of cefpodoxime in humans., Areas Covered: The PubMed, Google Scholar, Cochrane Library, and Science Direct, were systematically searched to identify studies on the PK of cefpodoxime. Out of 746 papers, 26 articles meeting the eligibility criteria were included that have reported the PK data. The drug exposure for the patients undergoing hemodialysis was 50% lower than healthy participants. The renal clearance was almost 27% less in pediatric patients than in adults. The plasma concentrations of cefpodoxime exceeded the minimum inhibitory concentration (MIC) for 90% of skin pathogens, including Streptococcus species and Staphylococcus species (i.e.) < 1 μg/mL and 2-4 μg/mL respectively., Expert Opinion: The current study includes detailed information on clinical PK of cefpodoxime in healthy, diseased, pediatric populations as well as drug-drug interactions and drug-food interactions. Moreover, this systematic review also explicated PK/PD properties of drug with a specific impact on MIC of drug. The present review will also assist clinicians in the development of PK models for cefpodoxime.

The lithium-pilocarpine model is commonly used to recapitulate characteristics of human intractable focal epilepsy. In the current study, we explored the impact of topiramate (TPM) alone and in combination with pregabalin and lacosamide administration for 6 weeks on the evolution of spontaneous recurrent seizures (SRS) and disease-modifying potential on associated neuropsychiatric comorbidities. In addition, redox impairments and neurodegeneration in hippocampus regions vulnerable to temporal lobe epilepsy (TLE) were assessed by cresyl violet staining. Results revealed that acute electrophysiological (EEG) profiling of the ASD cocktail markedly halted sharp ictogenic spikes as well as altered dynamics of brain wave oscillations thus validating the need for polytherapy vs. monotherapy. In TLE animals, pharmacological intervention for 6 weeks with topiramate 10 mg/kg in combination with PREG and LAC at the dose of 20 mg/kg exhibited marked protection from SRS incidence, improved body weight, offensive aggression, anxiety-like behavior, cognitive impairments, and depressive-like behavior (p < 0.05). Moreover, combination therapy impeded redox impairments as evidenced by decreased MDA and AchE levels and increased activity of antioxidant SOD, GSH enzymes. Furthermore, polytherapy rescued animals from SE-induced neurodegeneration with increased neuronal density in CA1, CA3c, CA3ab, hilus, and granular cell layer (GCL) of the dentate gyrus. In conclusion, early polytherapy with topiramate in combination with pregabalin and lacosamide prompted synergy and prevented epileptogenesis with associated psychological and neuropathologic alterations., Competing Interests: Declaration of competing interest The authors indicated no potential conflicts of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Pentylenetetrazole (PTZ)-induced kindling is a broadly used experimental model to study the anticonvulsive potential of new and existing chemical moieties with the aim of discovering drugs hindering seizure progression and associated neurological comorbidities. In the present study, the impact of brivaracetam (BRV) (10 and 20 mg/kg) as monotherapy as well as in combination with 0.25 mg/kg of perampanel (PRP) was investigated on seizure progression with simultaneous electroencephalographic changes in PTZ kindling mouse model. Subsequently, mice were experimentally analyzed for anxiety, cognition, and depression after which their brains were biochemically evaluated for oxidative stress. The outcomes demonstrated that BRV alone delayed the kindling process, but BRV + PRP combination significantly ( p < 0.0001) protected the mice from seizures of higher severity and demonstrated an antikindling effect. The PTZ-kindled mice exhibited anxiety, memory impairment, and depression in behavioral tests, which were remarkably less ( p < 0.001) in animals treated with drug combination (in a dose-dependent manner) as these mice explored central, illuminated, and exposed zones of open-field test, light/dark box, and elevated plus maze. Moreover, memory impairment was demonstrated by kindled mice, which was significantly ( p < 0.001) protected by BRV + PRP as animal's spontaneous alteration, object discrimination, and step-through latencies were increased in various tests employed for the assessment of cognitive abilities. The brains of PTZ-kindled mice had increased malondialdehyde and reduced antioxidant enzymes while treatment with BRV + PRP combination prevented kindling-induced elevation in oxidative markers. The outcomes of this study demonstrate that combining the PRP at low dose augmented the antiseizure properties of BRV as both drugs when administered simultaneously hindered the process of kindling by reducing PTZ-induced excessive electrical activity and oxidative stress in the brain., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

Purpose: Torasemide is a potassium-sparing loop diuretic used to treat fluid retention associated with congestive heart failure and kidney and hepatic diseases. This systematic review was conducted to combine all accessible data on the pharmacokinetics (PK) of torasemide in healthy and diseased populations, which may help clinicians avert adverse drug reactions and determine the correct dosage regimen., Methods: Four databases were systematically searched to screen for studies associated with the PK of torasemide, and 21 studies met the eligibility criteria. The review protocol was registered in the PROSPERO database (CRD42023390178)., Results: A decrease in maximum plasma concentration (C max ) was observed for torasemide after administration of the prolonged-release formulation in comparison to that after administration of the immediate-release formulation, that is, 1.12 ± 0.17 versus 1.6 ± 0.2 mcg/mL. After administering an oral dose of torasemide, a 2-fold increase in the area under the concentration-time curve (AUC) was reported in patients with congestive heart failure compared with the healthy population. Moreover, the patients with renal failure (clearance < 30 mL/min) showed an increase in value of AUC 0-∞ that is, 42.9 versus 8.091 mcg.h -1 .mL -1 compared with healthy subjects. In addition, some studies have reported interactions with different drugs, in which irbesartan showed a slight increase in the AUC 0-∞ of torasemide, whereas losartan and empagliflozin did not., Conclusions: The current review summarizes all available PK parameters of torasemide that may be beneficial for avoiding drug-drug interactions in subjects with renal and hepatic dysfunction and for predicting doses in patients with different diseases., Competing Interests: The authors declare no conflict of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Epilepsy is an abiding condition associated with recurrent seizure attacks along with associated neurological and psychological emanation owing to disparity of excitatory and inhibitory neurotransmission. The current study encompasses the assessment of the Nyctanthes arbor-tristis L. methanolic extract (Na.Cr) in the management of convulsive state and concomitant conditions owing to epilepsy. The latency of seizure incidence was assessed using pentylenetetrazol (PTZ) kindling models along with EEG in Na.Cr pretreated mice, trailed by behavior assessment (anxiety and memory), biochemical assay, histopathological alterations, chemical profiling through GCMS, and molecular docking. The chronic assessment of PTZ-induced kindled mice depicted salvation in a dose-related pattern and outcomes were noticeable with extract at 400 mg/kg. The extract at 400 mg/kg defends the progress of kindling seizures and associated EEG. Co-morbid conditions in mice emanating owing to epileptic outbreaks were validated by behavioral testing and the outcome depicted a noticeable defense related to anxiety (P<0.001) and cognitive deficit (P<0.001) at 400 mg/kg. The isolated brains were evaluated for oxidative stress and the outcome demonstrated a noticeable effect in a dose-dependent pattern. Treatment with Na.Cr. also preserved the brain from PTZ induced neuronal damage as indicated by histopathological analysis. Furthermore, the GCMS outcome predicted 28 compounds abundantly found in the plant. The results congregated in the current experiments deliver valued evidence about the defensive response apportioned by Na.Cr which might be due to decline in oxidative stress, AChE level, and GABAergic modulation. These activities may contribute to fundamental pharmacology and elucidate some mechanisms behind the activities of Nyctanthes arbor-tristis., Competing Interests: Declaration of Competing Interest The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Competing Interests: The authors report no conflicts of interest in this communication.

Introduction: Ureteric colic in pregnancy is one of the common non-obstetric reasons for emergency department visits. Ureteric calculi present a significant threat to maternal and fetal health and definitive management often becomes necessary. Our aim is to assess the safety and efficacy of ureteroscopic laser lithotripsy in the management of ureteric stones in pregnancy., Material and Methods: This is a prospective observational study of 3 years carried at a tertiary referral center. It includes all pregnant patients who underwent ureteroscopic laser lithotripsy for ureteric stones., Results: A total of 29 pregnant patients underwent ureteroscopic laser lithotripsy at our center in 3 years. The mean age of patients was 33.5 ± 6.2 years, and the mean gestation age at the time of ureteroscopy was 23.34 ± 5.9 weeks. The average stone size was 8.3 ± 3.6 mm and was predominantly found in upper ureter (62%). The mean operative time was 31 ± 8.9 min, and the average laser energy spent was 4.3 ± 1.1 kJ/case. There was no major Intraoperative complication, and the average hospital stay was 2.5 ± 1.5 days. Complete stone clearance was achieved in 93.1% of cases., Conclusion: Ureteroscopic laser lithotripsy is safe and effective treatment of ureteric stones in terms of obstetric outcome and stone clearance in pregnancy., Competing Interests: Conflict of interestThere is no conflict of interest in the present study., (© Federation of Obstetric & Gynecological Societies of India 2023. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

Due to industrialization and urbanization, the use of detergents inadvertently led to contamination of aquatic environments, thus posing potential threat to aquatic organisms and human health. One of the main components of detergents is linear alkylbenzene sulfonate (LAS), which can cause toxic effects on living organisms, particularly aquatic life in the environment. In this study, floating treatment wetlands (FTWs) mesocosms were developed and augmented with LAS-degrading bacteria. The plant species, Brachiaria mutica (Para grass), was vegetated to establish FTWs and bacterial consortium (1:1:1:1) of Pseudomonas aeruginosa strain PJRS20, Bacillus sp. BRRH60, Acinetobacter sp. strain CYRH21, and Burkholderia phytofirmans Ps.JN was augmented (free or immobilized) in these mesocosms. Results revealed that the FTWs removed LAS from the contaminated water and their augmentation with bacteria slightly increased LAS removal during course of the experiment. Maximum reduction in LAS concentration (94%), chemical oxygen demand (91%), biochemical oxygen demand (93%), and total organic carbon (91%) was observed in the contaminated water having FTWs augmented with bacterial consortium immobilized on polystyrene sheet. This study highlights that the FTWs supported with immobilized bacteria on polystyrene sheets can provide an eco-friendly and sustainable solution for the remediation of LAS-bearing water, especially for developing countries like Pakistan.

Chemical kindling is broadly used experimental model to investigate novel treatments on the process of epileptogenesis and coexisting behavioral comorbidities. The current study aimed to investigate the low dose perampanel (PER) (0.125 and 0.5 mg/kg) and pregabalin (PG) (15 mg/kg) as standalone treatments and in combination on kindling-induced seizure progression with concurrent electroencephalographic alterations. Mice were subjected to pentylenetetrazole (PTZ)-induced kindling followed by neurobehavioral assessment for anxiety-like activity and cognitive deficit through behavioral experiments. The monotherapy with PER at 0.5 mg/kg and PG at 15 mg/kg delayed the kindling process but PRP+PG yielded pronounced benefits and hindered the development of seizures of higher severity. PER+PG combination relieved the animals from anxiety-like behavior in various employed anxiogenic tests. Furthermore, the kindling-associated cognitive deficit was protected by PER+PG combination as increased alteration behavior, discrimination index and latencies to enter the dark zone were noted in y-maze, object recognition and passive avoidance tests, respectively while shorter escape latencies were noted in water maze. The brain samples of kindled mice had elevated malondialdehyde and reduced catalase, superoxide dismutase and glutathione peroxidase enzymes while treatment with PER and PG combination shielded the mice from heightened kindling-associated oxidative stress. Overall, the findings of the present study illustrate that concurrent administration of PER and PG effectively hindered the process of epileptogenesis by protecting neuronal excitability and brain oxidative stress. The results predict the dominance of PER and PG combination over monotherapy which might serve as an effective novel combination to combat drug resistance and behavioral disorders in epileptic patients., Competing Interests: Declaration of Competing Interest I hereby on the behalf of all contributing authors declare that we have no conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Perampanel (PER), a novel 3rd-generation antiseizure drug that modulates altered post-synaptic glutamatergic storming by selectively inhibiting AMPA receptors, is recently approved to treat intractable forms of seizures. However, to date, presumably consequences of long-term PER therapy on the comorbid deleterious psychiatric disturbances and its correlation with neuroinflammatory parameters are not fully investigated in chronic models of epilepsy. Therefore, we investigated the real-time effect of PER on brain electroencephalographic (EEG) activity, behavioral alterations, redox balance, and relative mRNA expression in pentylenetetrazole (PTZ) induced kindling. Male BALB/c mice were pretreated with PER (0.125, 0.25, and 0.5 mg/kg) for 3 weeks and challenged with 11 injections of PTZ at the sub-threshold dose of 40 mg/kg every other day. vEEG from implanted cortical electrodes was monitored to elucidate seizure propagation and behavioral manifestations. Recorded EEG signals exhibited that PER 0.5 mg/kg pretreatment exceptionally impeded the onset of sharp epileptic spike-wave discharges and associated motor symptoms. Additionally, qEEG analysis showed that PER prevented alterations in absolute mean spectral power and reduced RMS amplitude of epileptogenic spikes vs PTZ control. Furthermore, our outcomes illustrated that PER dose-dependently attenuated PTZ-evoked anxiety-like behavior, memory deficits, and depressive-like behavior that was validated by a series of behavioral experiments. Moreover PER, significantly reduced lipid peroxidation, AChE, and increased levels of SOD and total thiol in the mice brain via AMPAR antagonism. Post-PTZ kindling provoked overstimulation of BDNF/TrkB signaling and increased release of pro-inflammatory cytokines that were reversed by PER with suppression of iNOS in brain immune cells. In conclusion, our findings highlight that PER might play an auspicious preventive role in the proepileptic transformation of brain circuits via suppression of BDNF/TrkB signaling and reduced transcriptional levels of neuroinflammatory markers leading to improvised epilepsy-induced neurobehavioral and neurochemical effects., 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., (© 2023 The Author(s).)

Purpose: The prevalence of urinary stone disease in ESRD is 3.2%, leading to renal damage due to obstructive uropathy, infection, and frequent surgical intervention. PCNL, the gold standard for complex renal stone disease, has evolved with smaller access sheaths (14-20 F), improved optics, and fluoroscopic equipments. This study aims to assess the safety and feasibility of mini- PCNL in CKD patients with respect to postoperative outcome and its effect on stage of CKD., Patients and Methods: This prospective study was conducted in the Department of Urology, Sher-I-Kashmir Institute of Medical Sciences, from January 2022 to October 2022. This study included adult patients with nephrolithiasis at CKD stage 3 or higher. The primary objective of this research was to assess the impact of mini-PCNL on renal function, specifically measuring changes in estimated glomerular filtration rate (eGFR) from baseline to a 6-month follow-up. The secondary objective was to evaluate the feasibility of mini-PCNL in CKD patients in terms of complications, stone clearance rate, and duration of hospital stay. Four variable Modification of Diet in Renal Diseases(MDRD) equation was used to calculate the estimated GFR(eGFR) of each patient and NKF/KDOQI classification system to classify the stage of CKD., Results: A total of 46 patients were included in the study. We found that for management of nephrolithiasis in CKD patients, mini-PCNL leads to significant improvement in eGFR at 6 months follow-up (mean difference = 14.25 ml/min/1.73 m 2 ; p-value <0.01) with high stone-free rates (89.5%). The complication rates were comparable to standard PCNL., Conclusions: mini-PCNL is a bonanza for management of CKD patients with nephrolithiasis., Competing Interests: No potential conflict of interest was reported by the author(s)., (© 2023 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.)

Introduction: Vildagliptin, a dipeptidyl peptidase-4 inhibitor, is indicated to cure type 2 diabetes mellitus (T2DM). This systematic literature search aims to assess the current knowledge about the clinical pharmacokinetics (PK) of vildagliptin to provide recommendations for clinical use to prevent the harmful effects of this drug., Methods: The PubMed, Science Direct, EBSCO, Cochrane Central Register of Controlled Trials, and Google Scholar databases were screened for articles related to the clinical PK of vildagliptin using systematic search strategies., Results: The literature search identified 2118 records, among which 28 were subsumed in this systematic review that fulfilled the inclusion standards., Conclusions: This systematic review can help dose optimization among critically ill patients (e.g. renal impairment) without exposing them to the drug's toxic effects.

Nebivolol is a beta-1 receptor blocker used to treat hypertension, heart failure, erectile dysfunction, vascular disease, and diabetes mellitus. This review investigated the data regarding pharmacokinetic (PK) parameters, drug-drug interactions, dextrorotatory (D), and levorotatory (L) stereoisomers of nebivolol. The articles related to the PK of nebivolol were retrieved by searching the five databases; Google Scholar, PubMed, Cochrane Library, ScienceDirect, and EBSCO. A total of 20 studies comprising plasma concentration-time profile data following the nebivolol's oral and intravenous (IV) administration were included. The area under the concentration-time curve from zero to infinity (AUC 0-∞ ) was 15 times greater in poor metabolizers (PMs) than in extensive metabolizers (EMs). In hypertensive patients, L-nebivolol expressed a higher maximum plasma concentration (C max ) than D-nebivolol, i.e. 2.5 ng/ml vs 1.2 ng/ml. The AUC 0-∞ of nebivolol was 3-fold greater in chronic kidney disease (CKD). The clearance (CL) was increased in obese than in controls from 51.6 ± 11.6 L/h to 71.6 ± 17.4 L/h when 0.5 mg/ml IV solution was infused. Nebivolol showed higher C max , AUC 0-∞ and half-life (t 1/2 ) when co-administered with bupropion, duloxetine, fluvoxamine, paroxetine, lansoprazole, and fluoxetine. This concise review of nebivolol would be advantageous in assessing all PK parameters, which may be crucial for clinicians to avoid drug-drug interactions, prevent adverse drug events and optimize the dosage regimen in diseased patients diagnosed with hypertension and cardiovascular disorders.

In this article, we report the synthesis, characterization of novel biofriendly 2D/2D heterostructure WS 2 /ZnIn 2 S 4 material in which 2D WS 2 nanosheets are uniformly distributed spatially onto the spherically arranged 2D leaves of ZnIn 2 S 4 . We then studied the in-depth photocatalytic degradation activity of this novel nanocomposite and its pristine component materials on cationic dye: malachite green, anionic dye: congo red and reduction of heavy metal: chromium(VI) and the degradation efficiency of composite material was also tested on rhodamine-B, methylene blue, methyl orange dyes and acetaminophen/paracetamol drug. Form factor, structure factor and shape factor analysis has been carried out using X-ray diffractometry (XRD). Bond vibrations, functional groups and phonon vibration mode analysis has been done based on Fourier transform infrared (FTIR) spectroscopy and Raman spectroscopy. Morphological and compositional analysis has been done using field emission scanning electron microscopy (FE-SEM), energy dispersive X-ray spectroscopy (EDAX) and X-ray photoelectron spectroscopy (XPS), high-resolution transmission electron microscopy (HR-TEM). Surface area and pore size/distribution was characterized using Brunauer-Emmett-Teller (BET) method and Barrett-Joyner-Halenda Model. Degradation pathways and intermediate products are proposed using the high-performance liquid chromatography (HPLC). Photocatalytic activity of the nanocomposite WS 2 /ZnIn 2 S 4 is compared with pristine ZnIn 2 S 4 and pristine WS 2 , which shows more than 50% enhancement in both efficiency and rate of degradation/reduction for all the pollutants. A scavenger study was carried out to get insight of primary and secondary reactive oxygen species (ROS) taking part in degradation. Exciton lifetime, surface charge and stability, and flat band positions were studied based on time-correlated single photon counting (TCSPC) also known as time-resolved photoluminescence (TRPL), zeta potential, and Mott-Schottky respectively. Rate kinetics study was performed to analyze the physical and chemical behaviour of the nanocomposite with pollutants in consideration. Results show ∼100%, ∼90%, and ∼95% degradation efficiency by the heterostructure for malachite green (MG), congo red (CR), and reduction of heavy metal chromium (Cr(VI)) respectively within 5 min, which is a huge improvement as compared to pristine WS 2 and pristine ZnIn 2 S 4 , both of which show the efficiencies of only ∼25% to∼75% in all the cases., Competing Interests: Declaration of competing interest We declare that we have no conflict of interest that could inappropriately influence, or appear to influence, the content of our research. We have not received any financial or non-financial incentives that could be perceived as influencing the content of our research., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Herbal products have been very popular in Pakistan for their curative significance against various disorders. Demaghi (DEMG) is a widely used herbal product claimed to own natural substances having neuroprotective potential. The current study aims to scientifically validate the chemical composition as well as its neuroprotective claims of this widely used herbal tonic. The commercially available Demaghi product was chemically characterized for its phytocomposition. The mice were treated with two doses of Demaghi (DEMG 50 mg and 100 mg/kg/day), and the effects of its prolonged exposure on animal anxiety, memory, and depression were noted through a series of behavioral tests in the AlCl 3 -induced memory deficient mice model. Besides that, dissected brains were biochemically analyzed for oxidative stress markers and acetylcholinesterase activity, as well as histopathological changes. The study outcomes showed that DEMG (100 mg/kg/day) has prominent anti-anxiety effects, memory-enhancing properties, and anti-depressants effects observed in the AlCl 3 -induced memory-deficient mice model. Biochemical assays also showed a greater decrease in oxidative stress of tested animals treated with 100 mg/kg/day of DEMG. The histopathological analysis also revealed that administration of DEMG reduced the AlCl 3 -induced toxicity. UPLC-MS results revealed the presence of many phytoconstituents, which showed to support cholinergic signaling in in-silico studies. The current research validates the neurological benefits of Demaghi for memory-boosting properties. The phytocompounds present in Demaghi exert neuroprotective effects, possibly by enhancing the cholinergic neurotransmission and combating the neurotoxin-induced oxidative stress., 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., (© 2023 The Authors.)

Cancer is one of the leading causes of death worldwide, and its incidence and mortality are increasing each year. Improved therapeutic strategies against cancer have progressed, but remain insufficient to invert this trend. Along with several other risk factors, abnormal genetic and epigenetic regulations play a critical role in the initiation of cellular transformation, as well as tumorigenesis. The epigenetic regulator UHRF1 (ubiquitin-like, containing PHD and RING finger domains 1) is a multidomain protein with oncogenic abilities overexpressed in most cancers. Through the coordination of its multiple domains and other epigenetic key players, UHRF1 regulates DNA methylation and histone modifications. This well-coordinated dialogue leads to the silencing of tumor-suppressor genes (TSGs) and facilitates tumor cells' resistance toward anticancer drugs, ultimately promoting apoptosis escape and uncontrolled proliferation. Several studies have shown that the downregulation of UHRF1 with natural compounds in tumor cells induces the reactivation of various TSGs, inhibits cell growth, and promotes apoptosis. In this review, we discuss the underlying mechanisms and the potential of various natural and synthetic compounds that can inhibit/minimize UHRF1's oncogenic activities and/or its expression.

Tiagabine (Tia), a new-generation antiseizure drug that mimics the GABAergic signaling by inhibiting GABA transporter type-1, is the least studied molecule in chronic epilepsy models with comorbid neurobehavioral and neuroinflammatory parameters. Therefore, the current study investigated the effects of Tia in a real-time manner on electroencephalographic (EEG) activity, behavioral manifestations and mRNA expression in pentylenetetrazole (PTZ)-kindled mice. Male BALB/c mice were treated with tiagabine (0.5, 1 and 2 mg/kg) for 21 days with simultaneous PTZ (40 mg/kg) injection every other day for a total of 11 injections and monitored for seizure progression with synchronized validation through EEG recordings from cortical electrodes. The post-kindling protection from anxiety and memory deficit was verified by a battery of behavioral experiments. Isolated brains were evaluated for oxidative alterations and real-time changes in mRNA expression for BDNF/TrkB, GAT-1 and GAT-3 as well as neuroinflammatory markers. Experimental results revealed that Tia at the dose of 2 mg/kg maximally inhibited the development of full bloom seizure and reduced epileptic spike discharges from the cortex. Furthermore, Tia dose-dependently exerted the anxiolytic effects and protected from PTZ-evoked cognitive impairment. Tia reduced lipid peroxidation and increased superoxide dismutase and glutathione levels in the brain via augmentation of GABAergic modulation. PTZ-induced upregulated BDNF/TrkB signaling and pro-inflammatory cytokines were mitigated by Tia with upregulation of GAT-1 and GAT-3 transporters in whole brains. In conclusion, the observed effects of Tia might have resulted from reduced oxidative stress, BDNF/TrkB modulation and mitigated neuroinflammatory markers expression leading to reduced epileptogenesis and improved epilepsy-related neuropsychiatric effects., Competing Interests: Conflict of interest statement The authors declare no conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Introduction: Ailanthus altissima is an indigenous plant known for various remedial properties. The present study aimed to evaluate the neuroprotective potential of methanolic extract Ailanthus altissima (AA) bark as current scientific trend is searching plant for neurodegenerative diseases, worldwide., Methodology: In in-vitro experiments, the AA was analyzed for phenols, flavonoids, antioxidative and cholinesterase inhibitory properties with subsequent detailed characterization for secondary metabolites. The in-vivo neurological effects were evaluated in rats through behavioral assessment for anxiety and memory after chronic administration (28 days) of 50-200 mg/kg of AA. At the end of behavior studies, isolated brains were biochemically tested to determine antioxidant enzyme activity., Results: AA was found rich in phenols/flavonoids and active in radical scavenging with the presence of 13 secondary metabolites in UHPLC-MS analysis. The AA yielded anxiolytic effects dose-dependently in the open field, light/dark and elevated-plus maze tests as animals significantly (P < 0.05 vs control group) preferred open arena, illuminated zone and exposed arms of maze. Similarly, the animals treated with AA showed significant (P < 0.05 vs amnesic group) increase in spontaneous alternation, discrimination index in y-maze, novel object recognition tests. Further, AA.Cr treated rats showed noticeably shorter escape latencies in Morris water maze tests.In biochemical analysis, the dissected brains AA treated rats showed reduced levels of AChE and malondialdehyde with increased levels of first-line antioxidant enzymes i.e. glutathione peroxidase and superoxide dismutase. These observed biological effects might be attributed to phenols and flavonoids constituents owned by AA. - The in-silico studies showed thatconessine and lophirone J phytocompounds have good blood-brain barrier permeability and interaction with AChE., Conclusion: The outcomes of this study validate that bark of Ailanthus altissima might work as a source of bioactive phytochemicals of neuroprotective potential., 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., (© 2022 The Author(s).)

Terbutaline is used for the management of bronchospasm associated with asthma, bronchitis, emphysema, and chronic obstructive pulmonary disease. A systematic review would be beneficial to assess the impact of routes of administration, stereoisomerism, disease states, smoking, age, exercise, and chronobiology on pharmacokinetics (PK) of terbutaline in humans. PubMed and Google Scholar databases were searched to screen all the relevant articles consisting of at least one of the PK parameters after administration of oral, inhaled, and intravenous (IV) terbutaline in humans. Oral studies of terbutaline depicted a linear relationship between plasma concentration (C p ) and the administered dose. The IV studies demonstrated multi-exponential behavior for disposition and renal clearance. Higher systemic availability was observed with inhaled as compared to oral route, and chrono-pharmacokinetic behavior was notable. Time to reach maximum plasma concentration (T max ) was prolonged, and maximum plasma concentration (C max ) was lowered after exercise. The primary route of excretion in chronic kidney disease (CKD) patients is reported to be nonrenal. In pregnant women, the C p of terbutaline is lowered and clearance is increased. The addition of theophylline to terbutaline did not affect the PK of terbutaline; hence, both can be used without dose adjustment. This review summarizes all the available PK parameters of terbutaline, and it may be helpful for researchers in the development and evaluation of PK models as well as in designing optimal dosage regimens in different clinical conditions., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The Syzygium cumini (L.) Skeels is reported to have medicinal properties, but its benefits on age-related neurological changes have not been previously explored. In the current study, after phytochemical analysis of the pulp of Syzygium cumini (L.) Skeels fruit ( Sy. cmi ), young BALB/c mice have been supplemented with its 5, 15, and 30% dilution for 16 months, followed by behavioral experimentation and biochemical evaluation of isolated brains. The Sy. cmi has been found enriched with phenols/flavonoids while the occurrence of nine phytocompounds has been identified through GC-MS analysis. Further, Sy. cmi supplementation has caused significant ( p < 0.05) protection from anxiety-like behavior in aged mice, and they have explored open, illuminated, and exposed areas of open field, light/dark, and an elevated plus maze, respectively. Furthermore, these animals have shown improved cognitive abilities as their percent (%) spontaneous alteration and novelty preference are significantly greater in T-maze and Y-maze and familiarity/novelty recognition tests. Further, Sy. cmi -supplemented mice remember the aversive stimuli zone and escape box location in passive avoidance and Barnes maze tests, and their brains have low levels of malondialdehyde and acetylcholinesterase with elevated antioxidant enzymes. The outcomes have provided scientific insight into the beneficial effects of Sy. cmi on age-associated amnesia that might be attributed to antioxidant and anticholinergic effects exerted by phytocompounds (caryophyllene, humulene, β-Farnesene, and phytol) owned by Syzygium cumini .

Patients suffering from chronic diseases are more likely to experience pDDIs due to older age, prolonged treatment, severe illness and greater number of prescribed drugs. The objective of the current study was to assess the prevalence of pDDIs and risk factors associated with occurrence of pDDIs in chronic disease patients attending outpatient clinics for regular check-ups. Patients suffering from diabetes, chronic obstructive pulmonary disease (COPD), stroke and osteoporosis were included in the study. This study was a cross sectional, observational, prospective study that included 337 patients from outpatient clinics of respiratory ward, cardiac ward and orthopedic ward of Nishter Hospital Multan, Pakistan. The mean number of interactions per patient was 1.68. A greater risk for occurrence of pDDI was associated with older age ≥ 60 years (OR = 1.95, 95% CI = 1.44-2.37, p<0.001); polypharmacy (≥ 5 drugs) (OR = 3.74, 95% CI 2.32-4.54, p<0.001); overburden (OR = 2.23, 95% CI = 1.64-3.16, p<0.01); CCI score (OR = 1.28, 95% CI = 1.04-1.84, p<0.001); multiple prescribers to one patient (OR = 1.18, 95% CI = 1.06-1.41, p<0.01); and trainee practitioner (OR = 1.09, 95% CI = 1.01-1.28, p<0.01). Old age, polypharmacy, overburden healthcare system, higher comorbidity index, multiple prescribers to one patient and trainee practitioner were associated with increased risk of occurrence of pDDIs in chronic disease patients., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Rasool et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Introduction: Hydralazine is a vasodilator used to treat hypertension, pre-eclampsia, and heart failure. The current article reviews the clinical pharmacokinetics (PK) of hydralazine, which can be useful for clinicians in optimizing its dose and dosing frequency to avoid adverse effects and unexpected interactions that could risk patients' lives., Areas Covered: This review has summarized the PK parameters for hydralazine after performing an extensive literature search. It includes 20 publications that were selected after applying eligibility criteria out of a pool of literature that was searched using Google Scholar, PubMed, Cochrane Central, and EBSCO databases. The included studies consisted of concentration vs. time profiles of hydralazine. If the PK data were not tabulated in the given study, the concentration vs. time profiles were scanned for the extraction of the PK data. The PK parameters were calculated by applying a non-compartmental analysis (NCA)., Expert Opinion: The current review will aid clinicians in understanding hydralazine PK in different disease populations. This clinical PK data might also be helpful in the development of a pharmacokinetic model of hydralazine.

Introduction: Diabetes mellitus causes hyperglycemia and associated complications to the brain. In current study, the traditionally reported remedial claims of Agave americana var. marginata has been scientifically investigated in diabetic rats., Methodology: The methanolic extract of leaves of Agave americana var. marginata (Aa.Cr) was characterized for total phenols, flavonoids, and antioxidant potential through in-vitro testing. The rats chronically pre-treated with Aa.Cr (400 and 600 mg/kg) for 45 days were challenged with alloxan-induced hyperglycemia. The dose-dependent effects of Aa.Cr on blood glucose levels and body weights were compared with diabetic rats using glibenclamide (0.6 mg/kg) as a standard. The animals were tested for diabetes-associated neurological comorbidities through behavioral and biochemical evaluation., Results: The phenols and flavonoids enriched Aa.Cr caused a significant dose-dependent hypoglycemic effect. Aa.Cr showed protection from comorbid anxiety, depression and cognitive impairment as compared to diabetic rats. The alanine aminotransferase, total cholesterol, triglycerides and low-density lipoprotein were prominently reduced, and high-density lipoprotein was increased in rats treated with Aa.Cr. Moreover, the oxidative stress in isolated brains was reduced by Aa.Cr., Conclusion: These findings suggest that Aa.Cr is enriched with antioxidant and anti-inflammatory phytoconstituents valuable for diabetes and related neurological complications., 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., (© 2022 The Authors.)

What Is Known and Objective: Nadolol is a non-selective beta-adrenergic antagonist that is used for the treatment of hypertension and angina. The primary route for its administration is oral. It is given once daily as it has a longer half-life (t½). The purpose of conducting this systematic review is to provide a comprehensive view of all the available pharmacokinetic (PK) data on nadolol in humans. This review aimed to systematically collate and analyze publish data on the clinical PK of nadolol in humans and this can be beneficial for the clinicians in dosage adjustments., Methods: Two electronic databases PubMed and Google Scholar were used for conducting a systematic literature search. All the relevant articles containing PK data of nadolol in humans were retrieved. A total of 1275 articles were searched from both databases and after applying eligibility criteria finally, 22 articles were included for conducting the systematic review., Results and Discussion: The area under the plasma concentration curve (AUC) and maximum plasma concentration (C max ) of nadolol increased in a dose-dependent manner. The t½ of nadolol was increased to double (18.2-68.6 h) in the patients with chronic kidney disease while the serum t½ became shorter (3.2-4.3 h) when administered to the children. The bioavailability of nadolol was greatly reduced by the coadministration of green tea. Nadolol can be effectively removed by hemodialysis. It undergoes enterohepatic circulation thus activated charcoal decreased its bioavailability., What Is New and Conclusion: Since, there is no previous report of a systematic review on the PK of nadolol, the current review encompasses all the relevant published articles on nadolol in humans. The analysis and understanding of PK parameters (AUC, C max , and t½) of nadolol may be helpful in the development and evaluation of PK models., (© 2022 John Wiley & Sons Ltd.)

In this paper, we report the synthesis of zinc indium sulfide (ZnIn 2 S 4 ) microspheres synthesized via a low-temperature route, and the as-synthesized material was used for photocatalytic degradation of malachite green (MG), methyl orange (MO), and Direct Red 80 (DR-80) dyes. The as-synthesized material was characterized by powder X-ray diffraction and field-emission scanning electron microscopy for studying the crystal structure and surface morphology, respectively. Fourier transform infrared spectroscopy was performed to determine the functional groups attached. UV-Visible absorption spectrometry was done for light absorbance and band gap analysis, and Mott-Schottky analysis was performed to determine the nature and flat band potential of the material. A scavenger study was performed to analyze the active species taking part in the degradation process. The reusability of the material was tested up to four cycles to check the reduction in efficiency after each cycle. A time-correlated single-photon counting study was performed to observe the average lifetime of generated excitons during photocatalysis. It was found that the as-synthesized porous sample is more efficient in degrading the cationic dye than anionic dyes, which is further explained in the article., Competing Interests: The authors declare no competing financial interest., (© 2022 The Authors. Published by American Chemical Society.)

Introduction: The pentylenetetrazol (PTZ)-induced kindling model acts through the antagonism of central GABA A receptors and is one of the most widely used experimental animal models to study the characteristics of seizure development, behavioral manifestations and evaluation of antiseizure effects of existing and new drug candidates., Methodology: In the current study, we investigated the impact of chronically administered levetiracetam (50 mg/kg) and sodium selenite (Sod.Se: 0.25 and 0.5 mg/kg) alone and in combination during the kindling process (21 days) in rats. Moreover, the behavioral changes (through the integration of a wide array of behavioral tests) and markers of oxidative stress in isolated brain homogenates were assessed in PTZ- kindled rats., Results: The outcomes from the fully kindled rats revealed the increased seizure score and severity over time with marked behavioral deficits. However, the animals treated with the selected dose of LEV alone showed partial protection from epileptogenesis and amelioration (P < 0.05) of anxiety-like behavior (open filed, light/dark, elevated plus maze tests), cognitive impairment (y-maze, novel object recognition and water maze tests) and depression (sucrose preference test). Moreover, combining the LEV with sodium selenite resulted in a significant neuroprotective effect in comparison to monotherapy by reducing the disease progression and ameliorating behavioral outcomes. The combination of Sod.Se in a dose-dependent manner with LEV produced additive effects as maximum animals remained seizure-free compared to kindled rats (P < 0.05). The attenuation of PTZ induced oxidative stress was evident from the reduced malondialdehyde and elevated superoxide dismutase (SOD), catalase and glutathione peroxidase (GPx) level with P < 0.05, as compared to control epileptic rats. These observed results of combination therapy might be due to the antioxidant and neuroprotective properties of Sod.Se, thus augmenting the seizure-modifying potentials of levetiracetam., Conclusion: Overall, the current findings support the prominence of combining the Sod.Se with LEV, over monotherapy to deal with prevailing challenges of drug resistance and neuropsychiatric sufferings common in epileptic patients., 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., (© 2022 Published by Elsevier B.V. on behalf of King Saud University.)

The incidence of breast cancer is increasing in Pakistan as well as globally. Awareness of women about breast cancer plays a cornerstone role in its early detection, better management, and prevention. Keeping this in mind, a cross-sectional study was carried out to assess the awareness of female university students about breast cancer's risk factors, signs and symptoms, and breast cancer examination. The data was collected from female university students studying in Pakistan. A total of 774 participants completed the survey and recorded their responses on an online pre-tested self-administered questionnaire. Only 29.8% of the participants have identified breast cancer history in their first-degree relatives as a risk factor. Moreover, 14.1% of the participant considered that the use of oral contraceptives for more than 5 years can increase the risk of developing breast cancer. In addition, inward pulled nipple, wounds around the nipple, and abrupt changes in the breast size were considered as the sign and symptoms of breast cancer by 25.2%, 25.7%, and 31.7% of the participants, respectively. Moreover, only 20.9% of the participants identified the correct year for starting breast cancer examination and 44.4% of the respondents marked that mammography should be initiated after 40 years. Overall, the university female students of Pakistan were poorly aware of breast cancer's risk factors, signs and symptoms, and breast examination. This study has highlighted the need for initiation of aggressive strategies regarding breast cancer awareness in both the literate and illiterate female population of Pakistan., Competing Interests: The authors have declared that no competing interests exist.

Maritime pine bark is a rich source of polyphenolic compounds and is commonly employed as a herbal supplement worldwide. This study was designed to check the potential of maritime pine tannin extract (MPTE) in anticancer therapy and to determine the underlying mechanism of action. Our results showed that MPTE, containing procyanidin oligomers and lanostane type terpenoids, has an inhibitory effect on cancer cell proliferation through cell cycle arrest in the G2/M phase. Treatment with MPTE also induced apoptosis in a concentration-dependent manner in human cancer cell lines (HeLa and U2OS), as evidenced by the enhanced activation of caspase 3 and the cleavage of PARP along with the downregulation of the antiapoptotic protein Bcl-2. Interestingly, human non-cancerous fibroblasts are much less sensitive to MPTE, suggesting that it preferentially targets cancer cells. MPTE played a pro-oxidant role in cancer cells and promoted the expression of the p73 tumor suppressor gene in p53-deficient cells. It also downregulated the protooncogenic proteins UHRF1 and DNMT1, mediators of the DNA methylation machinery, and reduced the global methylation levels in HeLa cells. Overall, our results show that maritime pine tannin extract can play a favorable role in cancer treatment, and can be further explored by the pharmaceutical industry.

Purpose: Gastroesophageal reflux disease (GERD) is a highly prevalent gastrointestinal disorder with modifiable risk factors and it is associated with considerable health and economic burden. The current study was conducted to assess the frequency and risk factors related to GERD in the previously unstudied population of Southern Punjab, Pakistan., Methods: A cross-sectional study was conducted for assessing the frequency and risk factors of GERD by using a self-administered questionnaire. The gastroesophageal reflux disease questionnaire (GerdQ) was utilized to detect the presence of the disease., Results: The study included 308 participants; among them, 55.2% were female and 44.8% were male. The participants diagnosed with GERD (GerdQ score ≥8) were 26.6%. The various risk factors like higher BMI, past disease and smoking history, frequent use of NSAIDs, soft drinks, pickles, and spicy foods were significantly associated with GERD., Conclusion: The present study showed that GERD is prevalent in Southern Punjab and is associated with various modifiable risk factors. The ascendance of GERD can be prevented by public health education and awareness campaigns., Competing Interests: The authors report no conflicts of interest in this work., (© 2021 Rasool et al.)

Tat interactive protein, 60 kDa (TIP60) is an important partner of ubiquitin‑like, containing PHD and RING finger domains 1 (UHRF1), ensuring various cellular processes through its acetyltransferase activity. TIP60 is believed to play a tumor suppressive role, partly explained by its downregulated expression in a number of cancers. The aim of the present study was to investigate the role and mechanisms of action of TIP60 in the regulation of UHRF1 expression. The results revealed that TIP60 overexpression downregulated the UHRF1 and DNA methyltransferase 1 (DNMT1) expression levels. TIP60 interfered with USP7‑UHRF1 association and induced the degradation of UHRF1 in an auto‑ubiquitination‑dependent manner. Moreover, TIP60 activated the p73‑mediated apoptotic pathway. Taken together, the data of the present study suggest that the tumor suppressor role of TIP60 is mediated by its regulation to UHRF1.

The incidences of traumatic brain injuries (TBIs) are increasing globally because of expanding population and increased dependencies on motorized vehicles and machines. This has resulted in increased socio-economic burden on the healthcare system, as TBIs are often associated with mental and physical morbidities with lifelong dependencies, and have severely limited therapeutic options. There is an emerging need to identify the molecular mechanisms orchestrating these injuries to life-long neurodegenerative disease and a therapeutic strategy to counter them. This review highlights the dynamics and role of choline-containing phospholipids during TBIs and how they can be used to evaluate the severity of injuries and later targeted to mitigate neuro-degradation, based on clinical and preclinical studies. Choline-based phospholipids are involved in maintaining the structural integrity of the neuronal/glial cell membranes and are simultaneously the essential component of various biochemical pathways, such as cholinergic neuronal transmission in the brain. Choline or its metabolite levels increase during acute and chronic phases of TBI because of excitotoxicity, ischemia and oxidative stress; this can serve as useful biomarker to predict the severity and prognosis of TBIs. Moreover, the effect of choline-replenishing agents as a post-TBI management strategy has been reviewed in clinical and preclinical studies. Overall, this review determines the theranostic potential of choline phospholipids and provides new insights in the management of TBI.

Diazepam is one of the most prescribed anxiolytic and anticonvulsant that is administered through intravenous (IV), oral, intramuscular, intranasal, and rectal routes. To facilitate the clinical use of diazepam, there is a need to develop formulations that are convenient to administer in ambulatory settings. The present study aimed to develop and evaluate a physiologically based pharmacokinetic (PBPK) model for diazepam that is capable of predicting its pharmacokinetics (PK) after IV, oral, intranasal, and rectal applications using a whole-body population-based PBPK simulator, Simcyp ® . The model evaluation was carried out using visual predictive checks, observed/predicted ratios (R obs/pred ), and the average fold error (AFE) of PK parameters. The Diazepam PBPK model successfully predicted diazepam PK in an adult population after doses were administered through IV, oral, intranasal, and rectal routes, as the R obs/pred of all PK parameters were within a two-fold error range. The developed model can be used for the development and optimization of novel diazepam dosage forms, and it can be extended to simulate drug response in situations where no clinical data are available (healthy and disease).

During neuronal diseases, neuronal proteins get disturbed due to changes in the connections of neurons. As a result, neuronal proteins get disturbed and cause epilepsy. At the genetic level, many mutations may take place in proteins like axon guidance proteins, leucine-rich glioma inactivated 1 protein, microtubular protein, pore-forming, chromatin remodeling, and chemokine proteins which may lead toward temporal lobe epilepsy. These proteins can be targeted in the future for the treatment purpose of epilepsy. Novel avenues can be developed for therapeutic interventions by these new insights., (© 2021 John Wiley & Sons A/S.)

The increasing frequency of cesarean section (CS) is a major public health issue, and it is on the rise in Pakistan. A cross-sectional study approach was used to assess the frequency of CS and its contributing factors, along with the assessment of knowledge in mothers who had undergone CS in one of the under-developed regions of Pakistan. Data collection was done by using a self-developed study questionnaire. The statistical package for social sciences (SPSS) was utilized for the statistical analysis. During the study period, a total of 173 (69.7%) women have given births by CS; among those, 104 (60.1%) were elective/planned CSs while 69 (39.8%) were emergency CSs. The higher CS frequency was significantly associated with younger age ( p = 0.03) and pre-term gestational age ( p < 0.001). Pregnancy complications, such as gestational diabetes, hypertension, preeclampsia/eclampsia, and vaginal bleeding, were the significant risk factors for CS ( p < 0.001). The highlighted contributing factors to CS in the current study were preterm of gestational age, mothers of a younger age (20-24 years), and mothers that belong to urban populations. These risk factors can be addressed by implementing community-focused educational interventions during the gestational period. The sample size in this study was small; therefore, the results cannot be generalized to the whole population.

In the current study, we investigated the phytochemical and neuropharmacological potential of Indigofera sessiliflora , an indigenous least characterized plant widely distributed in deserted areas of Pakistan. The crude extract of the whole plant Indigofera sessiliflora (IS.CR) was preliminary tested in-vitro for the existence of polyphenol content, antioxidant and anticholinesterase potential followed by detailed chemical characterization through UHPLC-MS. Rats administered with different doses of IS.CR (100-300 mg/kg) for the duration of 4-weeks were behaviorally tested for anxiety and cognition followed by biochemical evaluation of dissected brain. The in-silico studies were employed to predict the blood-brain barrier crossing tendencies of secondary metabolites with the elucidation of the target binding site. The in-vitro assays revealed ample phenols and flavonoids content in IS.CR with adequate anti-oxidant and anticholinesterase potential. The dose-dependent anxiolytic potential of IS.CR was demonstrated in open field (OFT), light/dark (L/D) and elevated plus maze (EPM) tests as animals spent more time in open, illuminated and elevated zones (P < 0.05). In the behavioral tests for learning/memory, the IS.CR reversed the scopolamine-induced cognitive deficits, as animals showed better (P < 0.05) spontaneous alternation and discrimination index in y-maze and novel object recognition (NOR) tests. Similarly, as compared to amnesic rats, the step-through latencies were increased (P < 0.05) and escape latencies were decreased (P < 0.05) in passive avoidance (PAT) and Morris water maze (MWM) tests, respectively. Biochemical analysis of rat brains showed significant reduction in malondialdehyde and acetylcholinesterase levels, alongwith preservation of glutathione peroxidase and superoxide dismutase activity. The docking studies further portrayed a possible interaction of detected phytoconstituents with acetylcholinesterase target. The results of the study show valuable therapeutic potential of phytoconstituents present in IS.CR to correct the neurological disarrays which might be through antioxidant activity or via modulation of GABAergic and cholinergic systems by artocommunol, 1,9-dideoxyforskolin and 6E,9E-octadecadienoic acid., Competing Interests: The authors declare that they have no competing interests., (© 2021 The Author(s).)

The current study aims to assess the beliefs of the general public in Pakistan towards conspiracy theories, acceptance, willingness to pay, and preference for the COVID-19 vaccine. A cross-sectional study was conducted through an online self-administered questionnaire during January 2021. The Chi-square test or Fisher exact test was utilized for statistical data analysis. A total of 2158 respondents completed the questionnaire, among them 1192 (55.2%) were male with 23.87 (SD: ±6.23) years as mean age. The conspiracy beliefs circulating regarding the COVID-19 vaccine were believed by 9.3% to 28.4% of the study participants. Among them, 1040 (48.2%) agreed to vaccinate on its availability while 934 (43.3%) reported the Chinese vaccine as their preference. The conspiracy beliefs of the participants were significantly associated with acceptance of the COVID-19 vaccine. The existence of conspiracy beliefs and low vaccine acceptance among the general population is a serious threat to successful COVID-19 vaccination.

Background: The COVID-19 pandemic is not only affecting public health, but it is also impairing the specialized surgical care services in the hospitals. The present study aimed to assess the barriers faced by the surgeons while performing surgical procedures during the COVID-19 pandemic., Methods: A cross-sectional, web-based survey was conducted from September 10 to October 14, 2020. The study population consisted of surgeons practicing in Kpk, Pakistan. Descriptive statistics and binary logistic regression analysis were used to analyze the data., Results: A total of 292, out of 543, surgeons participated in the study (response rate: 59.6%). The younger surgeons (25-30 years) considered the lack of policies and practices regarding exposure to COVID-19 patients as a significant barrier to their practice. The surgeons practicing in private hospitals considered themselves at a higher risk while providing surgical care to the COVID-19 patients. The non-cooperation of the patients was the main barrier in delivering surgical care services., Conclusion and Recommendation: The current study highlighted the barriers to the surgeons while providing surgical care to patients in the current pandemic. The most pronounced barriers to the surgeons were the lack of policies regarding exposure to COVID-19 and practice and non-cooperation of the patient. To address these barriers, it is recommended that health regulatory agencies of Pakistan should implement strict infection control practices to ensure the safety of surgeons and allied healthcare staff during the COVID-19 pandemic., Competing Interests: The authors declare no conflicts of interest., (© 2021 Majeed et al.)

The current study was planned to investigate the pharmacological basis of Solanum virginianum extract (SV.CR) pertaining to anxiolytic, antidepressant and memory-enhancing effects in rats. The SV.CR was analyzed in-vitro for phytoconstituents, antioxidant potential and anticholinesterase activity. The rats treated in a dose-dependent manner (25, 50 and 100 mg/kg of SV.CR) were subjected to behavioral tests for anxiety, depression and memory judgment followed by biochemical studies. A notable dose-dependent anxiolytic potential of SV.CR was observed in elevated plus maze and open field tests (P < 0.05). The decreased immobility time of the treated rats in the forced swim test (P < 0.01) unveiled the plant's potential to reduce depression. Moreover, SV.CR treatment also reversed scopolamine-impaired cognition (P < 0.05) in various deployed memory and learning tasks. Biochemical studies of brain homogenates of SV.CR treated animals demonstrated decreased anticholinesterase activity and lipid peroxidation levels whereas increased levels of superoxide dismutase and glutathione peroxidase (P < 0.05 vs scopolamine group) were noted. The scientific validation of the study supported the use of Solanum virginianum in reducing anxiety, depression and amnesia in experimental models. Phytoconstituents in SV.CR such as oleanolic acid and caffeic acid might have played a significant neuroprotective role via modulation of oxidative stress and neurochemical aspects., Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2021.)

In 30% of epileptic individuals, intractable epilepsy represents a problem for the management of seizures and severely affects the patient's quality of life due to pharmacoresistance with commonly used antiseizure drugs (ASDs). Surgery is not the best option for all resistant patients due to its post-surgical consequences. Therefore, several alternative or complementary therapies have scientifically proven significant therapeutic potential for the management of seizures in intractable epilepsy patients with seizure-free occurrences. Various non-pharmacological interventions include metabolic therapy, brain stimulation therapy, and complementary therapy. Metabolic therapy works out by altering the energy metabolites and include the ketogenic diets (KD) (that is restricted in carbohydrates and mimics the metabolic state of the body as produced during fasting and exerts its antiepileptic effect) and anaplerotic diet (which revives the level of TCA cycle intermediates and this is responsible for its effect). Neuromodulation therapy includes vagus nerve stimulation (VNS), responsive neurostimulation therapy (RNS) and transcranial magnetic stimulation therapy (TMS). Complementary therapies such as biofeedback and music therapy have demonstrated promising results in pharmacoresistant epilepsies. The current emphasis of the review article is to explore the different integrated mechanisms of various treatments for adequate seizure control, and their limitations, and supportive pieces of evidence that show the efficacy and tolerability of these non-pharmacological options., 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., (© 2020 The Author(s).)

This report presents the superior visible-light-driven photocatalytic response of novel 2D/2D BiOCl/WS 2 (BW X ) hybrid nanosheet heterojunctions prepared by a simple solution based sonochemical technique. These BW X hybrid nanosheets are composed of 2D transition metal dichalcogenide material WS 2 and BiOCl nanosheets. The comparative study of photocatalytic activity of BiOCl and BiOCl/WS 2 hybrid nanosheets is carried out via photodegradation of Malachite Green (MG) and photoreduction of heavy metal ion Cr(vi) under visible light irradiation. The quantum efficiency of the samples is estimated in terms of the incident photon to electron conversion efficiency (IPCE) measurements. Nearly 98.4% of the MG degradation was achieved over BiOCl/WS 2 (2%) photocatalyst in 45 min of irradiation. BiOCl/WS 2 (2%) hybrid nanosheet catalyst showed the highest external quantum efficiency (EQE) in both the UV and visible regimes. This accomplishment demonstrated the promise of commercial application of the 2D/2D BiOCl/WS 2 (2%) hybrid nanosheet photocatalyst., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

During DNA replication, ubiquitin-like, containing PHD and RING fingers domains 1 (UHRF1) plays key roles in the inheritance of methylation patterns to daughter strands by recognizing through its SET and RING-associated domain (SRA) the methylated CpGs and recruiting DNA methyltransferase 1 (DNMT1). Herein, our goal is to identify UHRF1 inhibitors targeting the 5'-methylcytosine (5mC) binding pocket of the SRA domain to prevent the recognition and flipping of 5mC and determine the molecular and cellular consequences of this inhibition. For this, we used a multidisciplinary strategy combining virtual screening and molecular modeling with biophysical assays in solution and cells. We identified an anthraquinone compound able to bind to the 5mC binding pocket and inhibit the base-flipping process in the low micromolar range. We also showed in cells that this hit impaired the UHRF1/DNMT1 interaction and decreased the overall methylation of DNA, highlighting the critical role of base flipping for DNMT1 recruitment and providing the first proof of concept of the druggability of the 5mC binding pocket. The selected anthraquinone appears thus as a key tool to investigate the role of UHRF1 in the inheritance of methylation patterns, as well as a starting point for hit-to-lead optimizations., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Fumaria officinalis belongs to family papaveraceae and is traditionally used to treat hypertension, hepatitis and diabetes. The current study was conducted to evaluate in vitro and in vivo antidiabetic activity of Fumaria officinalis. Aerial parts of the plant were sequentially extracted with n-hexane, chloroform, methanol and water. Phytochemical analysis was carried out on all extracts. Antioxidant activity was determined by 2,2-diphenyl-1-picryl hydrazyl (DPPH) inhibition method. In vitro alpha-amylase inhibitory activity was performed on all extracts by using dinitrosalicylic acid. Effect of aqueous and methanolic extracts of F. officinalis on blood glucose was evaluated in normo-glycaemic rats and alloxan induced diabetic rats. Glimepiride 0.2 mg/kg was used as standard therapy in diabetic rats. Results showed that methanolic extract exhibited the maximum percentage inhibition of DPPH (86.30%) and alpha-amylase inhibition (94.01%) at 500 µg/ml and 16 mg/ml concentration respectively. Administration in normo-glycaemic rats did not show any significant decrease in blood glucose level at 500 and 750 mg/kg dosage. Aqueous and methanolic extracts exhibited a significant hypoglycaemic effect (p˂0.05) at all doses. A significant increase in the body weight and an improvement in liver and kidney function tests of diabetic rats were observed. These extracts also reduced the damage to the cells of glomeruli, interstitial inflammation, necrosis of tubular cells and thrombosis in the kidney, the enlargement of sinusoids and steatosis in the liver of diabetic rats. This study concludes that F. officinalis may have antidiabetic potential possibly due to its antioxidant and alpha-amylase inhibitory activities.

Background: The nuclear epigenetic integrator UHRF1 is known to play a key role with DNMT1 in maintaining the DNA methylation patterns during cell division. Among UHRF1 partners, TIP60 takes part in epigenetic regulations through its acetyltransferase activity. Both proteins are involved in multiple cellular functions such as chromatin remodeling, DNA damage repair and regulation of stability and activity of other proteins. The aim of this work was to investigate the interaction between UHRF1 and TIP60 in order to elucidate the dialogue between these two proteins., Methods: Biochemical (immunoprecipitation and pull-down assays) and microscopic (confocal and fluorescence lifetime imaging microscopy; FLIM) techniques were used to analyze the interaction between TIP60 and UHRF1 in vitro and in vivo. Global methylation levels were assessed by using a specific kit. The results were statistically analyzed using Graphpad prism and Origin., Results: Our study shows that UHRF1, TIP60 and DNMT1 were found in the same epigenetic macro-molecular complex. In vitro pull-down assay showed that deletion of either the zinc finger in MYST domain or deletion of whole MYST domain from TIP60 significantly reduced its interaction with UHRF1. Confocal and FLIM microscopy showed that UHRF1 co-localized with TIP60 in the nucleus and confirmed that both proteins interacted together through the MYST domain of TIP60. Moreover, overexpression of TIP60 reduced the DNA methylation levels in HeLa cells along with downregulation of UHRF1 and DNMT1., Conclusion: Our data demonstrate for the first time that TIP60 through its MYST domain directly interacts with UHRF1 which might be of high interest for the development of novel oncogenic inhibitors targeting this interaction.

Cancer is one of the deadliest diseases in the world causing record number of mortalities in both developed and undeveloped countries. Despite a lot of advances and breakthroughs in the field of oncology still, it is very hard to diagnose and treat the cancers at early stages. Here in this review we analyze the potential of Ubiquitin-like containing PHD and Ring Finger domain 1 (UHRF1) as a universal biomarker for cancers. UHRF1 is an important epigenetic regulator maintaining DNA methylation and histone code in the cell. It is highly expressed in a variety of cancers and is a well-known oncogene that can disrupt the epigenetic code and override the senescence machinery. Many studies have validated UHRF1 as a powerful diagnostic and prognostic tool to differentially diagnose cancer, predict the therapeutic response and assess the risk of tumor progression and recurrence. Highly sensitive, non-invasive and cost effective approaches are therefore needed to assess the level of UHRF1 in patients, which can be deployed in diagnostic laboratories to detect cancer and monitor disease progression., Competing Interests: CONFLICTS OF INTEREST All authors report no conflicts of interest.