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Writing in English language is one of the most challenging skills faced by English language learners in Malaysia especially if they do not have a good proficiency in the language. This study seeks to identify ways to minimize the influence of L1 (Bahasa Melayu) into L2 (English) tenses writing. The data collection instrument was interview. To execute the study 8 students were interviewed from a public school in Ipoh. This study also discovered that the majority of the methods recommended by the students were cognitive in nature such as listening to songs, and using PowerPoint slides were the most popularly mentioned in the interview session. This study will help educators, students, curriculum coordinators, and decision-makers create the most engaging curriculum possible using effective teaching methods, especially for English language beginners.

Audio-Visual tools are devices used in classrooms to encourage learning and make it easier and more interesting. This research analysed the Audio-Visual learning tools effectiveness among TESL Undergraduate students from a Private University in Ipoh. Moreover, another purpose of this study was to help students discover the most effective way of learning using Audio-Visual tools in the classroom. This study focused on the quantitative method and questionnaires were the main tool for this study. The questionnaire was administered to 30 students of TESL Undergraduates, and the collected data was analysed through the SPSS software. As a whole, this research found that incorporating Audio-Visual tools was effective as it enhanced students' English Language learning experience.

Andrographolide is one of the main active principles of

A checklist of Cyanobacteria (Blue-green algae) has been made by reviewing available literature in order to contribute to the knowledge of biodiversity of algae in the Punjab state of India. The list records 317 taxa of the phylum Cyanobacteria distributed among 74 genera, 32 families, and six orders. The order Oscillatoriales has 115 taxa, followed by Nostocales (84), Synechococcales (60), Chroococcales (49), Spirulinales (8), and Pleurocapsales (1). The family Nostocaceae has the maximum number of genera followed by Microcoleaceae, Chroococcaceae, Oscillatoriaceae and other reported families. The genera with the highest number of species were Phormidium (39 species), Lyngbya (15 species), Oscillatoria (14 species), and Leptolyngbya & Scytonema (13 species each). The checklist revealed a high degree of species richness within phylum Cyanobacteria found in Punjab. This checklist can provide a baseline for future floristic studies with taxonomically updated/accepted name of genera/species of cyanobacteria.

Rottlerin is a key bioactive phytoconstituent present in the pericarp of Mallotus philippensis. It shows promising multifaceted pharmacological actions against cancer. However, there is hardly any report for the quantification of rottlerin in the biological matrix and on its pharmacokinetic behavior. Therefore, we aimed in the present study to assess selective in vitro ADME properties and in vivo pharmacokinetics of isolated and characterized rottlerin using a newly developed and validated liquid chromatography–tandem mass spectrometry-based highly sensitive bioanalytical method. The method was found to be simple (mobile phase and analytical column), sensitive (1.9 ng/mL), and rapid (run time of 2.5 min). All the validation parameters were within the acceptable criteria of the United States Food and Drug Administration’s bioanalytical method validation guideline. The method was found to be very useful to assess lipophilicity, plasma stability, metabolic stability, plasma protein binding of rottlerin, as well as its oral and intravenous pharmacokinetics in mice. Rottlerin showed a number of drug-like pharmacokinetic properties (in vitro). Moreover, it displayed an excellent half-life (>2 h) and oral bioavailability (>35%) as compared to other members of natural phenolics. The present study is the first-time report of in vitro ADME properties and in vivo preclinical pharmacokinetics of rottlerin. The generated information is very much useful for its further development as a phytotherapeutics toward cancer therapy.

Present study addresses the challenge of incorporating hydrophilic streptomycin sulphate (STRS; log P −6.4) with high dose (1 g/day) into a lipid matrix of SLNs. Cold high-pressure homogenization technique used for SLN preparation achieved 30% drug loading and 51.17 ± 0.95% entrapment efficiency. Polyethylene glycol 600 as a supporting-surfactant assigned small size (218.1 ± 15.46 nm) and mucus-penetrating property. It was conceived to administer STRS-SLNs orally rather than intramuscularly. STRS-SLNs remained stable on incubation for varying times in SGF or SIF. STRS-SLNs were extensively characterised for microscopic (TEM and AFM), thermal (DSC), diffraction (XRD) and spectroscopic (NMR and FTIR) properties and showed zero-order controlled release. Enhanced (60 times) intracellular uptake was observed in THP-1 and Pgp expressing LoVo and DLD-1 cell lines, using fluorescein-SLNs. Presence of SLNs in LoVo cells was also revealed by TEM studies. STRS-SLNs showed 3 times reduction in MIC against Mycobacterium tuberculosis H37RV (256182) in comparison to free STRS. It also showed better activity against both M. bovis BCG and Mycobacterium tuberculosis H37RV (272994) in comparison to free STRS. Cytotoxicity and acute toxicity studies (OECD 425 guidelines) confirmed in vitro and in vivo safety of STRS-SLNs. Single-dose oral pharmacokinetic studies in rat plasma using validated LCMS/MS technique or the microbioassay showed significant oral absorption and bioavailability (160% − 710% increase than free drug).

CYP2E1 is directly or indirectly involved in the metabolism of ethanol and endogenous fatty acids but it plays a major role in the bio-activation of toxic substances that produce reactive metabolites leading to hepatotoxicity. Therefore, identification of CYP2E1 inhibitor from bioflavonoids class having useful pharmacological properties has dual benefit regarding avoidance of severe food-drug/nutraceutical-drug interaction and scope to develop a phytotherapeutics through an intended pharmacokinetic interaction.In the present study, we aimed to identify CYP2E1 inhibitor from experimental bioflavonoids which are unexplored for CYP2E1 inhibition till date using in-silico, in-vitro and in-vivo approaches.Results of in-vitro CYP2E1 inhibitory studies using CYP2E1-mediated chlorzoxazone 6-hydroxylation in human liver microsomes showed that glabridin have the highest potential than fisetin, epicatechin, nobiletin, and chrysin to inhibit CYP2E1 enzyme. Mechanistic investigations indicate that glabridin is a competitive CYP2E1 inhibitor. Molecular docking study results demonstrate that glabridin strongly interacted with the active site of human CYP2E1 enzyme. Pharmacokinetics of a CYP2E1 substrate in mice model indicates a significant alteration of chlorzoxazone and 6-hydroxychlorzoxazone plasma levels in the presence of glabridin. Further studies are needed to confirm the results at clinical level.Overall, glabridin is found to be a potential CYP2E1 inhibitor.

Diclofenac is a widely prescribed anti-inflammatory drug having cardiovascular complications as one of the main liabilities that restrict its therapeutic use. We aimed to investigate for any role of rutin against diclofenac-induced cardiac injury with underlying mechanisms as there is no such precedent to date. The effect of rutin (10 and 20 mg/kg) was evaluated upon concomitant oral administration for fifteen days with diclofenac (10 mg/kg). Rutin significantly attenuated diclofenac-induced alterations in the serum cardiac markers (LDH, CK-MB, and SGOT), serum cytokine levels (TNF-α and IL-6), and oxidative stress markers (MDA and GSH) in the cardiac tissue. Histopathological examination and Scanning Electron Microscopy (SEM) findings displayed a marked effect of rutin to prevent diclofenac-mediated cardiac injury. Altered protein expression of myocardial injury markers (cTnT, FABP3, and ANP) and apoptotic markers (Bcl-2 and Caspase-3) in the cardiac tissue upon diclofenac treatment was considerably shielded by rutin treatment. MYL3 was unaffected due to diclofenac or rutin treatment. Rutin also significantly improved diclofenac-induced gastrointestinal and hepatic alterations based on the observed ameliorative effects in key mediators, oxidative stress markers, histopathology examination, and SEM findings. Overall results suggest that rutin can protect the diclofenac-induced cardiac injury by lowering oxidative stress, inhibiting inflammation, and reducing apoptosis. Further research work directs toward the development of phytotherapeutics for cardioprotection.

Investigations on “Influence of nodal pruning on vegetative and reproductive attributes of Sardar guava” were carried out in the orchard of Amarjit Singh at village Bargari in district Faridkot of South-Western Punjab. Pruning intensities consisted of removal of shoot tip up to 0, 4th, 6th and 8th node. There were five replications and the data were analyzed using Randomized Block Design. As per university recommendation, farmers are advised to opt for light pruning in guava, i.e., removal of shoot tip up to 10 cm in first fortnight of March. However, guava orchardists are of the view that pruning levels should be in terms of how many nodes to prune as it is easier for them to guide the pruning labor in terms of number of nodes to be pruned rather than in centimeters. To ascertain the above facts, On Farm Trial was conducted to find out the effect of nodal pruning on vegetative and reproductive attributes of Sardar guava. The results of investigation revealed that with the increase in severity of pruning, there was significant increase in shoot length. Severe pruning minimized the span of flowering as severe pruning level of 8-node pruning intensity recorded the shortest duration of flowering during both the rainy and winter season crops of both the years. Although, there was increment in fruit set with the enhanced severity of pruning, the results were non significant. 6-node pruning intensity recorded significantly higher fruit yield per tree during both the cropping seasons of both the years. There was significant increase in fruit weight with the increase in severity of pruning during the rainy and winter season crops of both the years. TSS/Acid ratio was not altered much by pruning intensity. On the other, there was a significant increase in ascorbic acid content of the fruits with the enhanced severity of pruning. On the whole, pruning to 6 nodes gave the highest fruit yield and accounted for production of fruits of good quality.

English language is one of the most important and second language after Bahasa Melayu, which is also a national language in Malaysia. Writing in English language is one of the most difficult skills for Malaysian students, especially if they do not have a good proficiency in the language. Objective of this study is to identify L2 (English) syntax transferred negatively and positively from L1 (Bahasa Melayu) in writing English (L2) essays among Form Two secondary school students. The design of this study is a qualitative which is appropriate to identify the phenomena. The data collection instruments were document analysis and interview. To execute this study, 20 writing samples were chosen from low proficiency level of students. They were instructed to write about 100 word essays on a given topic in English language. The syntax was later corroborated and compared to substantiate the theoretical arguments in the field of language transfer. From the findings, it was found that first language highly interferes in students' English language writing skills. In addition, it was found that the sample employed a translation method although they understand the significance of English language worldwide. To conclude, more actions should be taken in order to teach contrastive analysis for a better understanding of the differences in the syntax between Bahasa Melayu and English language.

One hundred fifty three front line demonstrations (FLDs) were conducted on farmers’ fields to demonstrate the effect of improved technologies on the productivity of canola type gobhi sarson var. GSC-7 using cluster approach in district Faridkot of Punjab during Rabi 2016-17 and 2017-18. The productivity of gobhi sarson under demonstration plots ranged between 19.2 to 20.4 q and 19.9 to 20.8 q/ha, respectively, for year 2016-17 and 2017-18, whereas, under farmers’ practice, the productivity varied from 14.1 to 14.2 q and 16.6 to 17.1 q/ha for the respective years. The maximum value of extension gap to the tune of 5.10 q/ha was recorded in cluster IV followed by cluster III and V (4.75 q/ha), cluster II (4.65 q/ha) and the least was in cluster I (4.10 q/ha). The technology gap in the demonstration plots over potential yield was the lowest i.e. 1.80 q/ha in cluster IV, whereas, the highest technology gap was recorded in cluster I (2.70q/ha). The technology index was 8.09 per cent for cluster IV and the highest (12.13%) for cluster I while the mean technology index was 9.48 per cent. The value of net returns per ha under demonstration plots was Rs. 71594 and Rs. 72170, whereas, farmers’ practice gave net returns per ha of Rs. 40626 and Rs. 52626 for the year 2016- 17 and 2017-18, respectively. The benefit: Cost ratio varied between 3.76 to 4.05 for 2016-17 and 3.73 to 4.04 for 2017-18 under demonstration plots while the value of same under farmers’ practice varied between 2.46 to 2.55 and 2.80 to 2.93, respectively, for year 2016-17 and 2017-18.

A study was conducted in South Western Punjab (India) during 2016-18 to assess the economic performance of clusterwise front line demonstration on chickpea (var PBG-7). One hundred ninety five front line demonstrations (FLDs) were conducted at farmers’ fields to demonstrate the effect of improved technologies on the productivity of chickpea using cluster village approach in Faridkot district of Punjab duringRabi 2016-17 and 2017-18. The productivity of chickpea under demonstration plots ranged between 11.9 to 13.2 q and 12.2 to 14.1 q/ha during year 2016-17 and 2017-18, respectively, whereas, under farmers’ practice the productivity varied from 9.5 to 10.7 q and 9.0 to 11.2 q/ha for respective years. The extension gap in the demonstration plots over potential yield was the lowest i.e., 1.8 q/ha in cluster I, whereas, the highest extension gap was recorded in cluster II (3.35q/ha) while the average extension gap over all the clusters was 2.57q/ha. The highest value of technology gap of 7.95 q/ha was recorded in cluster I, however, the least value was recorded in cluster IV (6.35) with the average technology gap of 7.10 q/ha over all the clusters. The technology index (%) was 31.75 for cluster IV, 33.50 for V, 35.5 for III, 37.0 for II and the highest, 39.75 per cent for cluster I, while, the mean technology index was 35.5 per cent. The value of net returns per ha under demonstration plots was Rs. 23550 and Rs. 26310, whereas, farmers practice gave net returns of Rs.14110 and Rs.14180 per ha, respectively, for the years 2016-17 and 2017-18. The benefit : cost ratio ranged from 1.80 to 2.00 for 2016-17 and 1.81 to 2.10 for 2017-18 under demonstration plots while the value of same varied between 1.42 to 1.59 and 1.31 to 1.63 under farmers’ practice for year 2016-17 and 2017-18, respectively.

Diclofenac is an extensively used nonsteroidal anti-inflammatory drug, but gastrointestinal liabilities and cardiovascular complications take the shine away from such a widely prescribed drug. On the other hand, rutin, a dietary bioflavonoid, has quite a few pharmacological attributes to improve the efficacy and reduce the dose-related toxicities of diclofenac through the intended food-drug/herb-drug interaction. The aim of the present research work was to investigate the role of rutin on pharmacokinetic modulation and the consequent efficacy of diclofenac. At first, pharmacodynamics and pharmacokinetics of diclofenac as alone and in the presence of rutin were investigated orally in a rat model. Then, mechanistic studies were performed to explain the effect of rutin on improvement in oral exposure as well as the efficacy of diclofenac using a battery of in-vitro/in-situ/in-vivo studies. Results displayed that rutin enhanced efficacy as well as oral bioavailability of diclofenac in rats. A marked increase in permeability of diclofenac by rutin was displayed that is linked to inhibition of Breast Cancer Resistance Protein (BCRP) transporters. There was no significant effect of rutin on the modulation of intestinal transit, CYP2C9 inhibition in human liver microsomes, and CYP2C9/CYP2C11 expression in rat liver tissues to boost the oral exposure of diclofenac. Rutin is found to be an inhibitor for BCRP transporters and can act as an oral bioavailability enhancer for a drug like diclofenac.

Polymer-drug conjugates have been the cornerstone of several drug delivery systems owing to their numerous benefits such as improved drug solubilization, controlled release, increased efficacy, and improved pharmacokinetics. Herein, an acid-responsive macromolecular prodrug was synthesized by conjugation of Tacrolimus (TAC; FK506) with chemically modified hyaluronic acid (HA), and its physicochemical and pharmacokinetic properties were studied in detail. The prepared conjugate (HA-ADH-TAC) showed 1% drug loading, sustained drug release, and significantly enhanced solubility for the investigated drug. Additionally, cellular uptake study indicated augmented uptake of this conjugate, and hemolysis assay showed biocompatibility of the developed prodrug. Further, the pharmacokinetic behavior of the conjugate was investigated, and it was observed that pharmacokinetic parameters with the conjugate were improved. The results indicate that the developed HA-tacrolimus conjugate has the edge over the plain drug in terms of improved physicochemical properties and favorable pharmacokinetic response.

Background & objectives In patients of aortic stenosis and regurgitation, pressure and volume effects on left ventricular function are occult and missed by routine echocardiography markers like ejection fraction (EF). Speckle tracking analysis by measuring global longitudinal strain and global circumferential strain seems to ascertain this occult LV function parameters at an early phase in a more comprehensive manner. Limited studies have examined these parameters pre/post aortic valve replacement (AVR). Methods 94 consecutive patients with symptomatic severe aortic stenosis (AS) or aortic regurgitation (AR), planned for AVR were included (as per set inclusion criteria) along with 15 normal controls-15 months prospective study. Routine echocardiography and speckle tracking imaging was done at baseline (pre AVR) and post AVR at 1st week, 1st month and 3rd month of follow up. Results 90 patients completed study (70 in AS and 20 in AR group). In AS group mean values (± 2 standard deviations) of global longitudinal strain (GLS) improved from a baseline −10.9% (± 3.9) to −19.4% (±3.8) at 3rd month (p value < 0.0001). Mean values of global circumferential strain (GCS) too improved from −17.3% (±4.5) to −21.4% (±3.6) respectively (p value < 0.0001). In AR group too mean values of global longitudinal strain progressed from a baseline −12.6% (±3.9) to −19.4% (±3.4) at three months of follow (p value < 0.0001) and mean values of global circumferential strain also progressed from −15.3% (±3.4) at baseline to −21.7% (±3.1) respectively (p value < 0.0001). Conclusion Magnitude of recovery of GLS and GCS after AVR was more as compared to recovery in EF. Poor GLS/GCS values at baseline were associated with lesser recovery pressing need for an earlier intervention.

CYP2E1 plays a crucial role in the bio-activation of toxic substances leading to liver damage. In this context, CYP2E1 converts paracetamol (PCM) to N-acetyl-p-benzoquinone imine (NAPQI), which is prone to cause hepatotoxicity. Hence, we aimed to explore the protective effect of glabridin on widely used PCM-induced liver injury model in the present study and, after that, correlated with the role of CYP2E1 toward its efficacy. Glabridin was isolated from Glycyrrhiza glabra and characterized before the investigation in an in-vivo mice model of PCM-induced liver injury. Glabridin after oral treatment at 5-20 mg/kg showed a considerable improvement in serum biochemical parameters (ALT and AST) and oxidative stress markers (MDA, GSH, SOD, and catalase) in comparison to only PCM-treatment. Histopathological examination of the liver depicted that glabridin exhibited substantial protection from PCM-induced liver injury compared to the disease control group. Significant down-regulation of CYP2E1 protein and its mRNA expression levels were observed in the glabridin-treated groups compared to PCM-induced respective elevation of CYP2E1. Moreover, activation of NF-κB was significantly inhibited by glabridin. Therefore, glabridin has the potential to protect PCM-induced liver injury through CYP2E1 inhibition-mediated normalization of oxidative stress. Further research is warranted to establish glabridin as a phytotherapeutics for liver protection for which no effective and safe oral drug is available to date.

Drug discovery is generally considered as a costly affair and it takes approximately 15 years to reach a new chemical entity into the market. Among the recent potent drug molecules with most effective pharmacological properties, very few reached for Phase I clinical trial in humans. Unfortunately, the historical average reveals an almost 90% overall attrition rate in clinical trials. The solubility and permeability of a drug are the critical factors influencing the success of a drug. Oral drug delivery systems still continue to exist as the most favored, simplest and easiest administration route. A huge number of potential clinical candidates won’t make it to the market or accomplish their maximum capacity except if their solubility and oral bioavailability are enhanced by formulation. The solubility of drugs will continue to exist as important aspects of formulation development. With the emergence of synthetic methods for new molecule synthesis in chemistry and better screening methods, the number of poorly water soluble compounds has dramatically expanded in the last few years. Solid dispersion is one of the most important techniques as it can be prepared by several methods. It is mostly prepared with a drug having poor water solubility and it explores hydrophilic polymers either individually or in combination for the enhancement of solubility. In comparison to the conventional formulations such as tablets or capsules, there are different methods with which solid dispersions can be prepared and also have many benefits over conventional drug delivery approaches. Solid dispersion systems are potential for increasing the solubility, oral absorption and bioavailability of drugs and the significance of the solid dispersion technology is constantly increasing. The main focus of this review is to present recent advancements in the area of solid dispersion. This review also includes an account of recent patents on solid dispersion and clinical status of solid dispersion based formulations.

A continuous effort has been given to find out a new drug that is effective against tuberculosis (TB) from both susceptible and resistant strains of Mycobacterium tuberculosis. Bedaquiline represents a recently approved anti-TB drug, which has a unique mechanism of action to fight against multi drug resistance (MDR). Some severe side effects and drug-drug interactions are associated with the treatment of bedaquiline. Moreover, World Health Organisation (WHO) has also been provided guidelines in the year of 2013 for the use of bedaquiline and encourages additional investigation into it. Hence, the pharmacokinetics of bedaquiline upon coadministration with the drug has to be explored in the preclinical model and for which a liquid chromatography tandem mass spectrometry (LC-MS/MS) based bioanalytical method for quantitation of bedaquiline will be useful. A simple, sensitive and rapid LC-MS/MS method was developed, validated and successfully applied to drug interactions of bedaquiline upon coadministration with cytochrome P450 3A4 (CYP3A4) inducers/inhibitors orally in Wistar rats. Results reveal that ciprofloxacin and fluconazole have marked effect to hinder the pharmacokinetics of bedaquiline but isoniazid, verapamil and carbamazepine have no significant effect on bedaquiline pharmacokinetics. Overall, this new bioanalytical method for estimation of bedaquiline in rat plasma was found to be helpful to assess the pharmacokinetics of bedaquiline and very much useful for evaluation of preclinical drug-drug interaction before considering costly and perilous clinical exploration.

Rohitukine (referred to as RHK) is a bioactive chromone alkaloid isolated from the leaves of plant Dysoxylum binectariferum, which has been reported to possess diverse pharmacological properties for the treatment of inflammatory bowel disease (IBD), diarrhoea and anti-lipidemic. However, the underlying mechanism by which RHK exerts its anti-inflammatory activity has not yet demonstrated. This study aimed to elucidate the anti-inflammatory mechanism of RHK using lipopolysaccharide (LPS) - stimulated J774A.1 macrophage cells and in-vivo inflammatory models. Results demonstrated that RHK treatment could significantly decrease the LPS-induced production of nitric oxide, prostaglandin E2 (PGE2), interleukins (ILs) and tumour necrosis factor (TNF)-α in J774A.1 cells. Molecular studies revealed that RHK inhibited the activation of upstream mediator nuclear factor-κB by suppressing the phosphorylation of IκBα and p65. In in-vivo experiments showed prominent anti-inflammatory activity of RHK. Thus, RHK could be considered as a promising candidate for the treatment of inflammatory diseases.

Nephrotic syndrome arising from monogenic mutations differs substantially from acquired ones in their clinical prognosis, progression, and disease management. Several pathogenic mutations in the COQ8B gene are known to cause nephrotic syndrome. Here, we used the whole-exome sequencing (WES) technology to decipher the genetic cause of nephrotic syndrome (CKD stage-V) in a large affected consanguineous family. Our study exposed a novel missense homozygous mutation NC_000019.9:g.41209497C > T; NM_024876.4:c.748G > A; NP_079152.3:p.(Asp250Asn) in the 9th exon of the COQ8B gene, co-segregated well with the disease phenotype. Our study provides the first insight into this homozygous condition, which has not been previously reported in 1000Genome, ClinVar, ExAC, and genomAD databases. In addition to the pathogenic COQ8B variant, the WES data also revealed some novel and recurrent mutations in the GLA, NUP107, COQ2, COQ6, COQ7 and COQ9 genes. The novel variants observed in this study have been submitted to the ClinVar database and are publicly available online with the accessions: SCV001451361.1, SCV001451725.1 and SCV001451724.1. Based on the patient's clinical history and genomic data with in silico validation, we conclude that pathogenic mutation in the COQ8B gene was causing kidney failure in an autosomal recessive manner. We recommend WES technology for genetic testing in such a consanguineous family to not only prevent the future generation, but early detection can help in disease management and therapeutic interventions.

Non-syndromic hearing loss (NSHL) is one of the most frequent auditory deficits in humans characterized by high clinical and genetic heterogeneity. Very few studies have reported the relationship between OTOF (Locus: DFNB9) and hereditary hearing loss in India. We aimed to decipher the genetic cause of prelingual NSHL in a large affected Muslim consanguineous families using whole-exome sequencing (WES). The study was performed following the guidelines and regulations of the Indian Council of Medical Research (ICMR), New Delhi. The population was identified from Jammu and Kashmir, the Northernmost part of India. Near about 100 individuals were born deaf-mute in the village of 3,000 inhabitants. A total of 103 individuals (with 52 cases and 51 controls) agreed to participate in this study. Our study revealed a rare non-sense homozygous mutation NC_000002.11:g.2:26702224G>A; NM_001287489.2:c.2122C>T; NP_001274418.1:p.(Arg708∗) in the 18th exon of the OTOF gene. Our study provides the first insight into this homozygous condition, which has not been previously reported in ExAC, 1,000 Genome and genomAD databases. Furthermore, the variant was confirmed in the population cohort (n = 103) using Sanger sequencing. In addition to the pathogenic OTOF variant, the WES data also revealed novel and recurrent mutations in CDH23, GJB2, MYO15A, OTOG, and SLC26A4 genes. The rare pathogenic and the novel variants observed in this study have been submitted to the ClinVar database and are publicly available online with the accessions SCV001448680.1, SCV001448682.1 and SCV001448681.1. We conclude that OTOF-related NSHL hearing loss is prevalent in the region due to successive inbreeding in its generations. We recommend premarital genetic testing and genetic counseling strategies to minimize and control the disease risk in future generations.

Hydroxyurea (HU) is the first-ever approved drug by USFDA for sickle cell anemia (SCA). However, its treatment is associated with severe side effects like myelosuppression. Current studies are focused on the supplementation therapy for symptomatic management of SCA. In the present study, we aimed to explore rutin's and gallic acid's potential individually, for concomitant therapy with HU using pharmacokinetic and pharmacodynamic approaches since there is no such precedent till date. In vivo pharmacokinetic studies of HU in rats showed that rutin could be safely co-administered with HU, while gallic acid significantly raised the plasma concentration of HU. Both the phytochemicals did not have any marked inhibitory effect on urease but have considerable effects on horseradish peroxidase enzyme. The experimental phytoconstituents displayed a very low propensity to cause in vitro hemolysis. Gallic acid markedly enhanced the HU-induced decrease in lymphocyte proliferation. A substantial improvement by rutin or gallic acid was observed in HU-induced reduction of the main hematological parameters in rats. Combined treatment of HU with rutin and gallic acid reduced serum levels of both IL-6 and IL-17A. Overall, both rutin and gallic acid are found to have promising phytotherapy potential with HU. Further exploration needs to be done on both candidates for use as phytotherapeutics for SCA.

Despite unprecedented advances in modern medicine, no safe and effective drug is available to date for oral administration to combat drug-induced liver injury, which is a vital concern nowadays. The present study deals with the hepatoprotective effect of pure glabridin, a key phytoconstituent from Glycyrrhiza glabra with mechanistic investigations using an in-vivo methotrexate-induced liver injury model as there is no such precedent. The study was performed in the Swiss mice model where a single dose of methotrexate (40 mg/kg) was given on the 7th day through an intraperitoneal route to induce hepatotoxicity, and glabridin as a test compound was administered orally for eleven consecutive days at 10 to 40 mg/kg. Glabridin markedly improved serum biochemical parameters (SGPT, SGOT), proinflammatory cytokine (TNF-α) level, oxidative stress markers (MDA, GSH, SOD, CAT) as compared to methotrexate alone. Alterations in methotrexate-induced liver architecture were considerably prevented by glabridin treatment as suggested by liver histopathological examination and SEM investigation. Glabridin substantially prevented methotrexate-induced down-regulation of Nrf2, & activation of NF-κB, and caused up-regulation of BAX at different dose levels. Overall, glabridin is found to protect methotrexate-induced hepatotoxicity by improving important factors for oxidative stress, inflammation, and apoptosis.

CYP2E1 is directly or indirectly involved in the metabolism of ethanol and endogenous fatty acids but it plays a major role in the bio-activation of toxic substances that produce reactive metabolites leading to hepatotoxicity. Therefore, identification of CYP2E1 inhibitor from bioflavonoids class having useful pharmacological properties has dual benefit regarding avoidance of severe food-drug/nutraceutical-drug interaction and scope to develop a phytotherapeutics through an intended pharmacokinetic interaction.In the present study, we aimed to identify CYP2E1 inhibitor from experimental bioflavonoids which are unexplored for CYP2E1 inhibition till date using

Alzheimer disease (AD) is usually accompanied by two prominent pathological features, cerebral accumulation of amyloid-β (Aβ) plaques and presence of MAPT/tau neurofibrillary tangles. Dysregulated clearance of Aβ largely contributes to its accumulation and plaque formation in the brain. Macroautophagy/autophagy is a lysosomal degradative process, which plays an important role in the clearance of Aβ. Failure of autophagic clearance of Aβ is currently acknowledged as a contributing factor to increased accumulation of Aβ in AD brains. In this study, we have identified crocetin, a pharmacologically active constituent from the flower stigmas of Crocus sativus, as a potential inducer of autophagy in AD. In the cellular model, crocetin induced autophagy in N9 microglial and primary neuron cells through STK11/LKB1 (serine/threonine kinase 11)-mediated AMP-activated protein kinase (AMPK) pathway activation. Autophagy induction by crocetin significantly increased Aβ clearance in N9 cells. Moreover, crocetin crossed the blood-brain barrier and induced autophagy in the brains’ hippocampi of wild-type male C57BL/6 mice. Further studies in transgenic male 5XFAD mice, as a model of AD, revealed that one-month treatment with crocetin significantly reduced Aβ levels and neuroinflammation in the mice brains and improved memory function by inducing autophagy that was mediated by AMPK pathway activation. Our findings support further development of crocetin as a pharmacological inducer of autophagy to prevent, slow down progression, and/or treat AD. Abbreviations: Aβ: amyloid-β; ABCB1/P-gp/P-glycoprotein: ATP-binding cassette, subfamily B (MDR/TAP), member 1; AD: Alzheimer disease; AMPK/PRKAA: AMP-activated protein kinase; APP: amyloid beta (A4) precursor protein; ATG: autophagy related; BBB: blood-brain barrier; BECN1: beclin 1, autophagy related; CAMKK2/CaMKKβ: calcium/calmodulin-dependent protein kinase kinase 2, beta; CSE: Crocus sativus extract; CTSB: cathepsin B; EIF4EBP1: eukaryotic translation initiation factor 4E binding protein 1; GFAP: glial fibrillary acidic protein; GSK3B/GSK3β: glycogen synthase kinase 3 beta; Kp: brain partition coefficient; LRP1: low density lipoprotein receptor-related protein 1; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta; MAP2: microtubule-associated protein 2; MAPK/ERK: mitogen-activated protein kinase; MAPT/tau: microtubule-associated protein tau; MTT: 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; MTOR: mechanistic target of rapamycin kinase; MWM: Morris water maze; NFKB/NF-κB: nuclear factor of kappa light polypeptide gene enhancer in B cells; NMDA: N-methyl-d-aspartic acid; RPTOR: regulatory associated protein of MTOR; RPS6KB1/p70S6K: ribosomal protein S6 kinase 1; SQSTM1: sequestosome 1; SRB: sulforhodamine B; STK11/LKB1: serine/threonine kinase 11; TFEB: transcription factor EB; TSC2: TSC complex subunit 2; ULK1: unc-51 like kinase 1.

Background Datura stramonium L. is widely used across the world for its therapeutic potential to treat inflammatory disorders. The current work was designed to isolate and identify steroidal lactones from D. stramonium leaves and evaluate their anti-inflammatory and analgesic properties. Methods Several compounds were isolated from D. stramonium leaves and characterized by nuclear magnetic resonance and high-resonance electron spray ionization mass spectrometry techniques. Further, anti-inflammatory properties of these compounds were evaluated by in vitro assays, such as release of NO and pro-inflammatory cytokines by lipopolysaccharide (LPS)-activated J774A.1 macrophages. Using in vivo models, anti-inflammatory and analgesic effects were examined by mouse tail-flick, carrageenan-induced inflammation in rat paw model, vascular permeability in rats, and acetic acid-induced writhing in mice. The docking studies were performed for assessing the binding efficiency of the test compounds with cyclooxygenase-1 (COX-1) and COX-2, lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), inducible nitric oxide synthases (iNOS) and nuclear factor-κB (NF-κB). Results Three lactones were isolated and confirmed as daturalactone (D1), 12-deoxywithastramonolide (D23), and daturilin (D27). Further, the isolated compounds showed nitric oxide inhibition and pro-inflammatory cytokines released by LPS-activated J774A.1 macrophages. The in vivo results suggest that D1, D23 and D27 (20 mg/kg) were able to reduce the pain and inflammation in various animal models. The docking analysis showed that these three compounds actively bind with COX-1, COX-2, LOX-1, NF-κB, and iNOS, validating the anti-inflammatory effects of the lactones. Conclusion These findings demonstrate substantial anti-inflammatory and analgesic properties of D. stramonium-derived lactones and their potential as anti-inflammatory agents to treat chronic inflammatory ailments.

Safranal, a plant secondary metabolite isolated from saffron, has been reported for several promising pharmacological properties toward the management of Alzheimer's disease. In the present study, we observe and report for the first time about several druglike attributes of safranal, such as adherence to Lipinski's rule of five; optimum lipophilicity; high permeability; low blood-to-plasma ratio; less to moderate propensity to interact with P-glycoprotein (P-gp) or breast cancer-resistant protein (BCRP) transporters; and high plasma protein binding as common to most of the marketed drugs using in vitro and ex vivo models. In spite of the above attributes, in vivo oral absorption was found to be very poor, which is linked to the structural integrity of safranal in simulated gastric fluid, simulated intestinal fluid, plasma, and liver microsomes. Moreover, the presence of unsaturated aldehyde moiety in safranal remains in equilibrium with its hydroxylated acetal form. Further research work is required to find out the stable oral absorbable form of safranal by derivatization of its aldehyde group without losing its potency.

Despite various advances in the arena of the current system of medicine, there are numerous side effects associated with the therapeutics which essentially demand research on the development of safer therapeutics. One way is to explore the bioactive plant secondary metabolites and their semisynthetic derivatives. In context to this, we analyzed OA-DHZ, a dehydrozingerone derivative as the later has been reported to show anti-inflammatory and analgesic properties. OA-DHZ was found to be having promising anti-inflammatory and analgesic potential. OA-DHZ was found to inhibit the carrageenan-induced edema and leukocyte migration, acetic acid-induced increase in vascular permeability and lipopolysaccharide-induced pro-inflammatory cytokines like TNF-α, IL-6, and IL-1β. Meanwhile, it was also found to potentially inhibit thermally as well as chemically induced pain signifying its analgesic/nociceptive potential. Further, safety pharmacology studies using in vivo animal models for the central nervous system, gastrointestinal tract, the cardio-respiratory system suggest that optimum functioning of vital organ systems does not get altered after single oral administration. Also, the acute toxicity study revealed its nontoxic nature up to 2000 mg/kg. This study paves the way for future exploration and development of OA-DHZ based on its potent activity and nontoxic nature.

Deposition of amyloid-β in Alzheimer’s disease is accompanied by chronic inflammation, which involves raised levels of pro-inflammatory cytokines TNF-α, IL-6 and IL-1β. However, the role of Aβ1-42 in the inflammatory process, before it gets deposited into aggregates has not been investigated thoroughly. Through this study, we are illustrating the dual role of soluble Aβ1-42 (sAβ1-42) in activating the NLRP3 inflammasome and simultaneously inhibiting TNF-α secretion. Our data suggested that the treatment of chronically induced THP-1 macrophages and N9 microglial cells with sAβ1-42 can suppress the major inflammatory cytokine TNF-α without affecting the level of IL-6. However, the activation of NLRP3 inflammasome was well evidenced by secretion of IL-1β, increased expression of NLRP3 and caspase-1, implicating sAβ1-42 in enhancing and suppressing one or other type of inflammation. Further investigation revealed that sAβ1-42 was able to severely abrogate the expression of NF-κB, p50 and restricting the translocation of NF-κB, p65 to nucleus by inhibiting phosphorylation of IκB-α in THP-1 macrophages. These data indicate that the sAβ1-42 may play a dual role during inflammatory process, wherein, it may be involved in protecting the cells from inflammatory damage due to TNF-α. This ability of sAβ1-42 might be playing some role in protecting the brain cells during the process of aging and Alzheimer’s disease, where, chronic inflammatory environment plays a vital role.

Crocus sativus L. (family: Iridaceae) has been documented in traditional medicine with numerous medicinal properties. Recently, we have shown that C. sativus extract (IIIM-141) displays promising efficacy in a genetic mice (5XFAD) model of Alzheimer’s disease (AD) (ACS Chem. Neurosci. 2017,16, 1756). To translate the available traditional knowledge and the scientifically validated results into modern medicine, herein we aimed to carry out its preclinical development. IIIM-141 is primarily a mixture of crocins containing trans-4-GG-crocin (36 % w/w) as the principal component. The in vitro studies show that IIIM-141 has protective as well as therapeutic properties in assays related to AD. It induces the expression of P-gp, thereby enhancing the amyloid-β clearance from an AD brain. It also inhibits NLRP3 inflammasome and protects SH-SY5Y cells against amyloid-β- and glutamate-induced neurotoxicities. In behavioral models, it decreased the streptozotocin-induced memory impairment in rats and recovered the scopolamine-induced memory deficit in Swiss albino mice at 100 mg/kg dose. The acute oral toxicity study shows that IIIM-141 is safe up to the dose of 2000 mg/kg, with no effect on the body weight and on the biochemical/hematological parameters of the rats. The repeated oral administration of IIIM-141 for 28 days at 100 mg/kg dose did not cause any preterminal deaths and abnormalities in Wistar rats. The pharmacokinetic analysis indicated that after oral administration of IIIM-141, the majority of crocin gets hydrolyzed to its aglycone crocetin. The sustained release (SR) capsule formulation was developed, which showed an improved in vitro dissolution profile and a significantly enhanced plasma exposure in the pharmacokinetic study. The SR formulation resulted in 3.3-fold enhancement in the area under the curve of crocetin and doubling of the crocetin/crocin ratio in plasma compared with the extract. The data presented herein will serve as the benchmark for further research on this botanical candidate.