Development of multi-targetable chalcone derivatives bearing N-aryl piperazine moiety for the treatment of Alzheimer's disease.

The multi-target directed ligand (MTDL) discovery has been gaining immense attention in the development of therapeutics for Alzheimer's disease (AD). The strategy has been evolved as an auspicious approach suitable to combat the heterogeneity and the multifactorial nature of AD. Therefore, multi-targetable chalcone derivatives bearing N-aryl piperazine moiety were designed, synthesized, and evaluated for the treatment of AD. All the synthesized compounds were screened for thein vitro activityagainst acetylcholinesterase (AChE), butylcholinesterase (BuChE), ß-secretase-1 (BACE-1), and inhibition of amyloid ß (Aß) aggregation. Amongst all the tested derivatives, compound 41bearing unsubstituted benzylpiperazine fragment and para-bromo substitution at the chalcone scaffold exhibited balanced inhibitory profile against the selected targets. Compound 41 elicited favourable permeation across the blood-brain barrier in the PAMPA assay. The molecular docking and dynamics simulation studies revealed the binding mode analysis and protein-ligand stability ofthe compound with AChE and BACE-1. Furthermore,itameliorated cognitive dysfunctions and signified memory improvement in thein-vivobehavioural studies (scopolamine-induced amnesia model). Theex vivobiochemical analysis of mice brain homogenates established the reduced AChE and increased ACh levels. The antioxidant activity of compound 41 was accessed with the determination of catalase (CAT) and malondialdehyde (MDA) levels. The findings suggested thatcompound 41, containing a privileged chalcone scaffold, can act as a lead molecule for developing AD therapeutics.

Identification of novel potential cathepsin-B inhibitors through pharmacophore-based virtual screening, molecular docking, and dynamics simulation studies for the treatment of Alzheimer's disease.

Cathepsin B is a cysteine protease lysosomal enzyme involved in several physiological functions. Overexpression of the enzyme enhances its proteolytic activity and causes the breakdown of amyloid precursor protein (APP) into neurotoxic amyloid ß (Aß), a characteristic hallmark of Alzheimer's disease (AD). Therefore, inhibition of the enzyme is a crucial therapeutic aspect for treating the disease. Combined structure and ligand-based drug design strategies were employed in the current study to identify the novel potential cathepsin B inhibitors. Five different pharmacophore models were developed and used for the screening of the ZINC-15 database. The obtained hits were analyzed for the presence of duplicates, interfering PAINS moieties, and structural similarities based on Tanimoto's coefficient. The molecular docking study was performed to screen hits with better target binding affinity. The top seven hits were selected and were further evaluated based on their predicted ADME properties. The resulting best hits, ZINC827855702, ZINC123282431, and ZINC95386847, were finally subjected to molecular dynamics simulation studies to determine the stability of the protein-ligand complex during the run. ZINC123282431 was obtained as the virtual lead compound for cathepsin B inhibition and may be a promising novel anti-Alzheimer agent.

Recent application of protein hydrolysates in food texture modification.

The demand for clean labels has increased the importance of natural texture modifying ingredients. Proteins are unique compounds that can impart unique textural and structural changes in food. However, lack of solubility and extensive aggregability of proteins have increased the demand for enzymatically hydrolyzed proteins, to impart functional and structural modifications to food products. The review elaborates the recent application of various proteins, protein hydrolysates, and their role in texture modification. The impact of protein hydrolysates interaction with other food macromolecules, the effect of pretreatments, and dependence of various protein functionalities on textural and structural modification of food products with controlled enzymatic hydrolysis are explained in detail. Many researchers have acknowledged the positive effect of enzymatically hydrolyzed proteins on texture modification over natural protein. With enzymatic hydrolysis, various textural properties including foaming, gelling, emulsifying, water holding capacity have been effectively improved. It is evident that each protein is unique and imparts exceptional structural changes to different food products. Thus, selection of protein requires a fundamental understanding of its structure-substrate property relation. For wider applicability in the industrial sector, more studies on interactions at the molecular level, dosage, functionality changes, and sensorial attributes of protein hydrolysates in food systems are required.

Mapping of QTLs associated with yield and related traits under reproductive stage drought stress in rice using SNP linkage map.

BACKGROUND: Drought stress is a major constraint for rice production worldwide. Reproductive stage drought stress (RSDS) leads to heavy yield losses in rice. The prospecting of new donor cultivars for identification and introgression of QTLs of major effect (Quantitative trait locus) for drought tolerance is crucial for the development of drought-resilient rice varieties. METHODS AND RESULTS: Our study aimed to map QTLs associated with yield and its related traits under RSDS conditions. A saturated linkage map was constructed using 3417 GBS (Genotyping by sequencing) derived SNP (Single nucleotide polymorphism) markers spanning 1924.136 cM map length with an average marker density of 0.56 cM, in the F3 mapping population raised via cross made between the traditional ahu rice cultivar, Koniahu (drought tolerant) and a high-yielding variety, Disang (drought susceptible). Using the Inclusive composite interval mapping approach, 35 genomic regions governing yield and related traits were identified in pooled data from 198 F3 and F4 segregating lines evaluated for two consecutive seasons under both RSDS and irrigated control conditions. Of the 35 QTLs, 23 QTLs were identified under RSDS with LOD (Logarithm of odds) values ranging between 2.50 and 7.83 and PVE (phenotypic variance explained) values of 2.95-12.42%. Two major QTLs were found to be linked to plant height (qPH1.29) and number of filled grains per panicle (qNOG5.12) under RSDS. Five putative QTLs for grain yield namely, qGY2.00, qGY5.05, qGY6.16, qGY9.19, and qGY10.20 were identified within drought conditions. Fourteen QTL regions having ≤ 10 Mb QTL interval size were further analysed for candidate gene identification and a total of 4146 genes were detected out of these 2263 (54.63%) genes were annotated to at least one gene ontology (GO) term. CONCLUSION: Several QTLs associated with grain yield and yield components and putative candidate genes were identified. The putative QTLs and candidate genes identified could be employed to augment drought resilience in rice after further validation through MAS strategies.

Recent advances on the impact of novel non-thermal technologies on structure and functionality of plant proteins: A comprehensive review.

The recent trend in consumption of plant-based protein over animal protein opens up a new avenue for sustainable agriculture practice, less environmental impact and greenhouse gas emission. The modification of plant-based proteins by novel non-thermal technologies includes the structural transformation followed by the modulation of their functional properties that are exploited to develop a protein ingredient system for application in food formulation. This review explores the impact of non-thermal process technologies on structural modification of plant proteins followed by improvement in protein's function in food formulation. Novel concepts articulating the impact of non-thermal technologies on structural and functional modification of plant proteins affecting it's digestibility and bioavailability are addressed. Limitations and prospects of applying non-thermal technologies in developing an alternative plant-based protein food system are also summarized. Non-thermal processes are considered as the emerging technologies that results in conformational changes in secondary, tertiary and quaternary structure of plant proteins which helps in modification of functional properties without jeopardizing the organoleptic properties and bioactivity of the protein. However, extensive future study is needed to optimize the non-thermal process parameters along with the finding of new protein sources to achieve healthy and sustainable plant-based food system.

• Demand and consumption of plant proteins are increasing compared to animal proteins.• Non-thermal technologies changes protein structure and enhances the bio-functional properties.• Structural and functional modification influences the digestive properties of plant proteins.• Limitations and challenges of non-thermal technologies are addressed.

Generation of wild-type rat Glucocerebrosidase homology modeling: Identification of putative interactions site and mechanism for chaperone using combined in-silico and in-vitro studies.

Disease-modifying treatment strategy for Parkinson's disease (PD) by stabilization of Glucocerebrosidase (GCase) enzyme by chaperones is of particular interest. Wild-type rat is a widely used animal model for PD; however, the in-silico model to elucidate the nature of rat GCase (rGCase)-chaperone interactions, mechanisms, and structural stability is still unavailable. Hence, we have developed pH-dependent rGCase homology models, in-silico (docking and molecular dynamics), and in-vitro techniques (enzyme kinetics and thermal stability) to address this gap. The homology modeling results revealed ≥ 90% rGCase residues were in the favored regions, representing adequate models quality. In-silico studies showed an interaction between chaperone (Ambroxol, AMB) and the active site residues TYR 331, TYR 263, GLN 266, and GLU 358 with the higher affinity at neutral pH than acidic pH. In-vitro studies showed higher inhibitory activity (IC50) and binding affinity (Ki) of AMB at neutral pH (IC50: 8.2 ± 2.6 µM and Ki: 4.3 ± 1.2 µM) than acidic pH (IC50 and Ki: not identified). AMB improved rGCase thermostability was confirmed by thermal denaturation assay. We have developed the homology model for rGCase, which provides a perspective for designing and screening the chaperones at the initial phases of drug discovery to ameliorate PD.

Improved machine learning scoring functions for identification of Electrophorus electricus's acetylcholinesterase inhibitors.

Structure-based drug design (SBDD) is an important in silico technique, used for the identification of enzyme inhibitors. Acetylcholinesterase (AChE), obtained from Electrophorus electricus (ee), is widely used for the screening of AChE inhibitors. It shares structural homology with the AChE of human and other organisms. Till date, the three-dimensional crystal structure of enzyme from ee is not available that makes it challenging to use the SBDD approach for the identification of inhibitors. A homology model was developed for eeAChE in the present study, followed by its structural refinement through energy minimisation. The docking protocol was developed using a grid dimension of 84 × 66 × 72 and grid point spacing of 0.375 Å for eeAChE. The protocol was validated by redocking a set of co-crystallised inhibitors obtained from mouse AChE, and their interaction profiles were compared. The results indicated a poor performance of the Autodock scoring function. Hence, a batch of machine learning-based scoring functions were developed. The validation results displayed an accuracy of 81.68 ± 1.73% and 82.92 ± 3.05% for binary and multiclass classification scoring function, respectively. The regression-based scoring function produced [Formula: see text] and [Formula: see text] values of 0.94, 0.635 and 0.634, respectively.

First report of association of 'Candidatus Phytoplasma asteris' with Moringa oleifera leaf yellowing and stunting disease in India.

Moringa oleifera (family Moringaceae) also known as the 'drumstick tree' is a significant nutritious and medicinal plant that is commonly grown in India and contains a variety of vital phytochemicals. M. oleifera is used in several Indian herbal medicine formulations to treat a variety of illnesses (Kumar and Rao 2021). Typical phytoplasma symptoms of leaf yellowing and stunting were observed in M. oleifera trees up to 10% incidence at Acharya Narendra Dev University of Agriculture & Technology, Ayodhya, Uttar Pradesh, India in November 2021 and stunting with less fruit bearings symptoms with 8% incidence in October 2021 at Jonnalakothapalle village of Mudigubba mandal of Ananthapuramu district in Andhra Pradesh, India (Fig.1a, b). To investigate the possibility of a phytoplasma association with the symptoms, total DNA was isolated from the leaf samples collected from two diseased and two healthy plants from both the locations using CTAB method. The DNAs isolated were analysed by nested polymerase chain reaction (PCR) with universal phytoplasma primer pairs P1/P7 and R16F2n/R16R2 for the 16S rRNA gene (Deng and Hiruki 1991; Gundersen and Lee 1996) and secAfor1/sArev3 and SecAfor2/ SecArev3 for secA gene (Hodgetts et al. 2008). Amplicons of the expected size (~1.25kb from 16S rRNA gene and ~480bp from secA gene) were obtained from symptomatic plants only. The nested PCR products were cloned (pGEM-T Easy Vector, Promega), sequenced (ABA Biotech, India) and the sequences were deposited in GenBank with accession numbers OP358449, OP358450, OP358451, OP358452 for the 16SrRNA gene (~1.25 kb) and OP358443, OP358444, OP358445, OP358446 for the secA gene (~480 bp). BLASTn analysis revealed that the partial 16S rRNA gene sequences of M. oleifera phytoplasma isolate shared up to 99.9% sequence identity with the strain 'Candidatus Phytoplasma asteris' (Accession numbers MN909051, MN909047) and secA gene sequences shared up to 100% sequence identity with 'Ca. Phytoplasma asteris' (Accession numbers KJ434315, KJ462009) belonging to 16SrI group. The 16S rRNA and secA genes sequence-based phylogenetic analysis (Figure 1d,e) showed that the phytoplasma strain associated with M. oleifera leaf yellowing and stunting clustered within the 16SrI phytoplasma group closest to 16SrI-B ('Ca. P. asteris') subgroup strains. Furthermore, the virtual RFLP pattern derived from the query 16S rDNA F2nR2 fragment is identical (similarity coefficient 1.00) to the reference pattern of 16Sr group I, subgroup B (GenBank accession: AP006628). To the best of our knowledge, this is the first report of the 16SrI-B subgroup of the phytoplasma strains with M. oleifera in the world. 'Candidatus Phytoplasma asteris' (16SrI-B subgroup) strains have been reported from several other commercial crops and weed hosts in India and efficient leafhopper vectors have been identified (Rao 2021; Reddy 2021). This indicates that the 'Ca. P. asteris'-related strains (16SrI-B) are widespread and infecting several plant species in India. The increasing incidence of the 16SrI-B strain and its wide host range in India strongly suggests further research into the epidemiology involved in the dynamic spread of the disease in order to recommend a suitable management approach.

Non-coding RNAs: Regulators of valvular calcification.

There is currently a growing global burden of valvular heart diseases due to aging populations and changing lifestyles. Valvular heart diseases mainly include the malfunctioning of aortic and mitral valves and are characterized by extensive tissue remodeling, which includes calcification, endothelial dysfunction, and endothelial-mesenchymal transition. These valvular remodeling processes are known to be regulated by protein-coding genes as well as non-coding genes. Here, we have summarized studies highlighting the non-coding RNA mediated regulation of valvular tissue remodeling and their potential therapeutic benefits. Additionally, studies investigating the diagnostic capability of circulating non-coding RNA molecules in valvular diseases are also summarized. Overall, of the various candidates, several studies have highlighted miR-214 and miR-204 as central regulators of valvular calcification.

Benzothiazole derivative bearing amide moiety induces p53-mediated apoptosis in HPV16 positive cervical cancer cells.

In our previous study, we screened the anti-cancer properties of 10 benzothiazole derivatives in cervical cancer cell lines. In the present study, we aimed to delineate the mechanism of the apoptotic pathway (whether intrinsic or extrinsic) following the treatment of N-(4-(benzo[d]thiazol-2-yl)phenyl)-5-chloro-2-methoxybenzamide (named as A-07) on cervical cancer cell lines. Cellular stress by reactive oxygen species was measured using DCFDA dye by flowcytometry. Protein expression and localization was checked by immunofluorescence for γH2A.X, TP53, and CASP-3. Expression profiles of BAX and BCL-2 was done by semi-quantitative RT-PCR and PARP-1 (Poly(ADP-ribose) polymerase-1) by Western blot analysis. Bioinformatic studies were done using PDB websites, metaPocket 2.0 server, YASARA software and Discovery Studio 3.5 Visualizer. We demonstrate that the compound A-07 leads to ROS generation and double strand breaks in SiHa and C-33A cells. The induction of apoptosis in SiHa cells is associated with increased nuclear expression of the tumor suppressor protein, TP53. The shift in BAX/BCL-2 ratio, increased expression of Caspase-3 and cleaved Poly(ADP-ribose) polymerase-1 favour apoptotic signal in SiHa. In silico studies revealed that A-07 has inhibiting capabilities to the E6/E6AP/P53 complex. Our data suggest that treatment of A-07 causes p53 and caspase dependent apoptosis in HPV 16 infected SiHa cells.

Phytoremedial effect of Tinospora cordifolia against arsenic induced toxicity in Charles Foster rats.

Arsenic poisoning is one of the most serious health hazards of recent times. It has been estimated that more than 200 million people of about 105 countries in the world are affected due to arsenic poisoning. Except mitigation, there is no such mode by which the population can be prevented from being exposed to arsenic. Tinospora cordifolia (T. cordifolia) is widely used in the folk medicine system for the treatment of various diseases. Hence, the aim of the present study was to investigate the antidote effects of ethanolic extract of T. cordifolia stem against arsenic induced hepato-renal toxicity in rat model. Twenty-four male Charles Foster rats (weighing 160-180 g) were randomly divided into two groups, where six rats were used as control group. Eighteen rats were orally treated with arsenic at the dose of 8 mg/kg body weight for 90 days daily and then further divided into three sub groups (n = 6 each). Sub group I-arsenic treated rats, were sacrificed after treatment; sub group II rats were used as arsenic control and the sub group III rats were administrated with T. cordifolia at the dose of 400 mg/kg body weight/day for 90 days. After the completion of dose duration, all the control and treatment group rats were sacrificed to evaluate the various parameters. Arsenic induced rats had significantly (p < 0.0001) altered biochemical serum levels of SGPT, SGOT, ALP, total bilirubin, urea, uric acid, creatinine and albumin; But, after the administration of T. cordifolia there was significant (p < 0.0001) restoration observed in these liver and kidney function parameters. The T. cordifolia administration also significantly (p < 0.0001) restored the serum MDA levels and arsenic concentration in blood, liver and kidney tissues, as well as significant (p < 0.0001) improvement in haematological variables. In histopathological study, the arsenic treated rats showed degenerative changes in the liver and kidney tissues such as lesions and vacuolizations in hepatocytes and nephrocytes respectively. However, after the administration with T. cordifolia rats, there was considerably significant restoration in liver and kidney tissues. The entire study suggests that arsenic caused severe damage to the liver and kidney at haematological, biochemical and histopathological levels in rats. However, T. cordifolia played the vital role to combat the arsenic induced toxicity in rats. Hence, T. cordifolia might be used as a nutritional supplement to combat the arsenic led toxicity among the exposed population.

Highly fluorescent carbon dots from wheat bran as a novel drug delivery system for bacterial inhibition.

In this study, we prepared carbon dots (CDs) from wheat bran via hydrothermal treatment at 180°C for 3 h. The prepared CDs showed blue-green fluorescence under UV light. The fluorescence emission study of the CDs revealed that they showed maximum fluorescence emission at 500 nm. The prepared CDs showed a high quantum yield of 33.23%. Solvent-dependent fluorescence emission analysis of the CDs was performed to study the variation in fluorescence emission characteristics with solvent polarity. The prepared CDs were conjugated with amoxicillin (AMX) to explore its potential for use as a drug delivery agent for AMX. The drug release profile of the CD-AMX conjugates was analyzed at different pH (5.0, 6.8 and 7.2) to study drug release kinetics. CD-AMX conjugates showed notable bacterial inhibition against Gram-positive (S. aureus) and Gram-negative (E. coli) strains with minimal cytotoxic effects, indicating its potential as a promising antibacterial drug delivery system.

First report on clover proliferation phytoplasma related strain associated with Matthiola incana floral virescence in Uttar Pradesh, India.

Matthiola incana R. Br. (Fam: Brassicaceae) is an ornamental, commonly known as hoary stock has an extremely fragrant flowers, which blooms in dense clusters in a large variety of colors. During a survey of flower nurseries in March 2019 at Indian Institute of Sugarcane Research campus, Lucknow, floral virescence (MiV) symptoms (Fig. 1 A, B) were observed in M. incana pots with an incidence of over 40%. Leaf yellows symptoms were also observed on a weed Acalypha indica (AiLY) in Matthiola nursery (Fig. 1 C). Nested PCR assays were carried out to detect and identify the possible association of phytoplasmas with MiV and AiLY symptoms. Three each of symptomatic MiV and AiLY samples and two non-symptomatic samples were collected and processed for DNA extraction from the leaf midrib by CTAB method. Hishimonus phycitis (HP) (Hemiptera: Cicadellidae) leafhopper feeding on MiV symptomatic plants was also collected and DNA was extracted. The DNA of 8 symptomatic and 4 non-symptomatic plants and from the 10 leafhopper was used as a template for PCR assays. Phytoplasma specific 16Sr RNA gene specific primers (P1/P7 and 3Far/3Rev; Schneider et al. 1995; Manimekalai et al. 2010) and multilocus genes' specific primer pairs for secA (SecAfor1/SecArev3;SecAfo5r/SecARev2; Bekele et al. 2011), secY (SecYF1(VI)/SecYR1(VI);SecYF2(VI)/SecYR1(VI); Lee et al. 2010) and rp genes (rpFIC/rp(I)R1A; rp(VI)F2/ rp(VI)R2; Martini et al. 2007) were employed as previously described. Amplified products of ~1.3kb, ~600bp, ~1.7kb and ~1.0kb of 16S rRNA, secA, secY and rp genes of phytoplasma were consistently amplified in all the MiV and AiLY samples and in the HP leafhopper. No amplifications were achieved in any of the asymptomatic plant samples. Amplified products of all the four genes of MiV, AiLY and HP isolates were purified, sequenced and submitted in GenBank. Sequence comparison and phylogeny analysis of the sequences of the four genes of MiV, AiLY and HP isolates revealed 99% - 100% sequence identity and clustering with clover proliferation phytoplasma related strains (16SrVI group)(Fig.2 A,B,C and D). The virtual RFLP analysis of 17 restriction endonucleases corresponding to the 16S rDNA sequence of MiV, AiLY and HP phytoplasma strains by pDraw program, assigned them into a novel phytoplasma subgroup strain under 16SrVI group, since its HpaII restriction profile was different to earlier classified 16SrVI subgroups but was very close to16SrVI-E subgroup (GenBank acc. no. AY270156) (Fig 3). Earlier, peanut witches' broom (16SrII-A) phytoplasma was identified associated with M. incana from Italy (Davino et al. 2007). However, the association of clover proliferation phytoplasma (16SrVI) related strain associated with virescence symptom of M. incana is the first report in world. The weed (A. indica) and HP leafhopper were also reported as additional hosts of 16SrVI subgroup related new strain in India, which needs further investigation. The report of a new host and new subgroup of clover proliferation phytoplasma related strain in India is having an epidemiological significance and warrants attention.

Development of pyrazole and spiropyrazoline analogs as multifunctional agents for treatment of Alzheimer's disease.

Cholinergic hypothesis of Alzheimer's disease has been advocated as an essential tool in the last couple of decades for the drug development. Here in, we report de novo fragment growing strategy for the design of novel 3,5-diarylpyrazoles and hit optimization of spiropyrazoline derivatives as acetyl cholinesterase inhibitors. Both type of scaffolds numbering forty compounds were synthesized and evaluated for their potencies against AChE, BuChE and PAMPA. Introduction of lipophilic cyclohexane ring in 3,5-diarylpyrazole analogs led to spiropyrazoline derivatives, which facilitated and improved the potencies. Compound 44 (AChE = 1.937 ±â€¯0.066 µM; BuChE = 1.166 ±â€¯0.088 µM; hAChE = 1.758 ±â€¯0.095 µM; Pe = 9.491 ±â€¯0.34 × 10-6 cm s1) showed positive results, which on further optimization led to the development of compound 67 (AChE = 0.464 ±â€¯0.166 µM; BuChE = 0.754 ±â€¯0.121 µM; hAChE = 0.472 ±â€¯0.042 µM; Pe = 13.92 ±â€¯0.022 × 10-6 cm s1). Compounds 44 and 67 produced significant displacement of propidium iodide from the peripheral anionic site (PAS) of AChE. They were found to be safer to MC65 cells and decreased metal induced Aß1-42 aggregation. Further, in-vivo behavioral studies, on scopolamine induced amnesia model, the compounds resulted in better percentage spontaneous alternation scores and were safe, had no influence on locomotion in tested animal groups at dose of 3 mg/kg. Early pharmacokinetic assessment of optimized hit molecules was supportive for further drug development.

CYP4F2 1347 G > A & GGCX 12970 C > G polymorphisms: frequency in north Indians & their effect on dosing of acenocoumarol oral anticoagulant.

BACKGROUND & OBJECTIVES: CYP4F2 and γ-glutamyl carboxylase (GGCX) have small but significant roles in the maintenance dose of coumarinic oral anticoagulants (COAs). CYP4F2 1347 G > A and GGCX 12970 C > G polymorphisms have been used in the pharmacogenetic dosing algorithms of warfarin for Caucasians and Chinese populations. India has a large population with multiple ethnic groups but there are no reports about the frequencies of these polymorphisms in north Indians. In the present study, we aimed to find out the allelic frequencies of CYP4F2 1347 G > A and GGCX 12970 C > G polymorphisms in a north Indian population and relate these to daily maintenance drug dose requirements of COA. METHODS: CYP4F2 1347 G > A and GGCX 12970 C > G polymorphisms were genotyped by polymerase chain reaction - restriction fragment length polymorphism (PCR-RFLP) protocols and Taqman SNP discrimination assays in healthy volunteers (n=102) and patients (n=225) receiving acenocoumarol, an oral anticoagulant, after cardiac valve replacement surgery. RESULTS: In healthy volunteers, the allele frequencies for CYP4F2 1347 G > A and GGCX 12970 C > G were 43.14 and 1.43 per cent, respectively. No significant differences in mean weight normalized doses of acenocoumarol were found for these CYP4F2 and GGCX genotypes. Binary logistic regression analysis revealed no significant association of any of the genotypes or alleles with the dosing phenotypes for both the SNPs. INTERPRETATION & CONCLUSIONS: We report distinct frequencies of CYP4F2 1347 G > A and GGCX 12970 C > G polymorphisms in north Indians but these polymorphisms did not have significant bearing on maintenance dose of acenocoumarol oral anticoagulant in cardiac valve replacement patients.

Role of Posaconazole Drug in the Treatment of Invasive Fungal Disease: A Review.

Posaconazole is an antifungal medication used primarily to treat invasive fungal in-fections caused by various organisms, such as Aspergillus, Candida, and certain molds. It be-longs to the class of drugs known as triazole antifungals. Clinical studies have reported posaconazole to be effective in treating various invasive fungal infections, especially in patients who are immunocompromised, such as those with weakened immune systems due to conditions like HIV/AIDS, undergoing chemotherapy, or having received an organ transplant. It has ef-fectively treated invasive candidiasis, aspergillosis, zygomycosis, and other serious fungal in-fections. The effectiveness of the drug varies based on factors, such as the type of infection, the patient's immune status, and the site of infection. This review describes the types of infection, the drug's safety profile, the development of resistance to posaconazole, and strategies to man-age or prevent resistance.

Current Updates on Pathogenesis, Systemic Therapy, and Treatment of Invasive Fungal Infections.

Numerous health hazards are associated with fungal infections, ranging from asymptomatic cases to potentially fatal invasive diseases that are especially dangerous for those with impaired immune systems. The main causes behind these diseases are opportunistic fungi, namely Aspergillus, Candida, and Cryptococcus. Invasive fungal infections (IFIs) require a global response that includes the development of vaccines, standardized protocols for diagnosis, potent antifungal medications, and strategies to stop drug-resistant strains. Improving high-risk group diagnosis and treatment is essential to lowering death rates. This review highlights the substantial health concerns associated with fungal infections, especially in immunocompromised individuals, and identifies Aspergillus, Candida, and Cryptococcus as the main pathogens. It highlights the necessity of international efforts, such as the development of novel diagnostic instruments, imaging methods, and antifungal drugs, to combat these invasive infections. The review also addresses the increasing need for novel treatment approaches in light of the developing resistance to widely used antifungal medications. Furthermore, the significance of secretory proteins in fungal pathogenicity and the potential of combination therapy are investigated. It is also suggested that a multimodal strategy be used to fight these illnesses, given the promise of multivalent vaccinations. Overall, this study emphasizes how critical it is to develop better diagnostic and treatment strategies in order to successfully control and lessen the impact of invasive fungal diseases on the health of the world.

Preparation, Characterization, in-vitro and in-vivo Pharmacokinetic Evaluation of Thermostable Dimethyl Fumarate Cocrystals.

Dimethyl fumarate (DMF) is an FDA-approved drug for treating relapsing-remitting multiple sclerosis; but it is susceptible to sublimation leading to its loss during processing. Cocrystals can protect against thermal energy via the interaction of DMF with a coformer via weak forces of interaction. With this hypothesis, we have, for the first time, prepared DMF cocrystals using the solvent evaporation method using coformers like citric acid and succinic acid screened by in-silico predictions and hydrogen bonding properties. Analysis using infra-red (IR), powder x-ray diffraction (PXRD), thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), and sublimation evaluation characterized cocrystals and their thermostability. Comparative analysis of the release profile has been done by dissolution and pharmacokinetic study of DMF and its cocrystals. The cocrystals have improved thermal stability and better pharmacological activities than DMF. In the safety and efficacy evaluation of the formulated cocrystals, they were found to be non-cytotoxic, antioxidant, and inhibiting IL-6 and TNF-α in PBMC induced by lipopolysaccharide (LPS). We have obtained cocrystals of DMF with improved thermal stability and better pharmacological activities than DMF.

Viscoelastic behavior, gelation properties and structural characterization of Deccan hemp seed (Hibiscus cannabinus) protein: Influence of protein and ionic concentrations, pH, and temperature.

This study investigates the viscoelastic behavior, gelling properties, and structural characteristics of Deccan hemp seed protein (DHSP) to overcome limitations in its application in food formulations. Small amplitude oscillatory shear measurements were employed to investigate the impact of protein concentration, pH, ionic concentration, and temperature on DHSP's rheological features. The study revealed that the 20 % protein dispersion had the highest storage modulus (G') and yield stress at 63.96 ± 0.23 Pa and 0.61 Pa, respectively. DHSP dispersion exhibited pseudo-plastic behavior across various conditions. The gelling performance was higher at pH 4 and 8 and at ionic concentration in the range of 0.1 M - 0.5 M. Gelation time and temperature were observed from the temperature ramp test. Structural characterizations, including fluorescence spectroscopy, circular dichroism spectra, FTIR spectra, SEM, AFM images, zeta potential analysis, and DSC, provided insights into DHSP's tertiary and secondary conformation, surface characteristics, and thermal properties. Notably, the study highlighted DHSP's exceptional rheological properties, making it a promising gelling material for the food and nutraceutical industries. The findings also offer new insights into DHSP's structural characteristics, suggesting potential applications in food packaging and product development within the food industry.

Early Mortality in Cardiac Surgery - Is Lactate Significant?

INTRODUCTION: Serum lactate is a consequence of tissue hypoperfusion and has been used routinely for patient management following cardiac surgery. This study aims to determine the association of lactate with early mortality and postoperative morbidity. METHODS: This is a prospective cohort study carried out in the Department of Cardiovascular and Thoracic Surgery, King George's Medical University (India), from January 2020 to December 2022. A total of 270 patients were included in this study. Serum lactate levels were measured preoperatively, intraoperatively on-pump, coming off-pump, and at six, 12, 24, and 48 hours postoperatively. RESULTS: Early mortality was noted in 17 cases (6.3%). While both lactate and lactate clearance correlated with duration of mechanical ventilation, vasopressor duration, and intensive care unit and hospital stay, correlation with early mortality was noted only with lactate at 24 hours. Logistic regression analysis demonstrated that lactate levels at preoperative period (adjusted odds ratio [OR] 4.76 [1.67-13.59], P=0.004) and at 24 hours after bypass (OR 1.21 [1.00-1.47], P=0.046) and vasopressor duration (OR 1.11 [1.04-1.19], P=0.002) are independent predictors of mortality. Receiver operating characteristic curve analysis showed that arterial lactate on-pump, off-pump, and at six, 12, and 24 hours after surgery had significant area under the curve for predicting mortality. CONCLUSION: Arterial lactate and lactate clearance show good correlation with duration of mechanical ventilation, vasopressor support, and intensive care unit and hospital stay and can serve as a good indicator to guide therapeutic decisions in postoperative period. However, it fails to be a sensitive predictor of mortality.