A comprehensive review of synthetic and semisynthetic xanthine oxidase inhibitors: identification of potential leads based on in-silico computed ADME characteristics.

Xanthine oxidase (XO) inhibitors, both synthetic and semisynthetic, have been developed extensively over the past few decades. The increased level of XO is not only the major cause of gout but is also responsible for various conditions associated with hyperuricemia, such as cardiovascular disorders, chronic kidney disorders, diabetes, Alzheimer's disease and chronic wounds. Marketed available XO inhibitors (allopurinol, febuxostat, and topiroxostat) are used to treat hyperuricemia but they are associated with fatal side effects, which pose serious problems for the healthcare system, rising the need for new, more potent, safer compounds. This review summarizes recent findings on XO and describes their design, synthesis, biological significance in the development of anti-hyperuricemic drugs with ADME profile, structure activity relationship (SAR) and molecular docking studies. The results might help medicinal chemists to develop more efficacious XO inhibitors.

Mannose-Binding Lectin Gene Variants as Disease Susceptibility Biomarkers in Rheumatoid Arthritis.

Background: Rheumatoid arthritis (RA) is a chronic, inflammatory autoimmune disease characterized by progressive destruction of peripheral joints. About 1% of the human population worldwide is suffering from this disease. The pathophysiology of RA is largely being influenced by immune dysregulation. Mannose-binding lectin (MBL), an acute-phase protein, has been reported to play an important role in pathogenesis of RA by the activation of complement pathway. Various studies documented the established the role of MBL in pathogenesis of various autoimmune diseases, including RA. MBL protein is encoded by gene MBL2, mapped on chromosome 10q11.2-q21. Objective: Both MBL serum levels and activity are mainly determined genetically by its variants. So considering the putative clinical role of MBL2, this case-control association study was designed to assess its six functional variants in a northwestern Indian cohort. Methods: Genetic typing of six MBL2 variants was done by amplification refractory mutation system-polymerase chain reaction. Data were analyzed using suitable statistical tools. Results: Significant difference has been observed in genotypic and allelic distribution between cases and controls for rs11003125. Comparison of allelic distribution for rs1800450 showed significantly high prevalence of A allele in cases than controls. Conclusion: These results indicate that MBL2 variants may act as plausible marker for susceptibility toward RA. Keeping this in view, it is pertinent to screen these variants in other population groups of India.

Understanding the Stability of Highly Nitrated Sensitive Pyrazole Isomers.

Two energetic isomers of chemically unstable 3,5-bis(dinitromethyl)-4-nitro-1H-pyrazole (2), namely, 4-methyl-3,5-dinitro-1-(trinitromethyl)-1H-pyrazole (4) and 5-methyl-3,4-dinitro-1-(trinitromethyl)-1H-pyrazole (6), each containing five nitro groups and having the same chemical composition, exhibit major differences in their physiochemical properties. These include density, enthalpy of formation, temperature of decomposition, and sensitivity to impact and friction. Notably, both isomer 4 and isomer 6 demonstrate superior thermal stability compared to isomer 2, making them promising candidates as safer energetic materials.

Co-Occurring Methylenetetrahydrofolate Reductase (MTHFR) rs1801133 and rs1801131 Genotypes as Associative Genetic Modifiers of Clinical Severity in Rett Syndrome.

AIM: Remethylation disorders such as 5,10-methylenetetrahydrofolate reductase (MTHFR) deficiency reduce the remethylation of homocysteine to methionine. The resulting hyperhomocysteinemia can lead to serious neurological consequences and multisystem toxicity. The role of MTHFR genotypes has not been investigated in patients with Rett Syndrome (RTT). In this study, we sought to assess the impact of co-occurring MTHFR genotypes on symptom profiles in RTT. METHOD: Using pharmacogenomic (PGx) testing, the MTHFR genetic polymorphisms rs1801133 (c.665C>T mutation) and rs1801131 (c.1286A>C mutation) were determined in 65 patients (18.7 years ± 12.1 [mean ± standard deviation]) with RTT as part of routine clinical care within the Centre for Interventional Paediatric Psychopharmacology (CIPP) Rett Centre, a National and Specialist Child and Adolescent Mental Health Service (CAMHS) in the UK. The clinical severity of patients was assessed using the RTT-anchored Clinical Global Impression Scale (RTT-CGI). RESULTS: The clinical severity symptom distribution varied between the homozygous and heterozygous MTHFR rs1801133 and rs1801131 genotypes. Those with the homozygous genotype had a narrower spread of severity scores across several domains (language and communication, ambulation, hand-use and eye contact clinical domains). Patients with the homozygous genotype had statistically significantly greater CGI-Severity scores than individuals with a non-homozygous MTHFR genotype (Z = -2.44, p = 0.015). When comparing the ratings of moderately impaired (4), markedly impaired (5), severely impaired (6) and extremely impaired (7), individuals with the homozygous MTHFR genotype were more impaired than those with the non-homozygous MTHFR genotype (Z = -2.06, p = 0.039). There was no statistically significant difference in the number of prescribed anti-epileptic drugs between the genotypes. CONCLUSIONS: Our findings show that in those with a pathogenic RTT genetic variant, co-occurring homozygotic MTHFR rs1801133 and rs1801131 polymorphisms may act as associative genetic modifiers of clinical severity in a subset of patients. Profiling of rs1801133 and rs1801131 in RTT may therefore be useful, especially for high-risk patients who may be at the most risk from symptom deterioration.

A novel case of ulnar nerve compression neuropathy with co-existing accessory flexor carpi ulnaris and accessory abductor digiti minimi.

There are numerous cases reported of the accessory muscles of the hand and wrist in surgical, cadaveric, and imaging-based studies. Anatomical muscle variations in the flexor compartment of the wrist and forearm can present as a pseudo mass or space-occupying lesion causing external compression on the traversing nerves. Guyon's canal is a compact space with a high potential for nerve entrapment. Common etiologies include ganglion cysts, osteophytes, or soft tissue masses. This rare case illustrates the combined existence of two accessory muscles, an accessory flexor carpi ulnaris, and an accessory abductor digiti minimi, causing ulnar nerve compression in Guyon's canal with imaging correlation. One can raise the suspicion of an anomalous muscle when symptoms concern a patient of a younger age group in the absence of common etiologies. Furthermore, detailed anatomical knowledge of muscles around Guyon's canal is essential in making a diagnosis and aiding treatment.

Impact of 5' Near Gene Variants of Mannose Binding Lectin (MBL2) on Breast Cancer Risk.

The immune system plays a bifaceted role in tumour development through modulation of inflammation. MBL binds to damage-associated molecular patterns and induces inflammation through the activation of complement pathway. Dysregulated inflammation plays a major role in breast cancer pathogenesis, thereby suggesting its contribution towards breast cancer risk. Literature asserts single-nucleotide polymorphisms (SNPs) modulating serum MBL levels. Therefore, studying MBL2 SNPs in breast cancer might provide valuable insight in the disease pathogenesis. The present case-control association study aimed to elucidate the association between MBL2 5' near gene SNPs and breast cancer risk. Breast cancer patients were recruited from Government Medical College, G.N.D. Hospital, Amritsar. The age- and gender-matched genetically unrelated healthy individuals, from adjoining regions, with no history of malignancy up to three generations were recruited as controls. The SNPs of MBL2 from the 5' near gene region with putative functional significance were selected based upon the in silico analysis and literature review. The genotypic, allelic and haplotype frequencies for the studied variants were assessed and compared in the study participants by ARMS-PCR and PCR-RFLP. No difference in allelic, genotypic and haplotype frequencies was reported for rs7096206, rs7084554 and rs11003125 in both the participant groups. rs7084554 (CC) was found to confer risk towards hormone receptor-positive breast cancer. An intermediate LD was observed between rs7084554 and rs11003125. The study reports association between MBL2 variant (rs7084554) and hormone receptor-positive breast cancer risk. Further research in this direction might validate the findings.

Preserving plum perfection: Buckwheat starch edible coating with xanthan gum and lemongrass essential oil.

The research focused on the fabrication of composite coatings using buckwheat starch (BS) and xanthan gum (XG) with incorporation of lemongrass (Cymbopogon citratus) essential oil (LEO) with varying concentration (0.75 %, 1.0 % and 1.25 % (w/v). BS was extracted from buckwheat groats (Fagopyrum esculentum) and its physico-chemical characteristics were determined. BS showed spherical and polygonal morphology and its XRD pattern was similar to starch extracted from other cereal sources. The amount of reducing sugar, starch and amylose content in extracted BS were 0.99 ± 0.33 %, 86.32 ± 0.22 % and 21.02 ± 1.89 % respectively, which indicates that BS is a suitable base material for the formation of edible coatings. XG was mixed with BS in different ratios (1:1, 2:1, 3:1 and 4:1) to optimize the best ratio of combination for composite coatings. The coating with a ratio of 2:1 was very smooth and was chosen for incorporation of LEO and the coatings physical, functional, mechanical, thermal and micro-structural characteristics were examined. The coating S5 with 1.25 % (w/v) concentration of LEO showed the best results with least moisture content (MC), minimum water vapor permeability (WVP) and maximum contact angle value. Moreover, the S5 formulation had the highest antioxidant (73.3 %) ability and maximum antimicrobial efficiency with inhibition zones of 22.09 ± 0.06 mm and 28.65 ± 0.14 mm against S. aureus and E. coli respectively. The coatings were then coated on plum fruit, and various parameters like weight loss, pH, shrinkage and TSS were calculated every 4th day during the 20 days of refrigeration period. The coated plums' ripening pace was delayed by the S5 formulation which improved moisture retention, maintained the plums' TSS value and overall pH. Therefore, composite coatings made up of BS, XG and 1.25 % (w/v) can be used as a cost-effective bio-active coating material for plum preservation under refrigeration conditions.

Analysis of Molecular Genetic Variants of Lgals4 in Esophageal Cancer: A Preliminary Report.

Esophageal cancer is the eighth most common cancer worldwide and fourth most common in developing countries. Altered glycosylation pattern of cell membrane molecules along with inflammation is a characteristic attribute of oncogenesis. Galectin-4, a tandem repeat galectin, has shown effect on cancer progression/metastasis in digestive system cancers. This role of galectin-4 can be attributed to variations in LGALS4, gene encoding galectin-4. The present case-control study was designed to analyze four intronic SNPs in LGALS4 with susceptibility toward esophageal cancer.Esophageal cancer cases and age- and gender-matched apparently healthy individuals were recruited for the present study. Genotyping of rs8113319, rs4802886, rs4802887, and rs12610990 was carried out using Sanger sequencing and PCR-RFLP. MedCalc software, SNPStats and SHEsis online platform were used for statistical analysis.Genotypic analyses revealed an overall increased heterozygosity of rs12610990, rs4802886, and rs4802887, and AA genotype of rs8113319 in the study participants. Haplotypic analyses also revealed a predominance of AAAT haplotype in the cases. Moreover, combined presence of wild alleles of rs4802886 and rs4802887 could influence protection toward disease, and combined presence of wild alleles of rs12610990 and rs8113319 could influence disease susceptibility. Furthermore, a strong linkage disequilibrium was also observed between the SNPs. Further studies are underway to validate galectin-4 and its genetic variants as blood-based biomarkers in early disease diagnosis, improving treatment outcome.

Pushing the Limit of Oxygen Balance on a Benzofuroxan Framework: K2DNDP as an Extremely Dense and Thermally Stable Material as a Substitute for Lead Azide.

Because of environmental and health impacts, there is an ongoing necessity to develop sustainable primary explosives to replace existing lead-based analogues. Now we describe a potential primary explosive, dipotassium 4,6-dinitro-5,7-dioxidobenzo[c][1,2,5]oxadiazole 1-oxide (K2DNDP), which exhibits an excellent thermal stability (Tdec = 281 °C), positive oxygen balance (+4.79%), and a calculated crystal density of ρ = 2.274 g cm-3 at 100 K. Its physicochemical properties concomitantly with its straightforward synthesis make it a potential replacement for lead-based initiators.

Antidiabetic potential of thiazolidinedione derivatives with efficient design, molecular docking, structural activity relationship, and biological activity: an update review (2021-2023).

Thiazolidinedione has been used successfully by medicinal chemists all over the world in the development of potent antidiabetic derivatives. The few compounds with excellent antidiabetic potency that we have identified in this review could be used as a lead for further research into additional antidiabetic mechanisms. The information provided in this review regarding the design, biological activity, structure-activity relationships, and docking studies may be useful for scientists who wish to further explore this scaffold in order to fully utilize its biological potential and develop antidiabetic agents that would overcome the limitations of currently available medications for the treatment of diabetes. This review outlines the antidiabetic potential of Thiazolidinedione-based derivatives that have been published in the year 2021- till date.

Synthesis of the Indolizidine Core of Virosinine A via a Microwave-Promoted Cascade Cyclization Involving Iminyl Radicals.

The indolizidine core of virosinine A was synthesized by means of a microwave-promoted cascade reaction featuring 5-exo-trig iminyl radical cyclization, thiyl radical elimination, and intramolecular imine alkylation. The resulting bicyclic iminium ion underwent stereoselective reduction by Red-Al to deliver the target compound. DFT calculations suggested that both the radical cyclization and thiyl radical elimination steps are reversible at high reaction temperatures.

Suicidality Treatment Occurring in Paediatrics (STOP) Medication Suicidality Side Effects Scale in young people in two cohorts across Europe.

OBJECTIVES: As part of the 'Suicidality: Treatment Occurring in Paediatrics (STOP)' study, we developed and performed psychometric validation of an electronic-clinical-outcome-assessment (eCOA), which included a patient-reported-outcome (ePRO), an observer-rated-outcome (eObsRO) for parents/carers and a clinician-reported-outcome (eClinRO) that allows identification and monitoring of medication-related suicidality (MRS) in adolescents. DESIGN: STOP: Prospective study: A two phase validation study to assess the impact of medication on suicidal ideations. SETTING: Six participating countries: Netherlands, UK, Germany, France, Spain and Italy that were part of the Community's Seventh Framework Programme (FP7/2007-2013) under grant agreement no. 261411. PARTICIPANTS: Cohort 1 consisted of 41 adolescent-completions, 50 parent-completions and 56 clinician-completions. Cohort 2 consisted of 244 adolescent-completions, 198 parent-completions and 240 clinician-completions from across the six countries. The scale was administered only to participants who have screened positive for the STOP-Suicidality Assessment Scale (STOP-SAS). RESULTS: A total of 24 items for the development of the STOP-Medication Suicidality Side Effects Scale (STOP-MS3) were identified and three versions (for patients, parents and clinicians) of the STOP-MS3 were developed and validated in two separate study cohorts comprising of adolescents, their parents and clinicians. Cronbach's α coefficients were above 0.85 for all domains. The inter-rater reliability of the STOP-MS3 was good and significant for the adolescent (ePRO), clinician (eClinRO) (r=0.613), parent (eObsRO) versions of the scale (r=0.394) and parent and clinician (r=0.347). Exploratory factor analysis identified a 3-factor model across 24 items for the adolescent and parent version of the scale: (1) Emotional Dysregulation, (2) Somatic Dysregulation and (3) Behavioural Dysregulation. For the clinician version, a 4-factor model defined the scale structure: (1) Somatic Dysregulation, (2) Emotional Dysregulation, (3) Behavioural Dysregulation and (4) Mood Dysregulation. CONCLUSION: These findings suggest that the STOP-MS3 scale, a web-based eCOA, allows identification and monitoring of MRS in the adolescent population and shows good reliability and validity.