Cheminformatics identification of modulators of key carbohydrate-metabolizing enzymes from C. cujete for type-2 diabetes mellitus intervention.

Purpose: The therapeutic use of oral hypoglycaemic agents in the management of type-2 diabetes mellitus (T2DM) is without adverse effects; thus, calls for alternative and novel candidates from natural products in medicinal plants. Method: The study explored molecular docking and molecular dynamics (MD) simulation approaches to identify key antidiabetic metabolites from Crescentia cujete. Results: Molecular docking results identified four and/or five best compounds against each target enzyme (alpha-glucosidase, dipeptidyl peptidase-IV, aldose reductase, and protein tyrosine phosphatase-1B (PTP-1B)) implicated in diabetes. The resulting complexes (except against PTP-1B) had higher docking scores above respective standards (acarbose, Diprotin A, ranirestat). The MD simulation results revealed compounds such as benzoic acid (-48.414 kcal/mol) and phytol (-45.112 kcal/mol) as well as chlorogenic acid (-42.978 kcal/mol) and naringenin (-31.292 kcal/mol) had higher binding affinities than the standards [acarbose (-28.248 kcal/mol), ranirestat (-21.042 kcal/mol)] against alpha-glucosidase and aldose reductase, respectively while Diprotin A (-45.112 kcal/mol) and ursolic acid (-18.740 kcal/mol) presented superior binding affinities than the compounds [luteolin (-41.957 kcal/mol and naringenin (-16.518 kcal/mol)] against DPP-IV and PTP-1B respectively. Conclusion: While isoflavone (alpha-glucosidase), xylocaine (DPP-IV), luteolin (aldose reductase,) and chlorogenic acid (PTP-1B) were affirmed as the best inhibitors of respective enzyme targets, luteolin, and chlorogenic acid may be suggested and proposed as probable candidates against T2DM and related retinopathy complication based on their structural stability, compactness and affinity for three (DPP-IV, aldose reductase, and PTP-1B) of the four targets investigated. Further studies are warranted in vitro and in vivo on the antihyperglycaemic effects of these drug candidates. Supplementary Information: The online version contains supplementary material available at 10.1007/s40200-023-01249-7.

A Phase 2 Randomized Trial Evaluating the Antiviral Activity and Safety of the Direct-Acting Antiviral Bemnifosbuvir in Ambulatory Patients with Mild or Moderate COVID-19 (MOONSONG Study).

Bemnifosbuvir is an oral antiviral drug with a dual mechanism of action targeting viral RNA polymerase, with in vitro activity against SARS-CoV-2. We conducted a phase 2, double-blind study evaluating the antiviral activity, safety, efficacy, and pharmacokinetics of bemnifosbuvir in ambulatory patients with mild/moderate COVID-19. Patients were randomized 1:1 to bemnifosbuvir 550 mg or placebo (cohort A) and 3:1 to bemnifosbuvir 1,100 mg or placebo (cohort B); all doses were given twice daily for 5 days. The primary endpoint was a change from baseline in the amount of nasopharyngeal SARS-CoV-2 viral RNA by reverse transcription PCR (RT-PCR). The modified intent-to-treat infected population comprised 100 patients (bemnifosbuvir 550 mg, n = 30; bemnifosbuvir 1,100 mg, n = 30; cohort A placebo, n = 30; cohort B placebo, n = 10). The primary endpoint was not met: the difference in viral RNA adjusted means at day 7 was -0.25 log10 copies/mL between bemnifosbuvir 550 mg and cohort A placebo (80% confidence interval [CI], -0.66 to 0.16; P = 0.4260), and -0.08 log10 copies/mL between bemnifosbuvir 1,100 mg and pooled placebo (80% CI, -0.48 to 0.33; P = 0.8083). Bemnifosbuvir 550 mg was well tolerated. Incidence of nausea and vomiting was higher with bemnifosbuvir 1,100 mg (10.0% and 16.7% of patients, respectively) than pooled placebo (2.5% nausea, 2.5% vomiting). In the primary analysis, bemnifosbuvir did not show meaningful antiviral activity on nasopharyngeal viral load as measured by RT-PCR compared with placebo in patients with mild/moderate COVID-19. The trial is registered at ClinicalTrials.gov under registration number NCT04709835. IMPORTANCE COVID-19 continues to be a major global public health challenge, and there remains a need for effective and convenient direct-acting antivirals that can be administered outside health care settings. Bemnifosbuvir is an oral antiviral with a dual mechanism of action and potent in vitro activity against SARS-CoV-2. In this study, we evaluated the antiviral activity, safety, efficacy, and pharmacokinetics of bemnifosbuvir in ambulatory patients with mild/moderate COVID-19. In the primary analysis, bemnifosbuvir did not show meaningful antiviral activity compared with placebo as assessed by nasopharyngeal viral loads. The negative predictive value of nasopharyngeal viral load reduction for clinical outcomes in COVID-19 is currently unclear, and further evaluation of bemnifosbuvir for COVID-19 may be warranted despite the findings observed in this study.

Computational Insights and In Vitro Validation of Antibacterial Potential of Shikimate Pathway-Derived Phenolic Acids as NorA Efflux Pump Inhibitors.

The expression of the efflux pump systems is the most important mechanism of antibiotic resistance in bacteria, as it contributes to reduced concentration and the subsequent inactivity of administered antibiotics. NorA is one of the most studied antibacterial targets used as a model for efflux-mediated resistance. The present study evaluated shikimate pathway-derived phenolic acids against NorA (PDB ID: 1PW4) as a druggable target in antibacterial therapy using in silico modelling and in vitro methods. Of the 22 compounds evaluated, sinapic acid (-9.0 kcal/mol) and p-coumaric acid (-6.3 kcal/mol) had the best and most prominent affinity for NorA relative to ciprofloxacin, a reference standard (-4.9 kcal/mol). A further probe into the structural stability and flexibility of the resulting NorA-phenolic acids complexes through molecular dynamic simulations over a 100 ns period revealed p-coumaric acid as the best inhibitor of NorA relative to the reference standard. In addition, both phenolic acids formed H-bonds with TYR 76, a crucial residue implicated in NorA efflux pump inhibition. Furthermore, the phenolic acids demonstrated favourable drug likeliness and conformed to Lipinski's rule of five for ADME properties. For the in vitro evaluation, the phenolic acids had MIC values in the range 31.2 to 62.5 µg/mL against S. aureus, and E. coli, and there was an overall reduction in MIC following their combination with ciprofloxacin. Taken together, the findings from both the in silico and in vitro evaluations in this study have demonstrated high affinity of p-coumaric acid towards NorA and could be suggestive of its exploration as a novel NorA efflux pump inhibitor.

An investigation into the ethnic distribution of diabetes and awareness of diabetic retinopathy among members of the Diabetes Association of Trinidad and Tobago (DATT) for the period 2020 ­ 2021 and determination of how COVID-19 impacted their treatment

• Diabetic retinopathy (DR) is a condition whereby persons who suffer from diabetes have retinal damage resulting from consistently high blood glucose levels. • DR is the leading cause of blindness in Trinidad and Tobago, accounting for 11.4% cases of blindness. • Screening is the best way to prevent the development of DR as early medical intervention reduces the chances of blindness occurring • Limited awareness of DR among the population hinders the ability for earlier intervention

Separation of distinct exosome subpopulations: isolation and characterization approaches and their associated challenges.

Exosomes are nano-sized extracellular vesicles that serve as a communications system between cells and have shown tremendous promise as liquid biopsy biomarkers in diagnostic, prognostic, and even therapeutic use in different human diseases. Due to the natural heterogeneity of exosomes, there is a need to separate exosomes into distinct biophysical and/or biochemical subpopulations to enable full interrogation of exosome biology and function prior to the possibility of clinical translation. Currently, there exists a multitude of different exosome isolation and characterization approaches which can, in limited capacity, separate exosomes based on biophysical and/or biochemical characteristics. While notable reviews in recent years have reviewed these approaches for bulk exosome sorting, we herein present a comprehensive overview of various conventional technologies and modern microfluidic and nanotechnological advancements towards isolation and characterization of exosome subpopulations. The benefits and limitations of these different technologies to improve their use for distinct exosome subpopulations in clinical practices are also discussed. Furthermore, an overview of the most commonly encountered technical and biological challenges for effective separation of exosome subpopulations is presented.

GP educators' understanding, experience and attitudes to teaching global health.

Global health is becoming increasingly relevant to GPs in the UK. A gap analysis revealed many global health capabilities are not currently in the GP curriculum. We undertook a survey of 240 GP educators to understand their views on global health and capacity to deliver global health teaching to GP trainees. This revealed a wide variation of experience, training, and confidence in global health teaching. It is important that the needs of GP trainers are taken into account when considering how global health training will be delivered.

Management of hypothyroidism by Kshara Basti (therapeutic enema)- A case report.

Hypothyroidism is emerging as a common health concern in India as well as worldwide. An autoimmune cause accounts for approximately 90% of adult hypothyroidism mostly due to Hashimoto's disease. This autoimmunity goes parallel with the theory of Ama (intermediatory product) in Ayurveda. A case of a 27-year-old female patient, presenting with pain in multiple joints, deformity in the right little finger, morning stiffness lasting for more than 3 h, reduced appetite, constipation, and lethargy, diagnosed with Amavata (rheumatoid arthritis), was subclinically diagnosed with hypothyroidism and treated with Deepana (stimulates digestion), Pachana (promots digestion) and Koshtha Shuddhi (mild purgation) for 5 days followed by Kshara Basti (therapeutic enema) for 5 days. Reduction in serum- thyroid-stimulating hormone (S. TSH) (31.1 mIU/ml to 16.6 mIU/ml) along with relief in clinical manifestations of the disease was the outcome. Koshtha Shuddhi followed by Kshara Basti has its efficacy in hypothyroidism, as it not only improved signs and symptoms but S.TSH level was reduced significantly. This case report proposes an innovative treatment modality for the management of hypothyroidism, which needs to be validated through a well-planned study on a large sample size.

A clinical study to evaluate the role of Triphaladya Guggulu along with Punarnavadi Kashaya in the management of hypothyroidism.

CONTEXT: Hypothyroidism is one of the most common thyroid disorders in India, affecting one in ten adults. Although the diagnosis and treatment of hypothyroidism are often considered simple, there are large number of people with this condition who are suboptimally treated. Due to wide spectrum of the disease and high prevalence in the society, the current issue was opted for study and its management by means of Ayurvedic principles. MATERIALS AND METHODS: Fifteen eligible hypothyroid patients with serum thyroid-stimulating hormone >4.5 µIU/ml and serum T3 and T4 lower than their respective normal range were selected and treated with Triphladya Guggulu pills and Punarnavadi Kashayam (decoction) for 45 days. Patients were advised to discontinue any medicine they might be taking for the management of hypothyroidism to assess the unbiased effect of therapies. RESULTS: Significant improvement was observed on subjective parameters, but the results on objective parameters were statistically insignificant (P > 0.05). Of the 15 enrolled patients, excellent improvement was observed in 33.33% of the patients, while marked improvement was reported by 53.33% of the patients, moderate improvement was found in 6.66% of the patients and same number of patients, that is, 6.66% showed mild improvement. Moreover, few interesting observations were noted 4 months after completion of the trial. Out of 15 patients registered, 86.66% had positive drug history for levothyroxine. After clinical trial, 6.66% of the patients continued their previous dosage of levothyroxine, while 80% of the patients had withdrawn their hormone replacement therapy. CONCLUSION: Triphladya Guggulu and Punarnavadi decoction are effective in the management of hypothyroidism.