Methyl ß-D-galactopyranoside esters as potential inhibitors for SARS-CoV-2 protease enzyme: synthesis, antimicrobial, PASS, molecular docking, molecular dynamics simulations and quantum computations.

Carbohydrate esters are significant in medicinal chemistry because of their efficacy for the synthesis of biologically active drugs. In the present study, methyl ß-D-galactopyranoside (MGP) was treated with various acyl halides to produce 6-O-acyl MGP esters by direct acylation method with an excellent yield. To obtain newer products for antimicrobial assessment studies, the 6-O-MGP esters were further modified into 2,3,4-tri-O-acyl MGP esters containing a wide variety of functionalities in a single molecular framework. The chemical structures of the newly synthesized compounds were elucidated by analyzing their physicochemical, elemental, and spectroscopic data. In vitro antimicrobial testing against five bacteria and two fungi and the prediction of activity spectra for substances (PASS) revealed that these MGP estes have promising antifungal functionality compared to their antibacterial activities. The antimicrobial tests demonstrated that the compounds 3 and 10 were the most potent against Bacillus subtilis and Escherichia coli strains, with the minimum inhibitory concentration (MIC) values ranging from 0.352 ± 0.02 to 0.703 ± 0.01 mg/ml and minimum bactericidal concentration (MBC) values ranging from 0.704 ± 0.02 to 1.408 ± 0.04 mg/ml. Density functional theory (DFT) at the B3LYP/3-21G level of theory was employed to enumerate, frontier orbital energy, enthalpy, free energy, electronic energy, MEP, dipole moment which evaluated the effect of certain groups (aliphatic and aromatic) on drug properties. They discovered that all esters were more thermodynamically stable than the parent molecule. Molecular docking is performed using AutoDock Vina to determine the binding affinities and interactions between the MGP esters and the SARS-CoV-2 main protease. The modified esters strongly interact with the prime Cys145, His41, MET165, GLY143, THR26, and ASN142 residues. The MGP esters' shape and ability to form multiple electrostatic and hydrogen bonds with the active site match other minor-groove binders' binding modes. The molecular dynamics simulation validates the molecular docking results. The pharmacokinetic characterization of the optimized inhibitor demonstrates that these MGP esters appear to be safer inhibitors and a combination of in silico ADMET (absorption, distribution, metabolism, excretion, and toxicity) prediction and drug-likeness had promising results due to their improved kinetic properties. Structure activity relationships (SAR) study including in vitro and silico results revealed that the acyl chain, palmitoyl (C16) and 4-chlorobenzoyl (4.ClC6H4CO-) in combination with sugar were found the most potential activates against human and fungal pathogens. After all, our comprehensive computational and statistical analysis shows that these selected MGP esters can be used as potential inhibitors against the SARS-CoV-2.

Revolutionizing clinical trials: the role of AI in accelerating medical breakthroughs.

Clinical trials are the essential assessment for safe, reliable, and effective drug development. Data-related limitations, extensive manual efforts, remote patient monitoring, and the complexity of traditional clinical trials on patients drive the application of Artificial Intelligence (AI) in medical and healthcare organisations. For expeditious and streamlined clinical trials, a personalised AI solution is the best utilisation. AI provides broad utility options through structured, standardised, and digitally driven elements in medical research. The clinical trials are a time-consuming process with patient recruitment, enrolment, frequent monitoring, and medical adherence and retention. With an AI-powered tool, the automated data can be generated and managed for the trial lifecycle with all the records of the medical history of the patient as patient-centric AI. AI can intelligently interpret the data, feed downstream systems, and automatically fill out the required analysis report. This article explains how AI has revolutionised innovative ways of collecting data, biosimulation, and early disease diagnosis for clinical trials and overcomes the challenges more precisely through cost and time reduction, improved efficiency, and improved drug development research with less need for rework. The future implications of AI to accelerate clinical trials are important in medical research because of its fast output and overall utility.

Phenotypical and molecular assessments on the pharmacological effects of curcumin in Drosophila melanogaster.

Curcumin, a dietary polyphenol derived from turmeric's rhizome, exhibits a range of pharmacological activities, such as antioxidant, analgesic, antipyretic, and anti-inflammatory effects. It has been investigated for its therapeutic potential in chronic obstructive pulmonary disease (COPD) due to its ability to inhibit nuclear factor kappa B (NF-κB), modulate oxidative stress, impact cell viability, and regulate gene expression. However, most studies have been limited to in vitro conditions. To address this gap, we conducted in vivo experiments using the fruit fly Drosophila melanogaster to explore the antioxidant activities and biological significance of curcumin. Several parameters were assessed using different assays, including curcumin toxicity assay, fly survival, locomotor response to curcumin treatment (with or without cigarette smoke), trypan blue staining, larval crawling assays, and gene expression analysis. Our data revealed no significant differences in toxicity and locomotor tests across various curcumin concentrations. D. melanogaster tolerated curcumin at concentrations of 0.5 µM, 5 µM, 50 µM, and 500 µM, suggesting its safety without negatively impacting locomotor. Furthermore, curcumin at 5 µM extended the lifespan of D. melanogaster exposed to cigarette smoke, while reversing the negative effects of smoke exposure on gut cell viability and larval locomotor activity. In conclusion, curcumin administration appeared safe for D. melanogaster, with potential benefits for longevity and locomotory function. These findings support the idea that curcumin possesses in vivo antioxidant properties and may serve as a promising pharmacological agent. However, further study is needed to explore its potential applications in human health and disease management, particularly in the context of COPD.

Monkeypox virus infection and myocarditis: A review of current evidence and possible pathogenesis.

The recent spread of the monkeypox virus (MPXV), causing monkeypox (mpox), to non-endemic areas, and the atypical and unusual clinical manifestations observed during its 2022 outbreak has focused international interest on the clinical features of the disease. Mpox is usually a self-limiting disease with mild symptoms with common manifestations, including fever and skin lesions; however, severe manifestations could occur in some vulnerable groups (children and those with impaired immune systems) and may present multisystem complications and fatal outcomes. In most cases, a fever is the first sign of disease, followed by the development of various inflammatory lesions on the skin, such as vesiculopustular rashes and ulcers. Pneumonitis, encephalitis, keratitis, secondary bacterial infections, acute kidney injury, and myocarditis are all possible outcomes of the infection. Myocarditis has been reported to be caused by orthopoxviruses, and it is a serious condition of which its pathophysiology is little understood. Recent reports have indicated myocarditis with cardiac involvement as a possible atypical and unusual consequence of the MPXV infection during present outbreak. This review provides an overview of the clinical manifestations of mpox with a special focus on its effects on the heart, including myocarditis. The evidence of the myocarditis in mpox patients and its possible pathogenesis are discussed.

3-Substituted Coumarins Inhibit NorA and MepA Efflux Pumps of Staphylococcus aureus.

Coumarins are compounds with scientifically proven antibacterial properties, and modifications to the chemical structure are known to improve their effects. This information is even more relevant with the unbridled advances of antibiotic resistance, where Staphylococcus aureus and its efflux pumps play a prominent role. The study's objective was to evaluate the potential of synthetic coumarins with different substitutions in the C-3 position as possible inhibitors of the NorA and MepA efflux pumps of S. aureus. For this evaluation, the following steps took place: (i) the determination of the minimum inhibitory concentration (MIC); (ii) the association of coumarins with fluoroquinolones and ethidium bromide (EtBr); (iii) the assessment of the effect on EtBr fluorescence emission; (iv) molecular docking; and (v) an analysis of the effect on membrane permeability. Coumarins reduced the MICs of fluoroquinolones and EtBr between 50% and 87.5%. Coumarin C1 increased EtBr fluorescence emission between 20 and 40% by reinforcing the evidence of efflux inhibition. The molecular docking results demonstrated that coumarins have an affinity with efflux pumps and establish mainly hydrogen bonds and hydrophobic interactions. Furthermore, C1 did not change the permeability of the membrane. Therefore, we conclude that these 3-substituted coumarins act as inhibitors of the NorA and MepA efflux pumps of S. aureus.

Oral and intranasal vaccines against SARS-CoV-2: Current progress, prospects, advantages, and challenges.

BACKGROUND: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a deadly pandemic in the 21st century, resulting in many deaths, economic loss, and international immobility. Vaccination represents the only mechanism to defeat this virus. Several intramuscular vaccines have been approved and are currently used worldwide. MAIN BODY: However, global mass vaccination has not been achieved owing to several limitations, including the need for expertise to administer the injection-based vaccine, improper distribution of the vaccine, and lack of cold chain facilities, particularly in resource-poor, low-income countries. Mucosal vaccines are typically administered either orally or nasally, and several studies have shown promising results for developing these vaccines against SARS-CoV-2 that might serve as viable alternatives to current vaccines. SARS-CoV-2 invades the human body via oral and nasal mucosal surfaces; thus, an oral or nasal vaccine can trigger the immune system to inhibit the virus at the mucosal level, preventing further transmission via a strong mucosal and systematic immune response. Although several approaches toward developing a mucosal vaccine are currently being tested, additional attention is required. CONCLUSION: In this article, the current approaches used to develop effective oral and nasal mucosal vaccines against SARS-CoV-2 and their benefits, prospects, and challenges have been summarized.

Hepatitis E virus in pigs and the environment: An updated review of public health concerns.

Hepatitis E virus (HEV) is an important public health problem and is responsible for both acute and chronic viral hepatitis. Public health implications of HEV are derived from its transmission route, either water-borne or food-borne, and its zoonotic potential. Not only in developing countries, but HEV cases are also found in a high number in developed countries. The spread of HEV to the environment might pollute surface waters, which could act as the source of infection for both humans and animals. Identification of the virus in animal products suggests the circulation of HEV within water and food chains. High seroprevalence and circulation of HEV in livestock, in particular pigs, as well as in environmental samples warrants further investigation into pig markets. HEV virulence in different environments and meat supply chains could shed light on the possible sources of infection in humans and the degree of occupational risk. The purpose of this review is to discuss HEV infections with an emphasis on livestock- and environment-related risk factors, and food-borne, water-borne, and zoonotic transmissions.

Fast-food and obesity: Status among the young adult population in Bangladesh.

Increasing rate of fast-food consumption has been associated with different health related concerns (e.g., obesity, heart disease). This study aimed to determine the prevalence of fast-food consumption among young adult students in Chittagong, Bangladesh, and to assess the association of fast-food consumption with obesity. A total of 440 youth was included using a systemic random sampling from universities and colleges in Chittagong in order to perform a cross-sectional analysis. The students who reported frequent fast-food consumption (1-3 times per week) accounted for 30.5% (n=134) of the sample, while 32.5% (n=143) of participants reported consuming fast- food 8-15 times per month. There was a significant (p=0.030) difference between students who consumed and did not consume fast-food. Youth who reported consuming fast-food and soft drinks more than 4 times per week constituted 35.0% (n=154), followed by approximately 27.7% (n=122) who consumed these items 1-3 times per week. In addition, an obesity epidemic was observed among those who reported low levels of physical exercise or lack of sleep. The study illustrates that Bangladeshi youth face an increasing risk of becoming overweight and obese. Prevention is regarded as the most effective way to reduce the prevalence of obesity.

Elevated serum malondialdehyde (MDA), insulin, follicle-stimulating hormone (FSH), luteinizing hormone (LH), and thyroid- stimulating hormone (TSH), and reduced antioxidant vitamins in polycystic ovarian syndrome patients.

Elevated oxidative stress and hormonal imbalance have been suggested to associate with polycystic ovarian syndromes (PCOS), a causal factor for unsuccessful pregnancy outcomes and other associated complications in women. The aim of this study was to compare the oxidative stress markers and different relevant hormones between pregnant women with and without PCOS. The levels of malondialdehyde (MDA), insulin, follicle- stimulating hormone (FSH), luteinizing hormone (LH), thyroid-stimulating hormone (TSH), vitamin A and vitamin C were measured in 80 pregnant women with PCOS and 80 healthy pregnancies. The mean MDA and insulin levels were significantly elevated in pregnant women with PCOS compared to healthy controls (1.98±0.07 vs. 1.06±0.02 nmol/mL and 11.15±0.25 vs. 6.67±0.25 mIU/L, respectively with p<0.001 for both). Compared to healthy controls, the mean concentrations of FSH (3.65±0.16 vs. 1.75±0.10 IU/L) and LH (15.67±0.63 vs. 3.65±0.16 IU/L) were significantly higher in pregnant women with PCOS, p<0.001 for both comparisons. Similarly, the concentration of serum TSH was also higher in PCOS cases compared to controls (2.79±0.22 vs. 2.34±0.06, p=0.048). In contrast, the levels of vitamin A and C were lower in PCOS cases compared to healthy pregnancy group, 0.45±0.01 vs. 1.05±0.01 and 0.26±0.01 vs. 0.53±0.02, respectively with p-values <0.001 for both comparations. In conclusion, in PCOS cases, serum MDA, insulin, FSH, LH and TSH levels were found to be elevated while the levels of antioxidant vitamins were lower compared to healthy pregnant women. Unusual hormonal imbalance and increase of oxidative stress markers during the pregnancy might be important to establish the PCOS diagnosis.

Acute severe hepatitis of unknown etiology in children: A mini-review.

The emergence of acute, severe non hepA-E hepatitis of unknown etiology (ASHUE) has attracted global concern owing to the very young age of the patients and its unknown etiology. Although this condition has been linked to several possible causes, including viral infection, drugs and/or toxin exposure, the exact cause remains unknown; this makes treatment recommendation very difficult. In this review, we summarize recent updates on the clinical manifestations, complemented with laboratory results, case numbers with the global distribution and other epidemiological characteristics, and the possible etiologies. We also provide the proposed actions that could be undertaken to control and prevent further spread of this hepatitis. Since many etiological and pathological aspects of the acute non hepA-E hepatitis remain unclear, further research is needed to minimize the severe impact of this disease.

Vaccine hesitancy among communities in ten countries in Asia, Africa, and South America during the COVID-19 pandemic.

Vaccine hesitancy is considered one of the greatest threats to the ongoing coronavirus disease 2019 (COVID-19) vaccination programs. Lack of trust in vaccine benefits, along with concerns about side effects of the newly developed COVID-19 vaccine, might significantly contribute to COVID-19 vaccine hesitancy. The objective of this study was to determine the level of vaccine hesitancy among communities in particular their belief in vaccination benefits and perceived risks of new vaccines. An online cross-sectional study was conducted in 10 countries in Asia, Africa, and South America from February to May 2021. Seven items from the WHO SAGE Vaccine Hesitancy Scale were used to measure a construct of belief in vaccination benefit, and one item measured perceived riskiness of new vaccines. A logistic regression was used to determine which sociodemographic factors were associated with both vaccine hesitancy constructs. A total of 1,832 respondents were included in the final analysis of which 36.2% (range 5.6-52.2%) and 77.6% (range 38.3-91.2%) of them were classified as vaccine hesitant in terms of beliefs in vaccination benefits and concerns about new vaccines, respectively. Respondents from Pakistan had the highest vaccine hesitancy while those from Chile had the lowest. Being females, Muslim, having a non-healthcare-related job and not receiving a flu vaccination during the past 12 months were associated with poor beliefs of vaccination benefits. Those who were living in rural areas, Muslim, and those who did not received a flu vaccination during the past 12 months had relatively higher beliefs that new vaccines are riskier. High prevalence of vaccine hesitancy in some countries during the COVID-19 pandemic might hamper COVID-19 vaccination programs worldwide. Programs should be developed to promote vaccination in those sociodemographic groups with relatively high vaccine hesitancy.

Willingness-to-pay for COVID-19 vaccine in ten low-middle-income countries in Asia, Africa and South America: A cross-sectional study.

Vaccine hesitancy is considered as one of the greatest challenges to control the ongoing coronavirus disease 2019 (COVID-19) pandemic. A related challenge is the unwillingness of the general public to pay for vaccination. The objective of this study was to determine willingness-to-pay (WTP) for COVID-19 vaccine among individuals from ten low- middle-income countries (LMICs) in Asia, Africa, and South America. Data were collected using an online questionnaire distributed during February - May 2021 in ten LMICs (Bangladesh, Brazil, Chile, Egypt, India, Iran, Nigeria, Pakistan, Sudan, and Tunisia). The major response variable of in this study was WTP for a COVID-19 vaccine. The assessment of COVID-19 vaccine hesitancy was based on items adopted from the World Health Organization (WHO) Strategic Advisory Group of Experts (SAGE) vaccine hesitancy scale constructs. In this study, 1337 respondents included in the final analysis where the highest number of respondents was from India, while the lowest number was from Egypt. A total of 88.9% (1188/1337) respondents were willing to pay for the COVID-19 vaccination, and 11.1% (149/1337) were not. The average WTP for COVID-19 vaccination was 87.9 US dollars ($), (range: $5-$200). The multivariate model analysis showed that the country, monthly household income, having a history of respiratory disease, the agreement that routine vaccines recommended by health workers are beneficial and having received the flu vaccination within the previous 12 months were strongly associated with the WTP. Based on the country of origin, the highest mean WTP for COVID-19 vaccine was reported in Chile, while the lowest mean WTP for the vaccine was seen among the respondents from Sudan. The availability of free COVID-19 vaccination services appears as a top priority in the LMICs for successful control of the ongoing pandemic. This is particularly important for individuals of a lower socio- economic status. The effects of complacency regarding COVID-19 extends beyond vaccine hesitancy to involve less willingness to pay for COVID-19 vaccine and a lower value of WTP for the vaccine.