Comprehensive translational profiling and STE AI uncover rapid control of protein biosynthesis during cell stress.

Translational control is important in all life, but it remains a challenge to accurately quantify. When ribosomes translate messenger (m)RNA into proteins, they attach to the mRNA in series, forming poly(ribo)somes, and can co-localize. Here, we computationally model new types of co-localized ribosomal complexes on mRNA and identify them using enhanced translation complex profile sequencing (eTCP-seq) based on rapid in vivo crosslinking. We detect long disome footprints outside regions of non-random elongation stalls and show these are linked to translation initiation and protein biosynthesis rates. We subject footprints of disomes and other translation complexes to artificial intelligence (AI) analysis and construct a new, accurate and self-normalized measure of translation, termed stochastic translation efficiency (STE). We then apply STE to investigate rapid changes to mRNA translation in yeast undergoing glucose depletion. Importantly, we show that, well beyond tagging elongation stalls, footprints of co-localized ribosomes provide rich insight into translational mechanisms, polysome dynamics and topology. STE AI ranks cellular mRNAs by absolute translation rates under given conditions, can assist in identifying its control elements and will facilitate the development of next-generation synthetic biology designs and mRNA-based therapeutics.

Natural flavonoids effectively block the CD81 receptor of hepatocytes and inhibit HCV infection: a computational drug development approach.

Hepatitis C virus (HCV) infection is a major public health concern, and almost two million people are infected per year globally. This is occurred by the diverse spectrum of viral genotypes, which are directly associated with chronic liver disease (fibrosis, and cirrhosis). Indeed, the viral genome encodes three principal proteins as sequentially core, E1, and E2. Both E1 and E2 proteins play a crucial role in the attachment of the host system, but E2 plays a more fundamental role in attachment. The researchers have found the "E2-CD81 complex" at the entry site, and therefore, CD81 is the key receptor for HCV entrance in both humans, and chimpanzees. So, the researchers are trying to block the host CD81 receptor and halt the virus entry within the cellular system via plant-derived compounds. Perhaps that is why the current research protocol is designed to perform an in silico analysis of the flavonoid compounds for targeting the tetraspanin CD81 receptor of hepatocytes. To find out the best flavonoid compounds from our library, web-based tools (Swiss ADME, pKCSM), as well as computerized tools like the PyRx, PyMOL, BIOVIA Discovery Studio Visualizer, Ligplot+ V2.2, and YASARA were employed. For molecular docking studies, the flavonoid compounds docked with the targeted CD81 protein, and herein, the best-outperformed compounds are Taxifolin, Myricetin, Puerarin, Quercetin, and (-)-Epicatechin, and outstanding binding affinities are sequentially - 7.5, - 7.9, - 8.2, - 8.4, and - 8.5 kcal/mol, respectively. These compounds have possessed more interactions with the targeted protein. To validate the post docking data, we analyzed both 100 ns molecular dynamic simulation, and MM-PBSA via the YASARA simulator, and finally finds the more significant outcomes. It is concluded that in the future, these compounds may become one of the most important alternative antiviral agents in the fight against HCV infection. It is suggested that further in vivo, and in vitro research studies should be done to support the conclusions of this in silico research workflow.

Impacts of nutritive and bioactive compounds on cancer development and therapy.

For persons who survive with progressive cancer, nutritional therapy and exercise may be significant factors to improve the health condition and life quality of cancer patients. Nutritional therapy and medications are essential to managing progressive cancer. Cancer survivors, as well as cancer patients, are mostly extremely encouraged to search for knowledge about the selection of diet, exercise, and dietary supplements to recover as well as maintain their treatment consequences, living quality, and survival of patients. A healthy diet plays an important role in cancer treatment. Different articles are studied to collect information and knowledge about the use of nutrients in cancer treatment as well as cancer prevention. The report deliberates nutrition and exercise strategies during the range of cancer care, emphasizing significant concerns during treatment of cancer and for patients of advanced cancer, but concentrating mostly on the requirements of the population of persons who are healthy or who have constant disease following their repossession from management. It also deliberates choice nutrition and exercise problems such as dietary supplements, food care, food selections, and weight; problems interrelated to designated cancer sites, and common questions about diet, and cancer survival. Decrease the side effects of medicines both during and after treatment.

Phenolic compounds as α-glucosidase inhibitors: a docking and molecular dynamics simulation study.

Phenolic compounds possess significant biological activity. Several pieces of research emphasize the medicinal importance of phenolic compounds, including diabetes. The present study investigated the α-glucosidase inhibitory activity of phenolic compounds reported from several plants. The phenolic compounds reported in different literature were collected. Molecular docking was carried out using AutoDock Vina. Various physicochemical properties such as size, LogP, molecular complexity, hydrogen bonding properties of phenolic compounds were correlated with the binding affinities. Furthermore, MD simulation was carried out to study the structural stability of the docking complexes. A total of 155 phenolic compounds were reported from different plants. Amentoflavone showed the strongest binding affinity with α-glucosidase, much more potent than reference acarbose. The binding energy showed a good correlation with the molecular complexity, hydrogen bond donor and acceptor property and heavy atom counts of the compounds. The polarity of the surface area also showed a positive correlation with the binding affinity of the compounds. The best docking phenolic compound, amentoflavone, showed stable binding affinity and conformation during the simulation period compared to apoprotein and acarbose-docking complex. The top ten phenolic compounds, including amentoflavone, showed considerable drug-likeness properties with fewer toxicity effects. The study suggests that the amentoflavone could be a potential therapeutic drug as an α-glucosidase inhibitor and help control postprandial hyperglycemia.Communicated by Ramaswamy H. Sarma.

Volatile compounds of Bacillus pseudomycoides induce growth and drought tolerance in wheat (Triticum aestivum L.).

The plant growth-boosting biofilm-forming bacteria Bacillus pseudomycoides is able to promote growth and drought stress tolerance in wheat by suppressing the MYB gene, which synthesizes Myb protein (TaMpc1-D4) through secreted volatile compounds. In the present study, Triticum aestivum seeds were inoculated with five distinct bacterial strains. The growth, germination rate, root-shoot length, RWC, and chlorophyll content of seedlings were investigated. Furthermore, the levels of soluble sugars, proteins, H2O2, NO, cell death, and antioxidant enzymes (CAT, SOD, POD, and APX) were observed throughout the growth stage. All of the results showed that B. pseudomycoides had a substantially higher ability to form biofilm and promote these traits than the other strains. In terms of molecular gene expression, B. pseudomycoides inoculation strongly expressed the Dreb1 gene by silencing the expression of MYB gene through secreted volatile compounds. For identifying the specific volatile compound that silenced the MYB gene, molecular docking with Myb protein was performed. Out of 45 volatile compounds found, 2,6-ditert-butylcyclohexa-2,5-diene-1,4-dione and 3,5-ditert-butylphenol had a binding free energy of - 6.2 and - 6.5, Kcal/mol, respectively, which predicted that these compounds could suppress this protein's expression. In molecular dynamics simulations, the RMSD, SASA, Rg, RMSF, and hydrogen bonding values found assured the docked complexes' binding stability. These findings suggest that these targeted compounds may be suppressing Myb protein expression as well as the expression of Dreb1 and other drought response genes in wheat. More research (field trial) into plant growth and drought stress is needed to support the findings of this study.

Mineral and Phenolic Composition of Erodium guttatum Extracts and Investigation of Their Antioxidant Properties in Diabetic Mice.

Erodium guttatum is widely used in folk medicine in many countries to treat various ailments such as urinary inflammation, diabetes, constipation, and eczema. The aim of this study is the determination of mineral and phenolic compounds of E. guttatum extracts as well as the investigation of their antidiabetic and antioxidant properties. The mineral composition was determined by the methods of inductively coupled plasma atomic emission spectroscopy analysis. Phytochemical contents of total polyphenols, total flavonoids, and catechic tannins were estimated by colorimetric dosages. The phenolic composition was identified by high-resolution mass spectrometry (HRMS) analysis. The antioxidant activity of E. guttatum extracts was measured in vitro by five methods (DPPH, ABTS, FRAP, H2O2, and xanthine oxidase) and in vivo by assaying the malondialdehyde marker (MDA), superoxide dismutase (SOD), catalase (CAT), and glutathione (GSH). The obtained results showed that the root plant material is rich in minerals such as k, Ca, and Mg. The methanolic extract of E. guttatum is the richest in polyphenols (389.20 ± 1.55 mg EAG/gE), tannins (289.70 ± 3.57 mg EC/gE), and flavonoids (432.5 ± 3.21 mg ER/gE). Concerning the ESI-HRMS analysis, it showed the presence of numerous bioactive compounds, including shikimic acid, rottlerine, gallic acid, and vanillic acid. Moreover, the aqueous and alcoholic extracts of E. guttatum exhibited antiradical and antioxidant activity in five tests used, with the best effect of the methanolic extract. Moreover, findings showed that in vivo investigations confirmed those obtained in vitro. On the other hand, E. guttatum showed important antidiabetic effects in vivo. Indeed, diabetic mice treated with extracts of E. guttatum were able to significantly reduce MDA levels and increase the secretion of enzymatic and nonenzymatic antioxidants (SOD, CAT, and GSH, respectively). However, the antioxidant activity of the extracts might be attributed to the abundance of bioactive molecules; as results, this work serves as a foundation for additional pharmacological research.

Revealing the Acetylcholinesterase Inhibitory Potential of Phyllanthus amarus and Its Phytoconstituents: In Vitro and in Silico Approach.

The inhibition of acetylcholinesterase plays a vital role in the treatment of Alzheimer disease. This study aimed to explore the acetylcholinesterase inhibition potential of Phyllanthus amarus and its phytoconstituents through an in vitro and in silico approach. The in vitro acetylcholinesterase inhibitory activity of P amarus was carried out, followed by the molecular docking studies of its phytoconstituents. The top-ranked molecules identified through molecular docking were subjected to molecular dynamics simulation (MDS) and density functional theory (DFT) studies. The results obtained revealed the methanolic extract of P amarus as a potent acetylcholinesterase inhibitor, while amarosterol A, hinokinin, ß-sitosterol, stigmasterol and ellagic acid were identified as potential acetylcholinesterase inhibitors. The MDS and DFT results are in agreement with those obtained from the docking studies. Our findings suggest further studies on the hit molecules.

Isoxazole Derivatives against Carbonic Anhydrase: Synthesis, Molecular Docking, MD Simulations, and Free Energy Calculations Coupled with In Vitro Studies.

Heterocyclic compounds with a five-membered ring as a core, particularly those containing more than one heteroatom, have a wide spectrum of biological functions, especially in enzyme inhibition. In this study, we present the synthesis of five-membered heterocyclic isoxazole derivatives via sonication of ethyl butyrylacetate with aromatic aldehyde in the presence of a SnII-Mont K10 catalyst. The synthesized compounds were characterized using sophisticated spectroscopic methods. In vitro testing of the compounds reveals three derivatives with significant inhibitory action against carbonic anhydrase (CA) enzyme. The compound AC2 revealed the most promising inhibitory activity against CA among the entire series, with an IC50 = 112.3 ± 1.6 µM (%inh = 79.5) followed by AC3 with an IC50 = 228.4 ± 2.3 µM (%inh = 68.7) compared to the standard with 18.6 ± 0.5 µM (%inh = 87.0). Molecular docking (MD) study coupled with extensive MD simulations (400 ns) and MMPBSA study fully supported the in vitro enzyme inhibition results, evident from the computed ΔG bind (AC2 = -13.53 and AC3 = -12.49 kcal/mol). The in vitro and in silico studies are also augmented by a fluorescence-based enzymatic assay in which compounds AC2 and AC3 showed significant fluorescence enhancement. Therefore, on the basis of the present study, it is inferred that AC2 and AC3 may serve as a new framework for designing effective CA inhibitors.

The Current State of Knowledge in Biological Properties of Cirsimaritin.

The search for natural plant-based products as new pharmacological alternatives to treat various human pathologies has taken on great importance for researchers and research laboratories. In this context, research has intensified to extract and identify natural molecules endowed with biological effects. The objective of this study is to review the source and pharmacological properties of cirsimaritin. The identification and isolation of this flavonoid from various natural sources, including medicinal plants such as Artemisia judaica, Cirsium japonicum, Lithocarpus dealbatus, Microtea debilis, and Ocimum sanctum, has been carried out and verified using different spectral techniques. Biological effect investigations are carried out with a wide variety of experimental models in vitro and in vivo and laboratory techniques. The results of these research works showed the biological properties of cirsimaritin including anticancer, antimicrobial, antidiabetic, antiparasitic, antioxidant, and anti-inflammatory effects. The mechanisms involved in the multiple activities of this molecule are diverse and include sub-cellular, cellular, and molecular levels. Indeed, this bioactive induces anti-inflammatory and antiproliferative effects by inhibiting cell membrane receptors, interference with signaling pathways, and inhibiting transcriptional factors such as Nf-κB involved in cell promotion and proliferation. In the light of these results, cirsimaritin appears as a promising and viable alternative natural bioactive drug to treat many pathological conditions.

Missense mutations in spike protein of SARS-CoV-2 delta variant contribute to the alteration in viral structure and interaction with hACE2 receptor.

INTRODUCTION: Many of the global pandemics threaten human existence over the decades among which coronavirus disease (COVID-19) is the newest exposure circulating worldwide. The RNA encoded severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus is referred as the pivotal agent of this deadly disease that induces respiratory tract infection by interacting host ACE2 receptor with its spike glycoprotein. Rapidly evolving nature of this virus modified into new variants helps in perpetrating immune escape and protection against host defense mechanism. Consequently, a new isolate, delta variant originated from India is spreading perilously at a higher infection rate. METHODS: In this study, we focused to understand the conformational and functional significance of the missense mutations found in the spike glycoprotein of SARS-CoV-2 delta variant performing different computational analysis. RESULTS: From physiochemical analysis, we found that the acidic isoelectric point of the virus elevated to basic pH level due to the mutations. The targeted mutations were also found to change the interactive bonding pattern and conformational stability analyzed by the molecular dynamic's simulation. The molecular docking study also revealed that L452R and T478K mutations found in the RBD domain of delta variant spike protein contributed to alter interaction with the host ACE2 receptor. CONCLUSIONS: Overall, this study provided insightful evidence to understand the morphological and attributive impact of the mutations on SARS-CoV-2 delta variant.

Antiulcer Effect of Senna multiglandulosa via Increased Secretion of Mucus and Nonprotein Sulfhydryl Groups in an Experimental Murine Model.

Peptic ulcer is a universal condition that is a public health problem due to its prevalence, risk of complications and socioeconomic impact. This study aimed to determine the antiulcer effect of the hydroalcoholic extract from Senna multiglandulosa leaves against ethanol-induced gastric ulcer in rats. Thirty-six male albino Holtzman rats were assigned to six groups. Group I received physiological saline (PS) at doses of 10 mL/kg; group II: ethanol (PS + ethanol 5 mL/kg); group III; omeprazole 100 mg/kg/day (gold standard); groups IV, V and VI received doses of 100, 250 and 500 mg/kg/day of S. multiglandulosa extract, respectively. The stomach was removed to determine the ulcerative lesions and two sections of the glandular zone to carry out the analysis of the gastric mucus and sulfhydryl groups content. As result, S. multiglandulosa at doses of 250 and 500 mg/kg produced a significant decrease of the injured area, with values of 46.28 ± 7.95 mm2 and 6.91 ± 2.48 mm2, respectively (P < 0.001). The protective effect was showed at dose of 500 mg/kg (92.27%) and a significant increase in the production of mucus with a value of 83.13 ± 13.09 mg/mL/g of tissue (61.14%). The production of nonprotein sulfhydryl groups (NP-SG) also increased significantly at the three evaluated doses, being 250.34 ± 21.16 µg/g tissue at dose of 500 mg/kg (119.94%). It is concluded that S. multiglandulosa extract protected against ethanol-induced gastric ulcer due to increased gastric mucus secretion and its antioxidant activity due to the generation of nonprotein sulfhydryl groups.

Singular and Combined Effects of Essential Oil and Honey of Eucalyptus Globulus on Anti-Inflammatory, Antioxidant, Dermatoprotective, and Antimicrobial Properties: In Vitro and In Vivo Findings.

Eucalyptus globulus is a plant widely used by the world population, including Morocco, in the treatment of several pathologies. The aim of this work is to evaluate the antioxidant, anti-inflammatory, dermatoprotective, and antimicrobial effects of essential oil and honey from E. globulus, as well as their combination. Chemical composition was determined by GC-MS analysis. The antioxidant activity was evaluated by three tests, namely, DPPH, reducing power, and the ß-carotene/linoleic acid assay. The anti-inflammatory activity was investigated in vitro (5-lipoxygenase inhibition) and in vivo (carrageenan-induced paw edema model), while the dermatoprotective activity was tested in vitro (tyrosinase inhibition). Moreover, the antibacterial activity was assessed using agar well diffusion and microdilution methods. The results showed that eucalyptol presents the main compound of the essential oil of E. globulus (90.14%). The mixture of essential oil with honey showed the best antioxidant effects for all the tests used (0.07 < IC50 < 0.19 mg/mL), while the essential oil was the most active against tyrosinase (IC50 = 38.21 ± 0.13 µg/mL) and 5-lipoxygenase (IC50 = 0.88 ± 0.01 µg/mL), which corroborated the in vivo test. Additionally, the essential oil showed the best bactericidal effects against all strains tested, with inhibition diameter values ranging from 12.8 to 21.6 mm. The findings of this work showed that the combination of the essential oil with honey showed important results in terms of biological activity, but the determination of the underlying mechanisms of action remains a major prospect to be determined.

Plant-derived compounds effectively inhibit the main protease of SARS-CoV-2: An in silico approach.

The current coronavirus disease 2019 (COVID-19) pandemic, caused by the coronavirus 2 (SARS-CoV-2), involves severe acute respiratory syndrome and poses unprecedented challenges to global health. Structure-based drug design techniques have been developed targeting the main protease of the SARS-CoV-2, responsible for viral replication and transcription, to rapidly identify effective inhibitors and therapeutic targets. Herein, we constructed a phytochemical dataset of 1154 compounds using deep literature mining and explored their potential to bind with and inhibit the main protease of SARS-CoV-2. The three most effective phytochemicals Cosmosiine, Pelargonidin-3-O-glucoside, and Cleomiscosin A had binding energies of -8.4, -8.4, and -8.2 kcal/mol, respectively, in the docking analysis. These molecules could bind to Gln189, Glu166, Cys145, His41, and Met165 residues on the active site of the targeted protein, leading to specific inhibition. The pharmacological characteristics and toxicity of these compounds, examined using absorption, distribution, metabolism, excretion, and toxicity (ADMET) analyses, revealed no carcinogenicity or toxicity. Furthermore, the complexes were simulated with molecular dynamics for 100 ns to calculate the root mean square deviation (RMSD), root mean square fluctuation (RMSF), radius of gyration (Rg), solvent-accessible surface area (SASA), and hydrogen profiles from the simulation trajectories. Our analysis validated the rigidity of the docked protein-ligand. Taken together, our computational study findings might help develop potential drugs to combat the main protease of the SARS-CoV-2 and help alleviate the severity of the pandemic.

Inhibition of α-Amylase, α-Glucosidase, and Lipase, Intestinal Glucose Absorption, and Antidiabetic Properties by Extracts of Erodium guttatum.

Erodium guttatum is widely used in traditional medicine to treat various diseases, including diabetes. In this study, we evaluated in vitro inhibitory activity of extracts of E. guttatum on α-amylase, α-glucosidase, and lipase and then studied in vivo using different animal models. The results showed that the aqueous and alcoholic extracts of E. guttatum significantly inhibited digestive enzymes. The extracts of E. guttatum significantly reduced postprandial hyperglycemia after starch loading in normal rats. Additionally, extracts of E. guttatum significantly decrease the intestinal absorption of D-glucose. However, the methanolic extract of E. guttatum showed remarkable antidiabetic activity compared to the aqueous and ethanolic extracts of E. guttatum. In addition, the extracts significantly reduced blood sugar levels in albino mice and hematological and biochemical profiles. Therefore, the results of this study show that the extracts of E. guttatum have antidiabetic effects and could therefore be suggested in the management of type 2 diabetes.

Molecular Docking and Dynamics Simulation of Natural Compounds from Betel Leaves (Piper betle L.) for Investigating the Potential Inhibition of Alpha-Amylase and Alpha-Glucosidase of Type 2 Diabetes.

Piper betle L. is widely distributed and commonly used medicinally important herb. It can also be used as a medication for type 2 diabetes patients. In this study, compounds of P. betle were screened to investigate the inhibitory action of alpha-amylase and alpha-glucosidase against type 2 diabetes through molecular docking, molecular dynamics simulation, and ADMET (absorption, distribution, metabolism, excretion, and toxicity) analysis. The molecule apigenin-7-O-glucoside showed the highest binding affinity among 123 (one hundred twenty-three) tested compounds. This compound simultaneously bound with the two-target proteins alpha-amylase and alpha-glucosidase, with high molecular mechanics-generalized born surface area (MM/GBSA) values (ΔG Bind = -45.02 kcal mol-1 for alpha-amylase and -38.288 for alpha-glucosidase) compared with control inhibitor acarbose, which had binding affinities of -36.796 kcal mol-1 for alpha-amylase and -29.622 kcal mol-1 for alpha-glucosidase. The apigenin-7-O-glucoside was revealed to be the most stable molecule with the highest binding free energy through molecular dynamics simulation, indicating that it could compete with the inhibitors' native ligand. Based on ADMET analysis, this phytochemical exhibited a wide range of physicochemical, pharmacokinetic, and drug-like qualities and had no significant side effects, making them prospective drug candidates for type 2 diabetes. Additional in vitro, in vivo, and clinical investigations are needed to determine the precise efficacy of drugs.

Synthesis, antimicrobial, SAR, PASS, molecular docking, molecular dynamics and pharmacokinetics studies of 5'-O-uridine derivatives bearing acyl moieties: POM study and identification of the pharmacophore sites.

Because of their superior antibacterial and pharmacokinetic capabilities, many nucleoside-based esters show potential against microorganisms, and may be used as pharmacological agents to address multidrug-resistant pathogenic problems. In this study, several aliphatic and aromatic groups were inserted to synthesize various 5'-O-decanoyluridine (2-5) and 5'-O-lauroyluridine derivatives (6-7) for antimicrobial, in silico computational, pharmacokinetic and POM (Petra/Osiris/Molinspiration). The chemical structures of the synthesized uridine derivatives were confirmed by physicochemical, elemental, and spectroscopic analyses. In vitro antimicrobial screening against five bacteria and two fungi, as well as the prediction of substance activity spectra (PASS), revealed that these uridine derivatives have promising antifungal properties when compared to the antibacterial activities. Density functional theory (DFT) was used to calculate the thermodynamic and physicochemical properties. Molecular docking was conducted against lanosterol 14a-demethylase CYP51A1 (3JUV) and Aspergillus flavus (1R4U) and revealed binding affinities and non-covalent interactions with the target. Then, a 150 ns molecular dynamic simulation was performed to confirm the behavior of the complex structure formed by microbial protein under in silico physiological conditions to examine its stability over time, which revealed a stable conformation and binding pattern in a stimulating environment of uridine derivatives. The acyl chain {CH3(CH2)9CO-} and {CH3(CH2)10CO-} in conjunction with sugar, was determined to have the most potent activity against bacterial and fungal pathogens in a structure-activity relationships (SAR) investigation. POM analyses were conducted with the presence of an antifungal (O δ- -- O' δ-) pharmacophore site. Overall, the present study might be useful for the development of uridine-based novel multidrug-resistant antimicrobial.

Novel uridine derivatives were designed and synthesized. The chemical structures and purity of these new uridine derivatives were confirmed by usual spectroscopic techniques.In vitro antimicrobial activity and SAR study was investigated. The incorporation of various aliphatic and aromatic groups in uridine structure significantly increased their biological activity.PASS prediction analysis indicated that the compounds were less potent as anti-carcinogenic agents (0.31 < Pa < 0.52) than as antimicrobial agents.Molecular docking analysis showed that the novel uridine derivatives 2, 5 and 6 may possess excellent effectiveness for lanosterol 14a-demethylase CYP51A1 (3JUV) and Aspergillus flavus (1R4U).The stability of the docked complex was confirmed by performing molecular dynamics along with an estimation of MMPB/GBSA binding free energy which ensured that complex of derivatives 2, 5 and 6 were reported in improved dynamics stability as revealed by their uniform RMSD and RMSF profiles.In silico ADMET calculations predicted improved pharmacokinetic properties of all uridine derivatives.The POM analysis showed the presence of an antifungal (O ^δ− --- O' ^δ−) pharmacophore site.

Novel Galactopyranoside Esters: Synthesis, Mechanism, In Vitro Antimicrobial Evaluation and Molecular Docking Studies.

One-step direct unimolar valeroylation of methyl α-D-galactopyranoside (MDG) mainly furnished the corresponding 6-O-valeroate. However, DMAP catalyzed a similar reaction that produced 2,6-di-O-valeroate and 6-O-valeroate, with the reactivity sequence as 6-OH > 2-OH > 3-OH,4-OH. To obtain novel antimicrobial agents, 6-O- and 2,6-di-O-valeroate were converted into several 2,3,4-tri-O- and 3,4-di-O-acyl esters, respectively, with other acylating agents in good yields. The PASS activity spectra along with in vitro antimicrobial evaluation clearly indicated that these MDG esters had better antifungal activities than antibacterial agents. To rationalize higher antifungal potentiality, molecular docking was conducted with sterol 14α-demethylase (PDB ID: 4UYL, Aspergillus fumigatus), which clearly supported the in vitro antifungal results. In particular, MDG ester 7−12 showed higher binding energy than the antifungal drug, fluconazole. Additionally, these compounds were found to have more promising binding energy with the SARS-CoV-2 main protease (6LU7) than tetracycline, fluconazole, and native inhibitor N3. Detailed investigation of Ki values, absorption, distribution, metabolism, excretion, and toxicity (ADMET), and the drug-likeness profile indicated that most of these compounds satisfy the drug-likeness evaluation, bioavailability, and safety tests, and hence, these synthetic novel MDG esters could be new antifungal and antiviral drugs.

Use of Next-Generation Sequencing for Identifying Mitochondrial Disorders.

Mitochondria are major contributors to ATP synthesis, generating more than 90% of the total cellular energy production through oxidative phosphorylation (OXPHOS): metabolite oxidation, such as the ß-oxidation of fatty acids, and the Krebs's cycle. OXPHOS inadequacy due to large genetic lesions in mitochondrial as well as nuclear genes and homo- or heteroplasmic point mutations in mitochondrially encoded genes is a characteristic of heterogeneous, maternally inherited genetic disorders known as mitochondrial disorders that affect multisystemic tissues and organs with high energy requirements, resulting in various signs and symptoms. Several traditional diagnostic approaches, including magnetic resonance imaging of the brain, cardiac testing, biochemical screening, variable heteroplasmy genetic testing, identifying clinical features, and skeletal muscle biopsies, are associated with increased risks, high costs, a high degree of false-positive or false-negative results, or a lack of precision, which limits their diagnostic abilities for mitochondrial disorders. Variable heteroplasmy levels, mtDNA depletion, and the identification of pathogenic variants can be detected through genetic sequencing, including the gold standard Sanger sequencing. However, sequencing can be time consuming, and Sanger sequencing can result in the missed recognition of larger structural variations such as CNVs or copy-number variations. Although each sequencing method has its own limitations, genetic sequencing can be an alternative to traditional diagnostic methods. The ever-growing roster of possible mutations has led to the development of next-generation sequencing (NGS). The enhancement of NGS methods can offer a precise diagnosis of the mitochondrial disorder within a short period at a reasonable expense for both research and clinical applications.

Determination of Volatile Compounds of Mentha piperita and Lavandula multifida and Investigation of Their Antibacterial, Antioxidant, and Antidiabetic Properties.

Mentha piperita and Lavandula multifida are widely used in Moroccan traditional medicine for the treatment of diabetes and infectious diseases. The aims of this work were the determination of the chemical composition of Mentha piperita (MPEO) and Lavandula multifida (LMEO) essential oils and the evaluation of their antibacterial, antioxidant, and antidiabetic activities. The chemical composition was determined by GC-MS analysis. The antibacterial effects were evaluated against several bacterial strains using disc diffusion, MIC, and MBC methods. The antioxidant activity was evaluated in vitro using DPPH, H2O2, and xanthine oxidase, and the antidiabetic activity was estimated by the inhibitory effects of α-amylase, α-glucosidase, and lipase activities. GC-MS results showed that the main compounds of MPEO were menthone (29.24%), levomenthol (38.73%), and eucalyptol (6.75%). However, eucalyptol (28.11%), 2-bornanone (11.57%), endo-borneol (7.82%), and linalyl acetate (5.22%) are the major compounds of LMEO. The results exhibited important inhibitory effects against some bacterial strains with MIC = MBC = 0.39 mg/mL for MPEO against Staphylococcus aureus ATCC. However, LMEO exhibited remarkable antioxidant and antidiabetic activities compared to MPEO. Indeed, LMEO inhibited DPPH, H2O2, and xanthine oxidase with concentrations of 15.23, 21.52, and 8.89 µg/mL, respectively. Moreover, LMEO exhibited α-amylase and α-glucosidase at IC50 = 85.34 and IC50 = 59.36 µg/mL, respectively. The findings showed that both MPEO and LMEO exhibit promising biological properties. However, the application of these species or their main bioactive compounds requires further investigation.

The Emergence of SARS-CoV-2 Variants With a Lower Antibody Response: A Genomic and Clinical Perspective.

The emergence of several novel SARS-CoV-2 variants regarded as variants of concern (VOCs) has exacerbated pathogenic and immunologic prominences, as well as reduced diagnostic sensitivity due to phenotype modification-capable mutations. Furthermore, latent and more virulent strains that have arisen as a result of unique mutations with increased evolutionary potential represent a threat to vaccine effectiveness in terms of incoming and existing variants. As a result, resisting natural immunity, which leads to higher reinfection rates, and avoiding vaccination-induced immunization, which leads to a lack of vaccine effectiveness, has become a crucial problem for public health around the world. This study attempts to review the genomic variation and pandemic impact of emerging variations of concern based on clinical characteristics management and immunization effectiveness. The goal of this study is to gain a better understanding of the link between genome level polymorphism, clinical symptom manifestation, and current vaccination in the instance of VOCs.