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Probiotics are regarded as a potential source of functional foods for improving the microbiota in human gut. When consumed, these bacteria can control the metabolism of biomolecules, which has numerous positive effects on health. Our objective was to identify a probiotic putative Lactobacillus spp. from fermented sugarcane juice that can prevent α-glucosidase and α-amylase from hydrolyzing carbohydrates. Isolates from fermented sugarcane juice were subjected to biochemical, molecular characterization (16S rRNA) and assessed for probiotic traits. Cell-free supernatant (CS) and extract (CE) and also intact cells (IC) were examined for the inhibitory effect on α-glucosidase and α-amylase. CS of the strain showed the highest inhibition and was subjected to a liquid chromatography–mass spectrometry (LCMS) analysis to determine the organic acid profile. The in silico approach was employed to assess organic acid stability and comprehend enzyme inhibitors’ impact. Nine isolates were retained for further investigation based on the preliminary biochemical evaluation. Limosilactobacillus spp., Levilactobacillus spp., and Lacticaseibacillus spp. were identified based on similarity > 95% in homology search (NCBI database). The strains had a higher survival rate (>98%) than gastric and intestinal fluids, also a high capacity for adhesion (hydrophobicity > 56%; aggregation > 80%; HT-29 cells > 54%; buccal epithelial cells > 54%). The hemolytic assay indicated that the isolates could be considered safe. The isolates’ derivatives inhibited enzymes to varying degrees, with α-glucosidase inhibition ranging from 21 to 85% and α-amylase inhibition from 18 to 75%, respectively. The CS of RAMULAB54 was profiled for organic acid that showed the abundance of hydroxycitric acid, citric acid, and lactic acid indicating their role in the observed inhibitory effects. The in silico approach has led us to understand that hydroxycitric acid has the ability to inhibit both the enzymes (α-glucosidase and α-amylase) effectively. Inhibiting these enzymes helps moderate postprandial hyperglycemia and regulates blood glucose levels. Due to their promising antidiabetic potential, these isolates can be used to enhance intestinal health.

Cefixime; widely employed cephalosporin antibiotic is unfortunately coupled to poor water solubility with resultant low oral bioavailability issues. To solve this problem micro-emulsion technique was used to fabricate binary SLNs using blend of solid and liquid lipids, surfactant as well as co-surfactant. The optimized nano suspension was characterized followed by modification to solidified dosage form. During characterization, optimized nano-suspension (CFX-4) produced particle size 189±2.1 nm with PDI 0.310±0.02 as well as −33.9±2 mV zeta potential. Scanning electron microscopy (SEM) presented nearly identical and spherical shaped particles. Differential scanning calorimetry and X-ray powder diffraction analysis ascertained decrease in drug’s crystallinity. In-vitro release of drug pursued zero-order characteristics and demonstrated non-fickian pattern of diffusion. The freeze dried nano suspension (CFX-4) was transformed to capsule dosage form to perform comparison based In-Vivo studies. In-Vivo evaluation corresponded to 2.20-fold and 2.11-fold enhancement in relative bioavailability of CFX nano-formulation (CFX-4) as well as the prepared capsules respectively in contrast to the commercialized product (Cefiget®). In general; the obtained results substantiated superior oral bioavailability along with sustained pattern of drug release for CFX loaded binary nano particles. Thus, binary SLNs could be employed as a resourceful drug carrier for oral CFX delivery.

Objectives: To investigate the hypoglycemic and hypolipidemic potentials of Picris babylonica extract in streptozotocin (STZ) induced diabetes in rats. Methods: Animals were injected with 40mg/kg of STZ to induce diabetes, a common diabetic model. Development of the disease were assessed by measuring blood glucose level 3 days prior systemic administration of STZ and following STZ injection. Animals received 200mg/kg and 400mg/kg of Picris babylonica extract and 0.6mg/kg of glibenclamide, standard, by oral rout for 14 consecutive days. Results: Administration of the Picris babylonica extract significantly decreased serum blood glucose, total cholesterol, triglycerides, and low-density lipoprotein-cholesterol. In addition, high density lipoprotein-cholesterol level significantly enhanced as compared to standard. Conclusion: Picris babylonica extract demonstrated beneficial effects in lowering blood glucose and improving lipid profile, therefore, Picris babylonica extract could be developed as hypoglycemic and hypolipidemic therapy.

MCM7 (Minichromosome Maintenance Complex Component 7) is a component of the DNA replication licensing factor, which controls DNA replication. The MCM7 protein is linked to tumor cell proliferation and has a function in the development of several human cancers. Several types of cancer may be treated by inhibiting the protein, as it is strongly produced throughout this process. Significantly, Traditional Chinese Medicine (TCM), which has a long history of clinical adjuvant use against cancer, is rapidly gaining traction as a valuable medical resource for the development of novel cancer therapies, including immunotherapy. Therefore, the goal of the research was to find small molecular therapeutic candidates against the MCM7 protein that may be used to treat human cancers. A computational-based virtual screening of 36,000 natural TCM libraries is carried out for this goal using a molecular docking and dynamic simulation technique. Thereby, ∼8 novel potent compounds i.e., ZINC85542762, ZINC95911541, ZINC85542617, ZINC85542646, ZINC85592446, ZINC85568676, ZINC85531303, and ZINC95914464 were successfully shortlisted, each having the capacity to penetrate the cell as potent inhibitors for MCM7 to curb this disorder. These selected compounds were found to have high binding affinities compared to the reference (AGS compound) i.e. < −11.0 kcal/mol. ADMET and pharmacological properties showed that none of these 8 compounds poses any toxic property (carcinogenicity) and have anti-metastatic, and anticancer activity. Additionally, MD simulations were run to assess the compounds’ stability and dynamic behavior with the MCM7 complex for about 100 ns. Finally, ZINC95914464, ZINC95911541, ZINC85568676, ZINC85592446, ZINC85531303, and ZINC85542646 are identified as highly stable within the complex throughout the 100 ns simulations. Moreover, the results of binding free energy suggested that the selected virtual hits significantly bind to the MCM7 which implied these compounds may act as a potential MCM7 inhibitor. However, in vitro testing protocols are required to further support these results. Further, assessment through various lab-based trial methods can assist with deciding the action of the compound that will give options in contrast to human cancer immunotherapy. Communicated by Ramaswamy H. Sarma

Background & Objectives Low penetration efficiency and retention time are the main therapeutic concerns that make it difficult for most of the drugs to be delivered to the intraocular tissues. These challenging issues are often related to those drugs, which have low or poor solubility and low permeability. The goal of this study was designed to develop nanostructured lipid carriers (NLCs) loaded with itraconazole (ITZ) with the objective of enhancing topical ocular permeation and thereby improving clinical efficacy. Materials and Methods ITZ-loaded NLCs were fabricated by a high-speed homogenization technique using surfactant (Poloxamer 407), and lipids (stearic acid and oleic acid). Optimization of formulations was performed by 3 level factorial design and the selected formulation (F6) was evaluated by differential scanning calorimetry and transmission electron microscopy. Antifungal activity was assessed by measuring the zone of inhibition and irritation potential using the HET-CAM test. Results The independent variables (lipid ratio-X1 and percentage of emulsifier-X2) have a positive impact on percentage entrapment efficiency (Y2) and percentage release (Y3) but have a negative impact on particle size (Y1). Based on the better entrapment efficiency (94.65%), optimum particle size (150.67 nm), and percentage cumulative drug release (68.67%), batch F6 was selected for further evaluation. Electron microscopic images revealed that the prepared particles are spherical and have nano size. Antifungal studies demonstrated enhancement in the zone of inhibition by formulation F6 as compared to a commercial eye drop. The non-irritancy of optimized formulation (F6) was confirmed with a zero score. Interpretation & Conclusion In summary, the optimized NLCs seem to be a potent carrier for the effective delivery of itraconazole in ocular therapy.

Enterococcus faecium is regarded as fourth most emerging common pathogen causing hospital acquired infections (HAIs), with high mortality rate, especially in children, elderly and immunocompromised patients. Recently, due to the emergence of E. faecium resistant strains especially vancomycin resistance (VRE) and their continuously growing resistivity to antibiotics, design of safe vaccine remains a choice for its control. Alternative control through vaccination has received much attention, but there is no clinically approved vaccine against this pathogen. Therefore, in current study we have applied a triple helix approach i.e., Pan-genome, subtractive genome and reverse vaccinology to identify and design potential vaccine candidates and multiepitope-based vaccine (MEV) construct against E. faecium (via core genome analysis from 216 strains). In this study, only 2 outer membrane proteins were identified through genome subtraction of resistant strains genes against human and essential proteins. Subsequently, phosphate ABC transporter substrate binding protein (Psts) was selected as a promiscuous vaccine candidate to develop a potent vaccine model. A final of four epitopes from CD8 + T-cell, CD4 + T-cell epitopes, and B-cell were shortlisted from outer membrane protein with highly antigenic, IFN-γ inducer, and overlapping characteristics for the construction of twelve vaccine models. The V3 construct was found to be highly immunogenic, non-toxic, non-allergenic, highly antigenic and most stable in terms of molecular docking and simulation studies against six HLAs, TLR2, and TLR4 complex. So far, this protein and multiepitope have never been characterized as vaccine targets against E. faecium. The current study proposed V3 as a significant vaccine candidate that could help the scientific community to treat E. faecium infections.

The increasing frequency of S. aureus antimicrobial resistance has spurred interest in identifying alternative therapeutants. We investigated the S. aureus-inhibitory capacity of B. velezensis strains in mouse and bovine models. Among multiple B. velezensis strains that inhibited S. aureus growth in vitro, B. velezensis AP183 provided the most potent inhibition of S. aureus proliferation and bioluminescence in a mouse cutaneous wound (P = 0.02). Histology revealed abundant Gram-positive cocci in control wounds that were reduced in B. velezensis AP183-treated tissues. Experiments were then conducted to evaluate the ability of B. velezensis AP183 to prevent S. aureus biofilm formation on a tracheostomy tube substrate. B. velezensis AP183 could form a biofilm on a tracheostomy tube inner cannula substrate, and that this biofilm was antagonistic to S. aureus colonization. B. velezensis AP183 was also observed to inhibit the growth of S. aureus isolates originated from bovine mastitis cases. To evaluate the inflammatory response of mammary tissue to intramammary inoculation with B. velezensis AP183, we used high dose and low dose inocula in dairy cows. At the high dose, a significant increase in somatic cell count (SCC) and clinical mastitis was observed at all post-inoculation time points (P < 0.01), which resolved quickly compared to S. aureus-induced mastitis; in contrast, the lower dose of B. velezensis AP183 resulted in a slight increase of SCC and no clinical mastitis. In a subsequent experiment, all mammary quarters in four cows were induced to have grade 1 clinical mastitis by intramammary inoculation of a S. aureus mastitis isolate; following mastitis induction, eight quarters were treated with B. velezensis AP183 and milk samples were collected from pretreatment and post-treatment samples for 9 days. In groups treated with B. velezensis AP183, SCC and abundance of S. aureus decreased with significant reductions in S. aureus after 3 days post-inoculation with AP183 (P = 0.04). A milk microbiome analysis revealed significant reductions in S. aureus relative abundance in the AP183-treated group by 8 days post-inoculation (P = 0.02). These data indicate that B. velezensis AP183 can inhibit S. aureus biofilm formation and its proliferation in murine and bovine disease models.

Shigella flexneri is the main causative agent of the communicable diarrheal disease, shigellosis. It is estimated that about 80-165 million cases and 1 million deaths occur every year due to this disease. S. flexneri causes dysentery mostly in young children, elderly and immunocompromised patients, all over the globe. Recently, due to the emergence of S. flexneri antibiotic resistance strains, it is a dire need to predict novel therapeutic drug targets in the bacterium and screen natural products against it, which could eliminate the curse of antibiotic resistance. Therefore, in current study, available antibiotic-resistant genomes (n = 179) of S. flexneri were downloaded from PATRIC database and a pan-genome and resistome analysis was conducted. Around 5059 genes made up the accessory, 2469 genes made up the core, and 1558 genes made up the unique genome fraction, with 44, 34, and 13 antibiotic-resistant genes in each fraction, respectively. Core genome fraction (27% of the pan-genome), which was common to all strains, was used for subtractive genomics and resulted in 384 non-homologous, and 85 druggable targets. Dihydroorotase was chosen for further analysis and docked with natural product libraries (Ayurvedic and Streptomycin compounds), while the control was orotic acid or vitamin B13 (which is a natural binder of this protein). Dynamics simulation of 50 ns was carried out to validate findings for top-scored inhibitors. The current study proposed dihydroorotase as a significant drug target in S. flexneri and 4-tritriacontanonepatupilone compounds as potent drugs against shigellosis. Further experiments are required to ascertain validity of our findings.

Neuropathic pain affects more than one million people across the globe. The quality of life of people suffering from neuropathic pain has been considerably declining due to the unavailability of appropriate therapeutics. Currently, available treatment options can only treat patients symptomatically, but they are associated with severe adverse side effects and the development of tolerance over prolonged use. In the past decade, researchers were able to gain a better understanding of the mechanisms involved in neuropathic pain; thus, continuous efforts are evident, aiming to develop novel interventions with better efficacy instead of symptomatic treatment. The current review discusses the latest interventional strategies used in the treatment and management of neuropathic pain. This review also provides insights into the present scenario of pain research, particularly various interventional techniques such as spinal cord stimulation, steroid injection, neural blockade, transcranial/epidural stimulation, deep brain stimulation, percutaneous electrical nerve stimulation, neuroablative procedures, opto/chemogenetics, gene therapy, etc. In a nutshell, most of the above techniques are at preclinical stage and facing difficulty in translation to clinical studies due to the non-availability of appropriate methodologies. Therefore, continuing research on these interventional strategies may help in the development of promising novel therapies that can improve the quality of life of patients suffering from neuropathic pain.