Mining therapeutic targets from the antibiotic-resistant Campylobacter coli and virtual screening of natural product inhibitors against its riboflavin synthase.

Campylobacter coli resides in the intestine of several commonly consumed animals, as well as water and soil. It leads to campylobacteriosis when humans eat raw/undercooked meat or come into contact with infected animals. A common manifestation of the infection is fever, nausea, headache, and diarrhea. Increasing antibiotic resistance is being observed in this pathogen. The increased incidence of C. coli infection, and post-infection complications like Guillain-Barré syndrome, make it an important pathogen. It is essential to find novel therapeutic targets and drugs against it, especially with the emergence of antibiotic-resistant strains. In the current study, genomes of 89 antibiotic-resistant strains of C. coli were downloaded from the PATRIC database. Potent drug targets (n = 36) were prioritized from the core genome (n = 1,337 genes) of this species. Riboflavin synthase was selected as a drug target and pharmacophore-based virtual screening was performed to predict its inhibitors from the NPASS (n = ~ 30,000 compounds) natural product library. The top three docked compounds (NPC115144, NPC307895, and NPC470462) were selected for dynamics simulation (for 50 ns) and ADMET profiling. These identified compounds appear safe for targeting this pathogen and can be further validated by experimental analysis before clinical trials.

Phoenix dactylifera (Ajwa Dates) Alleviate LPS-Induced Sickness Behaviour in Rats by Attenuating Proinflammatory Cytokines and Oxidative Stress in the Brain.

Traditional medicine claims that various components of the Phoenix dactylifera (date plant) can be used to treat memory loss, fever, inflammation, loss of consciousness, and nerve disorders. The present study aims to evaluate the effectiveness of Phoenix dactylifera fruit extracts (PDF) against rat sickness behaviour caused by lipopolysaccharide (LPS) by assessing behavioural and biochemical parameters. PDF was prepared by extracting dry fruits of P. dactylifera with a methanol:water (4:1, v/v) mixture. The PDF was evaluated for phenolic and flavonoid content and HPLC analysis of quercetin estimation. Adult Wistar rats were treated with LPS, PDF + LPS and dexamethasone + LPS. Water and food intake, behavioural tests such as locomotor activity, tail suspension and forced swim tests were conducted. Furthermore, alanine transaminase (ALT) and aspartate transaminase (AST) were estimated in plasma and malondialdehyde (MDA), reduced glutathione (GSH), nitrite, tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), were estimated in the brain. PDF ameliorated LPS-induced sickness behaviour by reducing MDA, nitrite, IL-6, and TNF-α levels and improving GSH, behavioural alteration, water and food intake in the treated rats. In the plasma of the treated rats, PDF also decreased the levels of ALT and AST. The outcomes demonstrated the efficacy of PDF in reducing the sickness behaviour caused by LPS in rats. The authors believe that this study will provide the groundwork for future research to better understand the underlying mechanisms of action and therapeutic efficacy.

Nephroprotective effects of Helianthus annuus seeds extract in gentamicin induced nephrotoxic male mice.

Acute kidney injury (AKI) causes a decrease in renal function which leads to failure in balancing electrolyte, fluid and acid-base homoeostasis. AKI is a damaging and life-threatening disorder, but it can be managed if identified earlier. This study aimed to investigate the possible nephroprotective effect of Helianthus annuus seeds extract against gentamicin (GM) induced nephrotoxicity in male mice. The control group (0.5 ml normal saline i.p.,), Gentamycin (GM) group (GM 100 mg/kg i.p), silymarin + GM group (silymarin 50 mg/kg and GM 100 mg/kg i.p.,), H. annuus extract (HAE) and GM, group (HAE 250 mg/kg and GM 100 mg/kg i.p), HAE2 + GM group (HAE2; 500 mg/kg and GM 100 mg/kg i.p) and H. annuus oil (HAO) + GM (HAO 2.5 ml/kg and GM 100 mg/kg i.p). Serum creatinine, urea and blood urea nitrogen (BUN) were significantly (P< 0.001) elevated in the GM group compared to the control group. The elevated level of serum creatinine, urea and BUN were decreased significantly (P<0.001) in groups treated with HAE and HAO extracts compared to the GM group. The kidney histopathological study from the GM group showed tubular necrosis, vacuolation and fibrosis. However, the animal that received HAE and HAO showed no tubular necrosis and vacuolation. Only mild inflammation was observed compared to the GM group. In conclusion, the extract caused marked radical scavenger and protected the kidney from oxidative damage of GM. H. annuus seeds contain strong antioxidant compounds, including flavonoids, phenolic acids, tocopherols and minerals, which could be responsible for the current show.

Investigation of the Chemical Composition, Antihyperglycemic and Antilipidemic Effects of Bassia eriophora and Its Derived Constituent, Umbelliferone on High-Fat Diet and Streptozotocin-Induced Diabetic Rats.

This study was designed to investigate the chemical profile, antihyperglycemic and antilipidemic effect of total methanolic extract (TME) of Bassia eriophora and isolated pure compound umbelliferone (UFN) in high-fat diet (HFD)- and streptozotocin (STZ)- induced diabetic rats. TME was subjected to various techniques of chromatography to yield UFN. Diabetes was induced after eight weeks of HFD by administration of STZ (40 mg/kg) intraperitoneally, and experimental subjects were divided into five groups. The diabetic control showed an increase in levels of blood glucose throughout the experiment. Treatments were initiated in the other four groups with glibenclamide (GLB) (6 mg/kg), TME (200 mg/kg and 400 mg/kg) and isolated UFN (50 mg/kg) orally. The effect on blood glucose, lipid profile and histology of the pancreatic and adipose tissues was assessed. Both 200 and 400 mg/kg of TME produced a comparably significant decrease in blood glucose levels and an increase in insulin levels with GLB. UFN began to show a better blood sugar-lowering effect after 14 days of treatment, comparatively. However, both 400 mg/kg TME and UFN significantly returned blood glucose levels in diabetic rats compared to normal rats. Analysis of the lipid profile showed that while HFD + STZ increased all lipid profile parameters, TME administration produced a significant decrease in their levels. Histopathological examinations showed that treatment with TME and UFN revealed an improved cellular architecture, with the healthy islets of Langerhans and compact glandular cells for pancreatic cells distinct from damaged cells in non-treated groups. Conversely, the adipose tissue displayed apparently normal polygonal fat cells. Therefore, these results suggest that TME has the potential to ameliorate hyperglycemia conditions and control lipid profiles in HFD + STZ-induced diabetic rats.

How Curcumin Targets Inflammatory Mediators in Diabetes: Therapeutic Insights and Possible Solutions.

Diabetes mellitus is a multifactorial chronic metabolic disorder, characterized by altered metabolism of macro-nutrients, such as fats, proteins, and carbohydrates. Diabetic retinopathy, diabetic cardiomyopathy, diabetic encephalopathy, diabetic periodontitis, and diabetic nephropathy are the prominent complications of diabetes. Inflammatory mediators are primarily responsible for these complications. Curcumin, a polyphenol derived from turmeric, is well known for its anti-oxidant, anti-inflammatory, and anti-apoptotic properties. The regulation of several signaling pathways effectively targets inflammatory mediators in diabetes. Curcumin's anti-inflammatory and anti-oxidative activities against a wide range of molecular targets have been shown to have therapeutic potential for a variety of chronic inflammatory disorders, including diabetes. Curcumin's biological examination has shown that it is a powerful anti-oxidant that stops cells from growing by releasing active free thiol groups at the target location. Curcumin is a powerful anti-inflammatory agent that targets inflammatory mediators in diabetes, and its resistant form leads to better therapeutic outcomes in diabetes complications. Moreover, Curcumin is an anti-oxidant and NF-B inhibitor that may be useful in treating diabetes. Curcumin has been shown to inhibit diabetes-related enzymes, such as a-glucosidase, aldose reductase and aldose reductase inhibitors. Through its anti-oxidant and anti-inflammatory effects, and its suppression of vascular endothelial development and nuclear transcription factors, curcumin has the ability to prevent, or reduce, the course of diabetic retinopathy. Curcumin improves insulin sensitivity by suppressing phosphorylation of ERK/JNK in HG-induced insulin-resistant cells and strengthening the PI3K-AKT-GSK3B signaling pathway. In the present article, we aimed to discuss the anti-inflammatory mechanisms of curcumin in diabetes regulated by various molecular signaling pathways.

Prevalence, pandemic, preventions and policies to overcome antimicrobial resistance.

Antimicrobial resistance (AMR) is a growing concern in Asia, and it is essential to understand the prevalence, pandemic, prevention, and policies to overcome it. According to the World Health Organization (WHO), AMR is one of the main causes of death; in 2019, it was linked to 4.95 million fatalities and caused about 1.27 million deaths. A core package of actions has been provided by WHO to help countries prioritize their needs when creating, carrying out, and overseeing national action plans on antimicrobial resistance. Using a people-cantered approach to AMR, the interventions address the needs and obstacles that individuals and patients encounter when trying to obtain healthcare. The people-cantered core package of AMR treatments seeks to improve public and policymakers; awareness and comprehension of AMR by changing the narrative of AMR to emphasize the needs of people and systemic impairments. Additionally, it backs a more comprehensive and programmatic national response to AMR, which emphasizes the value of fair and inexpensive access to high-quality healthcare services for the avoidance, identification, and management of drug-resistant diseases. The report signals increasing resistance to antibiotics in bacterial infections in humans and the need for better data. In conclusion, the prevalence of AMR in Asia is a significant public health concern, and it is crucial to implement policies and interventions to overcome it.

Inflammatory setting, therapeutic strategies targeting some pro-inflammatory cytokines and pathways in mitigating ischemia/reperfusion-induced hepatic injury: a comprehensive review.

Ischemia/reperfusion injury (IRI) is a key determining agent in the pathophysiology of clinical organ dysfunction. It is characterized by an aseptic local inflammatory reaction due to a decrease in blood supply, hence deprivation of dependent oxygen and nutrients. In instances of liver transplantation, this injury may have irreversible implications, resulting in eventual organ rejection. The deterioration associated with IRI is affected by the hepatic health status and various factors such as alterations in metabolism, oxidative stress, and pro-inflammatory cytokines. The primary cause of inflammation is the initial immune response of pro-inflammatory cytokines, while Kupffer cells (KFCs) and neutrophil-produced chemokines also play a significant role. Upon reperfusion, the activation of inflammatory responses can elicit further cellular damage and organ dysfunction. This review discusses the interplay between chemokines, pro-inflammatory cytokines, and other inflammatory mediators that contribute to the damage to hepatocytes and liver failure in rats following IR. Furthermore, it delves into the impact of anti-inflammatory therapies in safeguarding against liver failure and hepatocellular damage in rats following IR. This review investigates the correlation between cytokine factors and liver dysfunction via examining databases, such as PubMed, Google Scholar, Science Direct, Egyptian Knowledge Bank (EKB), and Research Gate.

Phytochemical analysis, radical scavenging and glioblastoma U87 cells toxicity studies of stem bark of buckthorn (Rhamnus pentapomica R. Parker).

BACKGROUND: During the past two decades, the correlation between oxidative stress and a variety of serious illnesses such as atherosclerosis, chronic obstructive pulmonary disease (COPD), Alzheimer disease (AD) and cancer has been established. Medicinal plants and their derived phytochemicals have proven efficacy against free radicals and their associated diseases. The current work was aimed to evaluate the phytochemical constituents of Rhamnus pentapomica R. Parker via Gas Chromatography-Mass Spectrometry (GC-MS) and its antioxidant and anti-glioblastoma potentials. METHODS: The bioactive compounds were analysed in Rhamnus pentapomica R. Parker stem bark extracts by GC-MS analysis, and to evaluate their antioxidant and anti-glioblastoma effects following standard procedures. The stem bark was extracted with 80% methanol for 14 days to get crude methanolic extract (Rp.Cme) followed by polarity directed fractionation using solvents including ethyl acetate, chloroform, butanol to get ethyl acetate fraction (Rp.EtAc), chloroform fraction (Rp.Chf) and butanol fraction (Rp.Bt) respectively. Antioxidant assay was performed using DPPH free radicals and cell viability assay against U87 glioblastoma cancer cell lines was performed via MTT assay. RESULTS: In GC-MS analysis, thirty-one compounds were detected in Rp.Cme, 22 in Rp.Chf, 24 in Rp.EtAc and 18 compounds were detected in Rp.Bt. Among the identified compounds in Rp.Cme, 9-Octadecenoic acid (Z)-methyl ester (7.73%), Octasiloxane (5.13%) and Heptasiloxane (5.13%), Hexadecanoic acid, methyl ester (3.76%) and Pentadecanoic acid, 14-methyl-, methyl Ester (3.76%) were highly abundant.. In Rp.Chf, Benzene, 1,3-dimethyl- (3.24%) and in Rp.EtAc Benzene, 1,3-dimethyl-(11.29%) were highly abundant compounds. Antioxidant studies revealed that Rp.Cme and Rp.EtAc exhibit considerable antioxidant potentials with IC50 values of 153.53 µg/ml and 169.62 µg/ml respectively. Both fractions were also highly effective against glioblastoma cells with IC50 of 147.64 µg/ml and 76.41ug/ml respectively. CONCLUSION: Phytochemical analysis revealed the presence of important metabolites which might be active against free radicals and glioblastoma cells. Various samples of the plant exhibited considerable antioxidant and anti-glioblastoma potentials warranting further detailed studies.

Screening Marine Microbial Metabolites as Promising Inhibitors of Borrelia garinii: A Structural Docking Approach towards Developing Novel Lyme Disease Treatment.

Lyme disease caused by the Borrelia species is a growing health concern in many parts of the world. Current treatments for the disease may have side effects, and there is also a need for new therapies that can selectively target the bacteria. Pathogens responsible for Lyme disease include B. burgdorferi, B. afzelii, and B. garinii. In this study, we employed structural docking-based screening to identify potential lead-like inhibitors against the bacterium. We first identified the core essential genome fraction of the bacterium, using 37 strains. Later, we screened a library of lead-like marine microbial metabolites (n = 4730) against the arginine deiminase (ADI) protein of Borrelia garinii. This protein plays a crucial role in the survival of the bacteria, and inhibiting it can kill the bacterium. The prioritized lead compounds demonstrating favorable binding energies and interactions with the active site of ADI were then evaluated for their drug-like and pharmacokinetic parameters to assess their suitability for development as drugs. Results from molecular dynamics simulation (100 ns) and other scoring parameters suggest that the compound CMNPD18759 (common name: aureobasidin; IUPAC name: 2-[(4R,6R)-4,6-dihydroxydecanoyl]oxypropan-2-yl (3S,5R)-3,5-dihydroxydecanoate) holds promise as a potential drug candidate for the treatment of Lyme disease, caused by B. garinii. However, further experimental studies are needed to validate the efficacy and safety of this compound in vivo.

Pharmacokinetics and drug-likeness of anti-cancer traditional Chinese medicine: molecular docking and molecular dynamics simulation study.

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.

Glial Glutamate Transporter Modulation Prevents Development of Complete Freund's Adjuvant-Induced Hyperalgesia and Allodynia in Mice.

Glial glutamate transporter (GLT-1) modulation in the hippocampus and anterior cingulate cortex (ACC) is critically involved in nociceptive pain. The objective of the study was to investigate the effects of 3-[[(2-methylphenyl) methyl] thio]-6-(2-pyridinyl)-pyridazine (LDN-212320), a GLT-1 activator, against microglial activation induced by complete Freund's adjuvant (CFA) in a mouse model of inflammatory pain. Furthermore, the effects of LDN-212320 on the protein expression of glial markers, such as ionized calcium-binding adaptor molecule 1 (Iba1), cluster of differentiation molecule 11b (CD11b), mitogen-activated protein kinases (p38), astroglial GLT-1, and connexin 43 (CX43), were measured in the hippocampus and ACC following CFA injection using the Western blot analysis and immunofluorescence assay. The effects of LDN-212320 on the pro-inflammatory cytokine interleukin-1ß (IL-1ß) in the hippocampus and ACC were also assessed using an enzyme-linked immunosorbent assay. Pretreatment with LDN-212320 (20 mg/kg) significantly reduced the CFA-induced tactile allodynia and thermal hyperalgesia. The anti-hyperalgesic and anti-allodynic effects of LDN-212320 were reversed by the GLT-1 antagonist DHK (10 mg/kg). Pretreatment with LDN-212320 significantly reduced CFA-induced microglial Iba1, CD11b, and p38 expression in the hippocampus and ACC. LDN-212320 markedly modulated astroglial GLT-1, CX43, and, IL-1ß expression in the hippocampus and ACC. Overall, these results suggest that LDN-212320 prevents CFA-induced allodynia and hyperalgesia by upregulating astroglial GLT-1 and CX43 expression and decreasing microglial activation in the hippocampus and ACC. Therefore, LDN-212320 could be developed as a novel therapeutic drug candidate for chronic inflammatory pain.

ß-Caryophyllene-Loaded Microemulsion-Based Topical Hydrogel: A Promising Carrier to Enhance the Analgesic and Anti-Inflammatory Outcomes.

Musculoskeletal pain and inflammation can vary from localised pain like pain in the shoulders and neck to widespread pain like fibromyalgia, and as per estimates, around 90% of humans have experienced such pain. Oral non-steroidal anti-inflammatory drugs (NSAIDs) are frequently prescribed for such conditions but are associated with concerns like gastric irritation and bleeding. In the present study, a microemulsion-based gel comprising ß-caryophyllene, isopropyl myristate, Tween 80, and normal saline was prepared as a topical option for managing topical pain and inflammation. The globules of the microemulsion were below 100 nm with a zetapotential of around -10 mV. The drug entrapment was >87% with a drug loading of >23%. The permeation studies established better skin permeation (20.11 ± 0.96 µg cm-2 h-1) and retention of the drug (4.96 ± 0.02%) from the developed system vis-à-vis the conventional product (9.73 ± 0.35 µg cm-2 h-1; 1.03 ± 0.01%). The dermatokinetic studies established the better pharmacokinetic profile of the bioactive in the epidermis and dermis layers of the skin. The anti-inflammatory potential in carrageenan-induced rat paw oedema was more pronounced than the conventional product (~91% vis-à-vis ~77%), indicating a better pharmacodynamic outcome from the developed system. The nanotechnology-based natural bioactive product with improved efficacy and drug loading can provide a better alternative for the management of musculoskeletal pain.

Blood Pressure Control and Prescription Pattern of Antihypertensive Drugs in Adherence to the 2020 International Society of Hypertension (ISH) Global Hypertension Practice Guidelines in Saudi Arabia: A Retrospective Study.

Background Hypertension is the leading risk factor for cardiovascular disease and death. Appropriate treatment of hypertension is necessary to reduce mortality. A prescription-based study is one of the most influential and helpful methods to examine physicians' irrational prescribing practices. This study was designed to investigate the antihypertensive prescription of physicians and their adherence to the treatment guidelines, as well as the blood pressure (BP) control rate in a general hospital in the Kingdom of Saudi Arabia. Methodology A retrospective, cross-sectional study was conducted between February 2020 and June 2021 in an outpatient department. Patients diagnosed with hypertension as per the 2020 International Society of Hypertension guidelines and those who received antihypertensive drugs were included. Study data included prescriptions, patient's age, duration of hypertension, comorbidities, BP, drug therapy type, and antihypertensive class. Results Overall, angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers (67.1%) were the most prescribed agents, followed by dihydropyridine-calcium channel blockers (62.6%), diuretics (26.1%), and ß-blockers (10.1%). Comorbid and stage 2 hypertensive patients mainly received combination therapy (51.6%) rather than monotherapy (48.4%). The study revealed an 83.5% prescription adherence to the treatment guidelines. However, non-adherence was encountered in monotherapy, polytherapy, and elderly-treated patient groups. A 66.4% (at target BP in all cases <140/90 mmHg) and 39.3% (at target BP in comorbid patients <130/80 mmHg) rate of BP control was observed. Furthermore, the rate of BP control was significantly associated with prescription adherence (χ2 = 71.316; p < 0.001). Conclusions The degree of prescription adherence and rate of BP control were found to be compatible with other published hypertension studies. However, considerable scope exists for improvement in rational drug utilization and rate of BP control, particularly in high-risk patients. Therefore, treatment guidelines must be followed by clinicians to achieve BP goals and reduce cardiovascular events among the Saudi population.

An integrated computational approach to infer therapeutic targets from Campylobacter concisus and peptidomimetic based inhibition of its pyrimidine metabolism pathway.

Campylobacter concisus is a commensal of the human oral flora that has been allied with persistent diarrhea and inflammatory bowel disease (IBD). In children under the age of two, Campylobacter infections are common in the developing countries and have frequently been associated with mortality. They are becoming a prevalent cause of bacterial diarrhea in early adulthood in developed countries as well. The need for identifying new therapeutic targets and drugs is crucial for curbing such infections. Therefore, we identified 18 cytoplasmic potential therapeutic candidates against the type strain of C. concisus and deoxycytidine triphosphate deaminase (dCTP deaminase), involved in pyrimidine synthesis was selected for screening of peptidomimetic inhibitors (n > 30,000 peptidomimetics) against it. To the best of our knowledge, this target has not been studied for Campylobacter spp. Three potent inhibitors of this enzyme were prioritized i.e. peptidomimetic 27, 64, and 150. Dynamics simulation of 100 ns was carried out to validate findings for top-scored inhibitors along with physiology-based pharmacokinetics to estimate behavior in human body and predict dosing parameters. This verification demonstrates a first-in-human pharmacokinetic simulation for these peptidomimetics and can help enhance confidence in these peptide-like structures. Moiety 27 (IUPAC name: 5-[(3,5-dimethyl-1H-pyrazol-1-yl)methyl]-N-{[2-(2-methoxyethyl)-1-oxo-1H,2H,3H,4H-pyrrolo[1,2-a]pyrazin-3-yl]methyl}furan-2-carboxamide), 64 (IUPAC name: 3-(2-methylpropyl)-1-{3-[5-(5-oxo-1-phenylpyrrolidin-3-yl)-1,2,4-oxadiazol-3-yl]phenyl}urea), and 150 (IUPAC name: N-(3-methoxypropyl)-1-[6-(4-methylphenyl)-4H,6H,7H-[1,2,3]triazolo[4,3-c][1,4]oxazine-3-carbonyl]piperidine-4-carboxamide) were identified as potent inhibitors of C. concisus.Communicated by Ramaswamy H. Sarma.

Antidiabetic Activity of Potential Probiotics Limosilactobacillus spp., Levilactobacillus spp., and Lacticaseibacillus spp. Isolated from Fermented Sugarcane Juice: A Comprehensive In Vitro and In Silico Study.

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.

Nano-Gels: Recent Advancement in Fabrication Methods for Mitigation of Skin Cancer.

In the 21st century, melanoma and non-melanoma skin cancers have become an epidemic outbreak worldwide. Therefore, the exploration of all potential preventative and therapeutic measures based on either physical or bio-chemical mechanisms is essential via understanding precise pathophysiological pathways (Mitogen-activated protein kinase, Phosphatidylinositol 3-kinase Pathway, and Notch signaling pathway) and other aspects of such skin malignancies. Nano-gel, a three-dimensional polymeric cross-linked porous hydrogel having a diameter of 20-200 nm, possesses dual properties of both hydrogel and nanoparticle. The capacity of high drug entrapment efficiency with greater thermodynamic stability, remarkable solubilization potential, and swelling behavior of nano-gel becomes a promising candidate as a targeted drug delivery system in the treatment of skin cancer. Nano-gel can be either synthetically or architectonically modified for responding to either internal or external stimuli, including radiation, ultrasound, enzyme, magnetic, pH, temperature, and oxidation-reduction to achieve controlled release of pharmaceuticals and several bio-active molecules such as proteins, peptides, genes via amplifying drug aggregation in the active targeted tissue and reducing adverse pharmacological effects. Several drugs, such as anti-neoplastic biomolecules having short biological half-lives and prompt enzyme degradability capacity, must be appropriate for administration employing either chemically bridged or physically constructed nano-gel frameworks. The comprehensive review summarizes the advancement in the preparation and characterization methods of targeted nano-gel with enhanced pharmacological potential and preserved intracellular safety limits for the mitigation of skin malignancies with a special emphasize on skin cancer inducing pathophysiological pathways and prospective research opportunities for skin malignancy targeted nano-gels.

Serum Levels of Growth-Associated Protein-43 and Neurotrophin-3 in Childhood Epilepsy and Their Relation to Zinc Levels.

BACKGROUND: Epilepsy is one of the most common neurological disorders, and it places a significant economic strain on the healthcare system around the world. Although the exact mechanism of epilepsy has yet to be illustrated, various pathogenic cascades involving neurotransmitters and trace elements have been reported. We aimed to investigate the serum levels of growth-associated protein-43 (GAP-43) and neurotrophin-3 (NT-3) among cohort of Egyptian children with epilepsy and correlate these biomarkers with their zinc levels. METHODS: This case-control study included 50 pediatric patients with epilepsy who were comparable with 50 controls. Neurological assessment and electroencephalogram (EEG) were done to all included children. Biochemical measurements of serum GAP-43 and NT-3 using enzyme linked immunosorbent assays (ELISA), and total antioxidant capacity (TAC) and zinc using colorimetric assays, were performed to all participants. RESULTS: There was significantly frequent positive parental consanguinity among cases with significantly frequent generalized onset seizures (94%) than simple partial seizure (6%). There were significantly lower serum GAP-43 and zinc levels with significantly higher TAC among cases vs. the controls, p˂0.05 for all. There was no significant difference in the serum levels of NT-3 among epileptic children vs. the controls, p = 0.269. Serum Zn was positively correlated with GAP-43 level among epileptic children (r = 0.381, p = 0.006). Serum GAP-43 in diagnosing childhood epilepsy at cut-off point ≤ 0.6 ng/mL showed 78% sensitivity, 62% specificity, positive predictive value (PPV) = 50.6%, negative predictive value (NPP) = 84.9% with AUC = 0.574. CONCLUSION: GAP-43 can be considered a sensitive good negative biomarker in childhood epilepsy which correlated positively with the zinc status.

An in silico hierarchal approach for drug candidate mining and validation of natural product inhibitors against pyrimidine biosynthesis enzyme in the antibiotic-resistant Shigella flexneri.

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-tritriacontanone & patupilone compounds as potent drugs against shigellosis. Further experiments are required to ascertain validity of our findings.

Phytochemistry, Pharmacology and Molecular Mechanisms of Herbal Bioactive Compounds for Sickness Behaviour.

The host's response to acute infections or tissue injury is a sophisticated and coordinated adaptive modification called sickness behaviour. Many herbs have been studied for their ability to protect animals against experimentally induced sickness behaviour. However, there is a lack of knowledge and experimental evidence on the use of herbal bioactive compounds (HBACs) in the management of sick behaviour. The goal of this review is to provide a concise summary of the protective benefits and putative mechanisms of action of phytochemicals on the reduction of lipopolysaccharide (LPS)-induced sickness behaviour. Relevant studies were gathered from the search engines Scopus, ScienceDirect, PubMed, Google Scholar, and other scientific databases (between 2000 and to date). The keywords used for the search included "Lipopolysaccharide" OR "LPS" OR "Sickness behaviour" OR "Sickness" AND "Bioactive compounds" OR "Herbal medicine" OR "Herbal drug" OR "Natural products" OR "Isolated compounds". A total of 41 published articles that represented data on the effect of HBACs in LPS-induced sickness behaviour were reviewed and summarised systemically. There were 33 studies that were conducted in mice and 8 studies in rats. A total of 34 HBACs have had their effects against LPS-induced changes in behaviour and biochemistry investigated. In this review, we examined 34 herbal bioactive components that have been tested in animal models to see if they can fight LPS-induced sickness behaviour. Future research should concentrate on the efficacy, safety, and dosage needed to protect against illness behaviour in humans, because there is a critical shortage of data in this area.

Formulation Design, Characterization and In-Vivo Assessment of Cefixime Loaded Binary Solid Lipid Nanoparticles to Enhance Oral Bioavailability.

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.