Synthesis, antibacterial, antibiofilm, and docking studies of chalcones against multidrug resistance pathogens.

The escalating threat of drug-resistant microbes underscores the urgent need for novel antimicrobial agents. In response, considerable research effort has been directed towards developing innovative frameworks and strategies to address this challenge. Chalcones, known for their broad-spectrum biological activities, have emerged as promising candidates for combating drug resistance. In this study, a series of 2'-Hydroxychalcones (5a, 5b, 5c, and 5d) with varying electron withdrawing and donating groups were synthesized via Claisen Schmidt condensation. FT-IR, 1H NMR, and 13C NMR analyses were employed to confirm the structure of the synthesized compounds. Subsequent evaluation of the synthesized compounds revealed their potential as antibacterial and antibiofilm agents. Notably, compounds 5a and 5d exhibited potent antibacterial activity against multidrug-resistant (MDR) bacteria E. coli, P. aeruginosa, K. pneumoniae, and S. aureus, surpassing the reference drug Ciprofloxacin (30 µg/mL) and other synthesized compounds. Compound 5d showed a notable 19.5 mm zone of inhibition against K. pneumoniae. Furthermore, 5a (at a concentration of 30 µg) and 5d (at a concentration of 50 µg) exhibited statistically significant (P > 0.05) biofilm inhibition efficacy compared to Ciprofloxacin (30 µg/mL). The synthesized chalcones 5a-5d were also docked via PachDock molecular docking software for Glucosamine-6-phosphate (GlcN-6-P) synthase inhibition and showed that ligand 5a exhibited outstanding results with score 4238 and ACE value -160.89 kcal/mol, consistent with the observed antibacterial activity. These findings underscore the potential of chalcones, particularly 5a and 5d, as promising candidates for the development of new antimicrobial agents targeting drug-resistant microbes and biofilm formation.

Comparative Neurological and Behavioral Assessment of Central and Peripheral Stimulation Technologies for Induced Pain and Cognitive Tasks.

Pain is a multifaceted, multisystem disorder that adversely affects neuro-psychological processes. This study compares the effectiveness of central stimulation (transcranial direct current stimulation-tDCS over F3/F4) and peripheral stimulation (transcutaneous electrical nerve stimulation-TENS over the median nerve) in pain inhibition during a cognitive task in healthy volunteers and to observe potential neuro-cognitive improvements. Eighty healthy participants underwent a comprehensive experimental protocol, including cognitive assessments, the Cold Pressor Test (CPT) for pain induction, and tDCS/TENS administration. EEG recordings were conducted pre- and post-intervention across all conditions. The protocol for this study was categorized into four groups: G1 (control), G2 (TENS), G3 (anodal-tDCS), and G4 (cathodal-tDCS). Paired t-tests (p < 0.05) were conducted to compare Pre-Stage, Post-Stage, and neuromodulation conditions, with t-values providing insights into effect magnitudes. The result showed a reduction in pain intensity with TENS (p = 0.002, t-value = -5.34) and cathodal-tDCS (p = 0.023, t-value = -5.08) and increased pain tolerance with TENS (p = 0.009, t-value = 4.98) and cathodal-tDCS (p = 0.001, t-value = 5.78). Anodal-tDCS (p = 0.041, t-value = 4.86) improved cognitive performance. The EEG analysis revealed distinct neural oscillatory patterns across the groups. Specifically, G2 and G4 showed delta-power reductions, while G3 observed an increase. Moreover, G2 exhibited increased theta-power in the occipital region during CPT and Post-Stages. In the alpha-band, G2, G3, and G4 had reductions Post-Stage, while G1 and G3 increased. Additionally, beta-power increased in the frontal region for G2 and G3, contrasting with a reduction in G4. Furthermore, gamma-power globally increased during CPT1, with G1, G2, and G3 showing reductions Post-Stage, while G4 displayed a global decrease. The findings confirm the efficacy of TENS and tDCS as possible non-drug therapeutic alternatives for cognition with alleviation from pain.

Exploring the Significance of Vitamin D Levels as a Biomarker in Ear Diseases: A Narrative Review.

This narrative review examines the role of vitamin D as a biomarker in ear disorders, including benign paroxysmal positional vertigo (BPPV), otitis media, bell's palsy, Meniere's disease, and hearing loss. PubMed, The Cochrane Library, and Google Scholar were utilized to conduct a comprehensive literature search, and findings were combined from studies from 2014 to 2024. As highlighted in this review, there is a consistent association between vitamin D deficiency and an increased risk and recurrence of disease especially in BPPV and otitis media. Its importance as a prognostic biomarker is emphasized in Bell's palsy, where higher levels of deficiencies in vitamin D are associated with higher grades of severity on the House Brackmann grading system. Vitamin D deficiency can also lead to sensorineural hearing loss due to its receptors present in the inner ear or its effect on calcium metabolism. Serum levels of vitamin D have also been shown to influence treatment outcome of sensorineural hearing loss. The role of vitamin D in Meniere's disease is unclear as no cause has been identified for the increase in endolymphatic fluid. The findings of this review emphasize the importance of serum vitamin D as a biomarker in ear disorders and advocate for more studies to be conducted to assess the importance of optimal dosing of vitamin D for the progression and outcome of these diseases.

Spinel nanocomposite (nMnZnFe2O4) synchronously promotes grain yield and Fe-Zn biofortification in non-aromatic rice.

Soils deficient in essential micro-nutrients produce nutritionally starved crops that do not fulfill human nutritional requirements. This is getting serious since progressively increasing nutritional disorders are being diagnosed in residents of third-world countries like Pakistan. During this study, we synthesized a spinel nanocomposite (nMnZnFe2O4) and investigated its effectiveness in improving the micronutrient status and yield traits of rice. The nMnZnFe2O4 exhibited a cubic structure at the most prominent peak (311); a crystallite size of 44 nm, and an average grain size ranging from 7 to 9 µm. Foliar application of this nanocomposite was performed to 45 days old plants at concentrations 0, 10, 20, 30, 40, and 50 mg L-1, and data from rice plant parts (straw, husk, and grain) was recorded at maturity. Agronomic traits like the number of tillers, straw dry weight, root dry biomass, and grain yield per plant were improved by nMnZnFe2O4 application (+34.4% yield). Whereas some biochemical traits like amino acids, soluble sugars, flavonoids, and phenolics varied significantly in rice plant parts compared to the control. Above all, the maximum Zn and Fe concentrations in rice grain were recorded through foliar application of spinel nanocomposite (40 and 50 mg L-1). Therefore, results indicated that micronutrient supply in the form of a nanocomposite could positively regulate nutritional quality and rice grain yield.

The Comparative Pharmaco- and Histokinetics of the Therapeutic Dose of Estradiol Valerate and Bromocriptine in Common Quails.

The current study is aimed at examining the overall effects of steroids on the tissues of organisms and pharmacotherapeutics and pharmaco-histokinetics of several steroids, including Bromocriptine as mesylate and estradiol valerate in common quails (Coturnix coturnix). A total of 100 birds were used for pharmaco-histokinetics. The research was carried out in two separate trials, one during the fall season and the other during the spring season. Each experiment lasted for five, ten, fifteen, and twenty days. Each study group used 20 birds while basing their experiments on a control group of 5. At the stretch of five, ten, fifteen, and twenty days in each season, therapeutic dosages were administered to a sum of two groups representing two separate steroid trial groups. Each steroid was administered to each bird in a therapeutic dose, which was three drops administered twice daily. Clinical symptoms include despondency, sluggishness, and variations in weight and temperature that almost all treated birds display. However, only in trials conducted in the fall was a sizable degree of body enlargement in one treated bird noticed. The winter testing showed a mortality rate. Four birds have died in the twenty-day group. One bird died when treated with estradiol valerate, and three birds died treated with Bromocriptine as mesylate. Both the male and female birds showed signs of having lost some of their body weight. The treated birds' kidney, stomach, hearts, and livers exhibited some edema. In comparison, almost all birds show enteritis, which indicates that steroids mainly affect the intestine. There were apparent differences in the histological analysis of heart and skeletal muscle and some treated birds with the control group. The kidney, liver, and intestine show the major histopathological change in all treated birds.

Machine vision-based Statistical texture analysis techniques for characterization of liver tissues using CT images.

OBJECTIVE: To characterize human liver tissues by demonstrating the ability of machine vision, and to propose a new auto-generated report based on texture analysis that may work with co-occurrence matrix statistics. METHODS: The retrospective study was conducted at Bahawal Victoria Hospital (BVH), Bahawalpur, Pakistan, and comprised clinically verified computed tomography imaging data between October 2018 and September 2020. The image samples and related data were used to segregate classes 1-4. Appropriate image classes belonging to the same disease were trained to confirm the abnormalities in liver tissues using supervised learning methods, principal component analysis, linear discriminant analysis, and non-linear discriminant analysis. Robust and reliable texture features were investigated by generating testing classes. Overall performance of the presented machine vision approach was analyzed using four parameters; precision, recall/sensitivity, F1-score, and accuracy. Statistical analysis was done using B11 software. RESULTS: There were 312 image samples from 71 patients; 51(71.8%) males and 20(28.2%) females. Among the patients, 19(26.7%) had abscess, 15(21.1%) had metastatic disease, 23(32.4%) had tumour necrosis, 6(8.5%) had vascular disorder, and 8(11.3%) were normal. Principal component analysis, linear discriminant analysis, and non-linear discriminant analysis showed high >97.86% values, but the discrimination rate was 100% for class 4. CONCLUSIONS: Abnormalities in the human liver could be discriminated and diagnosed by texture analysis techniques using second-order statistics that may assist the radiologist and medical physicists in predicting the severity and proliferation of abnormalities in liver diseases.

Contemporary uses of old folks: the immunomodulatory and toxic potential of fenbufen.

Fenbfen is used for pain, pyrexia and in the management of osteoarthritis, rheumatoid arthritis and other musculoskeletal disorders. The present research was planned to examine the immunomodulatory activity of fenbufen in different models of cell-mediated immunity (CMI) and humoral immunity (HI). The CMI was evaluated by delayed-type hypersensitivity (DTH) and cyclophosphamide-induced neutropenia assays while HI was appraised by hemagglutination (HA) assay by administering fenbufen at 2, 6 and 10 mg.kg-1 and azathioprine 40 mg.kg-1 (as standard therapy) to albino mice by intraperitoneal route. The ex vivo immunomodulatory action was determined by red blood cell (RBC) membrane stabilization and protein denaturation assays. The results showed that fenbufen treatment had significantly (p<0.05-p<0.001) reduced white blood cells, hemoglobin content, and red blood cells in the healthy and neutropenic mice. A significant (p<0.001) reduction in activities of superoxide dismutase and catalase and glutathione contents, and enhancement of malondialdehyde level were observed in neutropenic mice that were restored by fenbufen treatment. It suppressed DTH reaction after 24, 48 and 72 h post topical application of 2, 4-dinitrofluorobenzene (DNFB). Fenbufen or azathioprine treated groups also showed a significant reduction in the antibody titer against human RBCs induced immune activation in mice as compared to the disease control mice. Fenbufen showed IC50 of 14.0, 50.5 and 66.2 µg.ml-1 whereas, diclofenac sodium showed IC50 of 61.0, 126 and 50.5 µg/ml in RBCs membrane stabilization, egg albumin and bovine serum albumin denaturation assays respectively. The current study shows that fenbufen might have potential immunomodulatory activity against CMI and HI. It can be utilized to treat immune system disorders.

Peak Growth Hormone Level Variability during Insulin Tolerance Test in Children with Short Stature.

OBJECTIVE: To determine the variations in peak growth hormone levels during insulin tolerance test (ITT) in diagnosis of growth hormone deficiency (GHD) in children presenting with short stature. STUDY DESIGN: Descriptive study. PLACE AND DURATION OF STUDY: Department of Pediatric Endocrinology, National Institute of Child Health (NICH), from January to December 2018. METHODOLOGY: Clinical records of all children who underwent ITT during the above mentioned period were reviewed. All 348 children of either gender from 2-17 years of age with height more than 2SD below the mean (<3rd percentile) suspected GHD and subjected for ITT were included. Verbal consent was taken from all parents. Children below 2 years and with other causes of Short Stature like hypothyroid, celiac, cardiac, chronic liver, kidney diseases and syndrome were excluded. RESULTS: Total 348 children were subjected to ITT. Out of these 48.3% were found to have GH levels <5ng/ml, 33.6% b/w 5-10 ng/ml and 18.1% >10 ng/ml. Precisely peak GH levels at different time intervals are 1.1%, 19.3%, 47.4%, 29.9%, and 2.3% for 0, 30, 60, 90 and 120 minutes respectively. Mostly peak growth hormone levels were accomplished at 60 minutes followed by 90 and then at 30 minutes. Hypoglycemia was achieved 0.8%, 47%, 26%, 24% and 1% at 0, 30, 60, 90, and 120 minutes. CONCLUSION: The 0, 30, 60, and 90 minutes samples are adequate to confirm the diagnosis of GH deficiency. This shorter duration of ITT to 90 minutes is cost effective as it decreases the financial burden of unnecessary testing. Additionally, it reduces the risk of side effect like hypoglycemia. Key Words: Short stature, Growth hormone deficiency, Insulin tolerance test.

Natural Product Mediated Regulation of Death Receptors and Intracellular Machinery: Fresh from the Pipeline about TRAIL-Mediated Signaling and Natural TRAIL Sensitizers.

Rapidly developing resistance against different therapeutics is a major stumbling block in the standardization of therapy. Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)-mediated signaling has emerged as one of the most highly and extensively studied signal transduction cascade that induces apoptosis in cancer cells. Rapidly emerging cutting-edge research has helped us to develop a better understanding of the signaling machinery involved in inducing apoptotic cell death. However, excitingly, cancer cells develop resistance against TRAIL-induced apoptosis through different modes. Loss of cell surface expression of TRAIL receptors and imbalance of stoichiometric ratios of pro- and anti-apoptotic proteins play instrumental roles in rewiring the machinery of cancer cells to develop resistance against TRAIL-based therapeutics. Natural products have shown excellent potential to restore apoptosis in TRAIL-resistant cancer cell lines and in mice xenografted with TRAIL-resistant cancer cells. Significantly refined information has previously been added and continues to enrich the existing pool of knowledge related to the natural-product-mediated upregulation of death receptors, rebalancing of pro- and anti-apoptotic proteins in different cancers. In this mini review, we will set spotlight on the most recently published high-impact research related to underlying mechanisms of TRAIL resistance and how these deregulations can be targeted by natural products to restore TRAIL-mediated apoptosis in different cancers.

Synthesis of novel 5-(aroylhydrazinocarbonyl)escitalopram as cholinesterase inhibitors.

A novel series of 5-(aroylhydrazinocarbonyl)escitalopram (58-84) have been designed, synthesized and tested for their inhibitory potential against cholinesterases. 3-Chlorobenzoyl- (71) was found to be the most potent compound of this series having IC50 1.80 ± 0.11 µM for acetylcholinesterase (AChE) inhibition. For the butyrylcholinesterase (BChE) inhibition, 2-bromobenzoyl- (76) was the most active compound of the series with IC50 2.11 ± 0.31 µM. Structure-activity relationship illustrated that mild electron donating groups enhanced enzyme inhibition while electron withdrawing groups reduced the inhibition except o-NO2. However, size and position of the substituents affected enzyme inhibitions. . In docking study of AChE, the ligands 71, 72 and 76 showed the scores of 5874, 5756 and 5666 and ACE of -64.92,-203.25 and -140.29 kcal/mol, respectively. In case of BChE, ligands 71, 76 and 81 depicted high scores 6016, 6150 and 5994 with ACE values -170.91, -256.84 and -235.97 kcal/mol, respectively.

Potential antibacterial activity of coumarin and coumarin-3-acetic acid derivatives.

Coumarin and coumarin-3-acetic acid derivatives were synthesized by reacting phenols with malic acid, ethyl acetoacetate and ethyl acetylsuccinate in appropriate reaction conditions. All synthesized compounds were subjected to test for their antimicrobial activities against variety of gram positive (Bacillus subtilis, Staphylococcus aureus) and gram negative bacterial stains (Shigella sonnei, Escherichia coli) by agar dilution method. Several of them exhibited appreciable good antibacterial activity against the different strains of gram positive and gram negative bacteria. These findings suggest a great potential of these compounds for screening and use as antibacterial agents for further studies with a battery of bacteria.

Kefir and health: a contemporary perspective.

Kefir and its related products are renowned nutraceutical dairy products produced through fermentation of yeasts and bacteria naturally present in grains of kefir. The nutritional attributes of this self-carbonated beverage are due to presence of vital nutrients such as carbohydrates, proteins, minerals, vitamins, and some nutraceutical components. Antimicrobial activity, better gut health, anticarcinogenic activity, control on serum glucose and cholesterol, control on lactose intolerance and better immune system can be achieved through its regular consumption. Moreover, on the one side kefir is good dietetic beverage, and of particular interest of athletes, and on the other side the whole kefir is good for feeding small babies and pre-schoolers for good tolerance against disease and quick weight gain. Lots of works have been done on kefir from a health point of view. This study summarizes all the data that have been compiled to date. The purpose of this review is to gather information about microbiological, chemical, nutritional, and therapeutic aspects of kefir and kefir-like products to provide justification for its consumption. This review leads us to conclude that kefir begins a new dawn of food for the mankind.

Investigation of piperidine derivatives in ex vivo models of pain and platelet aggregation.

Piperidine derivatives are known to exhibit analgesic activities and are likely to possess the ability to block the effects of prostaglandins through inhibition of downstream signaling pathways. The present study investigated the activity of five derivatives (PD2-6) of 4-(4'-bromophenyl)-4-piperidinol (PD1), against pain and platelet aggregation mediated by the release of prostaglandins and thromboxane A2, respectively. The results showed that compound PD1 and its two phenacyl derivatives PD3 and PD5 exhibited a highly significant analgesic effect (p < 0.01), whereas PD4 and PD6 also showed significant activity. PD3, the most active analgesic compound when docked to the opioid receptor, had interactions between the oxygen of its nitro group and the amino group of ARG 573, indicating a distance of 1.2563 Å. The antiplatelet data showed that compound PD5 (4-(4'-bromo-phenyl)-4-hydroxy-1-[2-(2″,4″-dimethoxyphenyl)-2-oxo-ethyl]-piperidinium bromide) had an IC(50) = 0.06 mM, which was the most active compound, whereas PD3 was the second most active compound against platelet aggregating factor-induced aggregation with an IC(50) = 80 mM. Acetyl salicylic acid (IC(50) = 150 µM) was used as a positive control.

New benzimidazole derivatives as antiplasmodial agents and plasmepsin inhibitors: synthesis and analysis of structure-activity relationships.

The newly synthesized benzimidazole compounds were suggested to be inhibitors of Plasmodium falciparum plasmepsin II and human cathepsin D by virtual screening of an internal library of synthetic compounds. This was confirmed by enzyme inhibition studies that gave IC(50) values in the low micromolar range (2-48µM). Ligand docking studies with plasmepsin II predicted binding of benzimidazole compounds at the center of the extended substrate-binding cleft. According to the plausible mode of binding, the pyridine ring of benzimidazole compounds interacted with S1' subsite residues whereas the acetophenone moiety was in contact with S1-S3 subsites of plasmepsin II active center. The benzimidazole derivatives were evaluated for capacity to inhibit the growth of intraerythrocytic P. falciparum in culture. Four benzimidazole compounds inhibited parasite growth at ⩽3µM. The most active compound 10, 1-(4-phenylphenyl)-2[2-(pyridinyl-2-yl)-1,3-benzdiazol-1-yl]ethanone showed an IC(50) of 160nM. The substitution of a phenyl group and a chlorine atom at the para position of the acetophenone moiety were shown to be crucial for antiplasmodial activity.

Characterisation of Plasmodium falciparum aspartic protease inhibition by piperidine derivatives.

Piperidine derivatives are reported to exhibit a variety of pharmacological activities. In this article, synthesis and aspartic protease inhibitory activity of three nitrophenacyl derivatives of N-methyl-4-hydroxy piperidine are reported. Enzyme assays showed that the attachment of a nitro group in the benzene ring plays an important role in the inhibition of plasmepsin-II of Plasmodium falciparum. The compound 1-methyl-1-(4'-nitrophenacyl)-4-hydroxypiperidinium bromide (3), consisting of a nitro group at the para position, was the most active at the concentration of 1.0 µM. The activity of the compounds was evaluated through the observed orientation and diagrammatic representation of nitrophenacyl derivatives of 4-hydroxy piperidine.

3-Methyl-1H-pyrrolo[2,1-c][1,4]oxazin-1-one.

In the title mol-ecule, C(8)H(7)NO(2), all the non-H atoms lie essentially in the same plane (r.m.s. deviation = 0.019 Å) In the crystal structure, weak inter-molecular C-H⋯O inter-actions link mol-ecules into chains along [100]. In addition, there are π-π stacking inter-actions between mol-ecules related by the c-glide plane, with alternating centroid-centroid distances of 3.434 (2) and 3.639 (2) Å.

External cephalic version for breech presentation at term.

OBJECTIVE: To assess the success rate of External Cephalic Version (ECV) at term and its effects on measures of pregnancy outcome. DESIGN: A quasi-experimental study. PLACE AND DURATION OF STUDY: The study was conducted at Hayatabad Medical Complex, Peshawar, from December 2003 to January 2005. PATIENTS AND METHODS: A total of 40 patients were offered ECV over a period of fourteen months. All singleton breech presentations with an otherwise normal antenatal course between 36-41 weeks of gestation were included in the study. Exclusion criteria included contraindications to ECV i.e. multiple pregnancy, oligohydramnios, growth retardation, antepartum hemorrhage, rupture of membranes toxemias of pregnancy, non-reassuring fetal monitoring pattern, previous uterine scar, bad obstetric history, any contraindication to vaginal delivery, labour and patient wishes after thorough counseling. Overall success rate of the procedure and its effect on maternal and fetal outcome was determined. Significance of results was determined using Chi-square test. RESULTS: A total of 40 patients were recruited for the trial. Overall success rate was 67.5% with only 30% being primi-gravida (p < 0.05). Multi-gravida showed higher success rate of 80%. Following successful ECV, spontaneous vaginal delivery was attained in 77.7% (n=21), while caesarean section was performed due to various indications in about 6 cases (p < 0.05). Following failed version, 61.5% (n=8) had elective C/S and only 5 delivered vaginally. Route of delivery did not affect the perinatal outcome except for congenital abnormalities. Following successful ECV, there was only one stillbirth. Overall live births associated with successful version was 96.2% (p < 0.05), while in failed version, there were no fetal deaths. CONCLUSION: ECV at term appears to be a useful procedure to reduce the number and associated complications of term breech presentation. It is safe for the mother and the fetus and helps to avoid a significant number of caesarean sections.