Diabetes-related lower limb wounds: Antibiotic susceptibility pattern and biofilm formation.

The expeditious incidence of diabetes mellitus in Riyadh, Saudi Arabia, there is a significant increase in the total number of people with diabetic foot ulcers. For diabetic lower limb wound infections (DLWs) to be effectively treated, information on the prevalence of bacteria that cause in this region as well as their patterns of antibiotic resistance is significant. Growing evidence indicates that biofilm formers are present in chronic DFU and that these biofilm formers promote the emergence of multi-drug antibiotic resistant (MDR) strains and therapeutic rejection. The current study targeted to isolate bacteria from wounds caused by diabetes specifically at hospitals in Riyadh and assess the bacterium's resistance to antibiotics and propensity to develop biofilms. Totally 63 pathogenic microbes were identified from 70 patients suffering from DFU. Sixteen (25.4%) of the 63 bacterial strains were gram-positive, and 47 (74.6%) were gram-negative. Most of the gram-negative bacteria were resistant to tigecycline, nitrofurantoin, ampicillin, amoxicillin, cefalotin, and cefoxitin. Several gram-negative bacteria are susceptible to piperacillin, meropenem, amikacin, gentamicin, imipenem, ciprofloxacin, and trimethoprim. The most significant antibiotic that demonstrated 100% susceptibility to all pathogens was meropenem. Serratia marcescens and Staphylococcus aureus were shown to have significant biofilm formers. MDR bacterial strains comprised about 87.5% of the biofilm former strains. To the best of our knowledge, Riyadh, Saudi Arabia is the first region where Serratia marcescens was the most common bacteria from DFU infections. Our research findings would deliver information on evidence-based alternative strategies to develop effective treatment approaches for DFU treatment.

Seed biopriming with Ochrobactrum ciceri mediated defense responses in Zea mays (L.) against Fusarium rot.

Seed bio-priming is a simple and friendly technique to improve stress resilience against fungal diseases in plants. An integrated approach of maize seeds biopriming with Ochrobactrum ciceri was applied in Zn-amended soil to observe the response against Fusarium rot disease of Zea mays (L.) caused by Fusarium verticillioides. Initially, the pathogen isolated from the infected corn was identified as F. verticillioides based on morphology and sequences of the internally transcribed spacer region of the ribosomal RNA gene. Re-inoculation of maize seed with the isolated pathogen confirmed the pathogenicity of the fungus on the maize seeds. In vitro, the inhibitory potential of O. ciceri assessed on Zn-amended/un-amended growth medium revealed that antifungal potential of O. ciceri significantly improved in the Zn-amended medium, leading to 88% inhibition in fungal growth. Further assays with different concentrations (25, 50, and 75%) of cell pellet and the cultural filtrate of O. ciceri (with/without the Zn-amendment) showed a dose-dependent inhibitory effect on mycelial growth of the pathogen that also led to discoloration, fragmentation, and complete disintegration of the fungus hyphae and spores at 75% dose. In planta, biopriming of maize seeds with O. ciceri significantly managed disease, improved the growth and biochemical attributes (up to two-fold), and accelerated accumulation of lignin, polyphenols, and starch, especially in the presence of basal Zn. The results indicated that bioprimed seeds along with Zn as the most promising treatment for managing disease and improving plant growth traits through the enhanced accumulation of lignin, polyphenols, and starch, respectively.

Chemical Characterization of Phoenix dactylifera L. Seeds and their Beneficial Effects on the Vascular Response in Hypertensive Rats.

Although Phoenix dactylifera dates are traditionally consumed for their health benefits, no research has been done on the vascular response in hypertensive animals. This study evaluated the vascular relaxation of hydroalcoholic extracts from seeds of three varieties of P. dactylifera; Sukkari seed (SS), Ajwa seed (AS), and Mabroom seed (MS) on L-NAME-induced hypertension and spontaneously hypertensive rats (SHR). Results showed that all extracts (10 µg/mL) caused relaxations higher than 60% in the aortic rings precontracted with 10- 6 M phenylephrine in normotensive rats, the SS extract was the most potent. Endothelial nitric oxide (NO) pathway is involved as significantly reduced vascular relaxation in denuded-endothelium rat aorta and with an inhibitor (10- 4 M L-Nω-Nitro arginine methyl ester; L-NAME) of endothelial nitric oxide synthase (eNOS). Confocal microscopy confirmed that 10 µg/mL SS extract increases NO generation as detected by DAF-FM fluorescence in intact aortic rings. Consistent with these findings, vascular relaxation in intact aortic rings at 10 µg/mL SS extract was significantly decreased in L-NAME-induced hypertensive rats (endothelial dysfunction model), but not in SHR. In both hypertensive models, the denuded endothelium blunted the vascular relaxation. In conclusion, the hydroalcoholic extract of the seed of P. dactylifera (Sukkari, Ajwa and Mabroom varieties) presents a potent endothelium-dependent vascular relaxation, via NO, in normotensive rats as well as in two different models of hypertension. This effect could be mediated by the presence of phenolic compounds identified by UHPLC-ESI-MS/MS, such as protocatechuic acid, and caftaric acid.

Alleviation of cadmium toxicity in pea (Pisum sativum L.) through Zn-Lys supplementation and its effects on growth and antioxidant defense.

Cadmium significantly impacts plant growth and productivity by disrupting physiological, biochemical, and oxidative defenses, leading to severe damage. The application of Zn-Lys improves plant growth while reducing the stress caused by heavy metals on plants. By focusing on cadmium stress and potential of Zn-Lys on pea, we conducted a pot-based study, organized under completely randomized block design CRD-factorial at the Botanical Garden of Government College University, Faisalabad. Both pea cultivars were grown in several concentrations of cadmium @ 0, 50 and 100 µM, and Zn-Lys were exogenously applied @ 0 mg/L and 10 mg/L with three replicates for each treatment. Cd-toxicity potentially reduces plant growth, chlorophyll contents, osmoprotectants, and anthocyanin content; however, an increase in MDA, H2O2 initiation, enzymatic antioxidant activities as well as phenolic, flavonoid, proline was observed. Remarkably, exogenously applied Zn-Lys significantly enhanced the plant growth, biomass, photosynthetic attributes, osmoprotectants, and anthocyanin contents, while further increase in enzymatic antioxidant activities, total phenolic, flavonoid, and proline contents were noticed. However, application of Zn-Lys instigated a remarkable decrease in levels of MDA and H2O2. It can be suggested with recommendation to check the potential of Zn-Lys on plants under cadmium-based toxic soil.

Anti-inflammatory potential of some eudesmanolide and guaianolide sesquiterpenes.

Ten sesquiterpene lactones isolated from Anvillea garcinii (Burm.f.) DC ethanolic extract were assessed for their anti-inflammatory potential by myeloperoxidase (MPO) activity assignment, and mice paw swelling model. 3α,4α-10ß-trihydroxy-8α-acetyloxyguaian-12,6α-olide (1), epi-vulgarin (3), 9a-hydroxyparthenolide (4), garcinamine C (7), garcinamine D (8), garcinamine E (9), and 4, 9-dihydroxyguaian-10(14)-en-12-olide (10) showed explicit anti-inflammatory activity in rodent paw edema and MPO assignment. The findings of this study showed that the α-methylene γ-lactone moiety does not always guarantee an anti-inflammatory effect, but the presence of proline at the C3 of the lactone ring improves the binding of sesquiterpene lactones with MPO isoenzymes, resulting in a more potent inhibition.

Foliar application of iron-lysine to boost growth attributes, photosynthetic pigments and biochemical defense system in canola (Brassica napus L.) under cadmium stress.

In the current industrial scenario, cadmium (Cd) as a metal is of great importance but poses a major threat to the ecosystem. However, the role of micronutrient - amino chelates such as iron - lysine (Fe - lys) in reducing Cr toxicity in crop plants was recently introduced. In the current experiment, the exogenous applications of Fe - lys i.e., 0 and10 mg L - 1, were examined, using an in vivo approach that involved plant growth and biomass, photosynthetic pigments, oxidative stress indicators and antioxidant response, sugar and osmolytes under the soil contaminated with varying levels of Cd i.e., 0, 50 and 100 µM using two different varieties of canola i.e., Sarbaz and Pea - 09. Results revealed that the increasing levels of Cd in the soil decreased plant growth and growth-related attributes and photosynthetic apparatus and also the soluble protein and soluble sugar. In contrast, the addition of different levels of Cd in the soil significantly increased the contents of malondialdehyde (MDA) and hydrogen peroxide (H2O2), which induced oxidative damage in both varieties of canola i.e., Sarbaz and Pea - 09. However, canola plants increased the activities of superoxide dismutase (SOD), peroxidase (POD), catalase (CAT), and non-enzymatic compounds such as phenolic, flavonoid, proline, and anthocyanin, which scavenge the over-production of reactive oxygen species (ROS). Cd toxicity can be overcome by the supplementation of Fe - lys, which significantly increased plant growth and biomass, improved photosynthetic machinery and sugar contents, and increased the activities of different antioxidative enzymes, even in the plants grown under different levels of Cd in the soil. Research findings, therefore, suggested that the Fe - lys application can ameliorate Cd toxicity in canola and result in improved plant growth and composition under metal stress.

Potential Hepatoprotective Effects of Chamaecyparis lawsoniana against Methotrexate-Induced Liver Injury: Integrated Phytochemical Profiling, Target Network Analysis, and Experimental Validation.

Methotrexate (MTX) therapy encounters significant limitations due to the significant concern of drug-induced liver injury (DILI), which poses a significant challenge to its usage. To mitigate the deleterious effects of MTX on hepatic function, researchers have explored plant sources to discover potential hepatoprotective agents. This study investigated the hepatoprotective effects of the ethanolic extract derived from the aerial parts of Chamaecyparis lawsoniana (CLAE) against DILI, specifically focusing on MTX-induced hepatotoxicity. UPLC-ESI-MS/MS was used to identify 61 compounds in CLAE, with 31 potential bioactive compounds determined through pharmacokinetic analysis. Network pharmacology analysis revealed 195 potential DILI targets for the bioactive compounds, including TP53, IL6, TNF, HSP90AA1, EGFR, IL1B, BCL2, and CASP3 as top targets. In vivo experiments conducted on rats with acute MTX-hepatotoxicity revealed that administering CLAE orally at 200 and 400 mg/kg/day for ten days dose-dependently improved liver function, attenuated hepatic oxidative stress, inflammation, and apoptosis, and reversed the disarrayed hepatic histological features induced by MTX. In general, the findings of the present study provide evidence in favor of the hepatoprotective capabilities of CLAE in DILI, thereby justifying the need for additional preclinical and clinical investigations.

Isochlorogenic Acid Glucosides from the Arabian Medicinal Plant Artemisia sieberi and Their Antimicrobial Activities.

A phytochemical investigation of the stems of the Arabian plant Artemisia sieberi afforded three new isochlorogenic acid derivatives, namely isochlorogenic acid A-3'-O-ß-glucopyranoside (1), isochlorogenic acid A-3'-O-ß-glucopyranoside methyl ester (2), and isochlorogenic acid C-3'-O-ß-glucopyranoside (3), obtained along with thirteen known secondary metabolites belonging to distinct structural classes. The structures of the new metabolites were elucidated by modern spectroscopic techniues based on high-resolution mass spectrometry (HR-ESIMS) and 1D/2D nuclear magnetic resonance (NMR). All isolated compounds were tested for their potential antimicrobial activity against four different bacterial strains (Bacillus subtilis, Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa), in addition to a fungal strain (Candida tropicalis), The results were expressed as the diameter of the clear zone (in millimetres) around each well. Compounds 1 and 3 (isochlorogenic acid A-3'-O-ß-glucopyranoside and isochlorogenic acid C-3'-O-ß-glucopyranoside, respectively) displayed remarkable antifungal effect and potent antibacterial activities against B. subtilis and S. aureus, respectively. 3α,4α-10ß-trihydroxy-8α-acetyloxyguaian-12,6α-olide (6) and angelicoidenol 2-O-ß-d-glucopyranoside (9) emerged as interesting dual antibacterial (selective on P. aeruginosa)/antifungal agents.

Situational analysis of antimicrobial stewardship program (ASP) among public and private sector tertiary care hospitals in Karachi, Pakistan: A qualitative case study.

Objective: To assess the current status of implementation of the Antimicrobial Stewardship Program (ASP) across Tertiary Care Hospitals in Karachi, Pakistan. Design: Exploratory qualitative case study. Setting: Public and private tertiary care hospitals in Karachi, Pakistan. Participants and Methods: The study data were collected from 3 public and 4 private tertiary care hospitals. Twenty-eight in-depth interviews were conducted from the Chief Executive Officer, Chief Medical Officer, Medical Superintendent, and departmental heads of internal medicine, general surgery, and pediatric, respectively. Purposive sampling was done to include higher and middle managers, whereas the infectious diseases consultant, infectious diseases/clinical pharmacist, and clinical microbiologist were interviewed through snowball sampling methodology. Analysis was done using NVivo. Data were source-triangulated within and among the study setting and study participants. Results: We found that more than two-thirds (n = 5, 71%) of tertiary care hospitals in Karachi do not have a structured ASP which includes major public sector hospitals (n = 3, 43%) and half of the private sector hospitals (n = 4, 29%). The study results led to four broad themes, (1) ASP structure, (2) ASP interventions, (3) hospital medical record-keeping system, and (4) structured way for analyzing and reporting mechanism of data related to the ASP. At H1 and H2, there was a consistency in ASP structure and interventions, whereas paucity seen among remaining tertiary care hospitals. Conclusion: There is an alarming need for ASP in the public and private sector hospitals in Karachi. This study can inform future stakeholders regarding ASP and strategies for structural change at hospitals.

Chamaecyparis lawsoniana Leaf Essential Oil as a Potential Anticancer Agent: Experimental and Computational Studies.

Cancer remains one of the leading causes of death worldwide, affected by several factors including oxidative stress; and although conventional synthetic medicines have been used to treat cancer, they often result in various side effects. Consequently, there is a growing need for newer, safer and more effective alternatives, such as natural plant products. Essential oils (EOs) are one such alternative, offering a wide range of bioactivities, including antibacterial, antiviral, antioxidant, and anticancer properties. Accordingly, the objective of the present study was to investigate the chemical composition, as well as the antioxidant and anticancer properties of the leaf essential oil of Chamaecyparis lawsoniana (CLLEO) belonging to the Cupressaceae family. Totally, 59 constituents were identified by gas chromatography-mass spectrometry (GC-MS) analysis. cis-Abienol, trans-ferruginol, α-cadinol, δ-muurolene and α-pinene were the major components. The in vitro cytotoxicity study against human breast (MCF-7), colon (HCT-116), lung (A-549), hepatocellular (HepG-2) carcinoma cells using MTT assay indicated a promising cytotoxic activity against all the tested cancer cells, particularly HepG-2, with significant selectivity indices. CLLEO exhibited weak antioxidant activity according to the DPPH, ABTS and FRAP assays. In silico docking of these constituents against the epidermal growth factor receptor (EGFR), the myeloid cell leukemia-1 (Mcl-1) and caspase-8 using Molecular Operating Environment (MOE) software demonstrated good binding affinities of the components with the active site of these targets. These findings suggested using CLLEO, or its individual components, as a potentially viable therapeutic option for managing cancerous conditions.

Efficient Synthesis, Spectroscopic Characterization, and Nonlinear Optical Properties of Novel Salicylaldehyde-Based Thiosemicarbazones: Experimental and Theoretical Studies.

Currently, we reported the synthesis of six novel salicylaldehyde-based thiosemicarbazones (BHCT1-HBCT6) via condensation of salicylaldehyde with respective thiosemicarbazide. Through various spectroscopic methods, UV-visible and NMR, the chemical structures of BHCT1-HBCT6 compounds were determined. Along with synthesis, a computational study was also performed at the M06/6-31G(d,p) functional. Various analyses such as natural bond orbital (NBO) analysis, natural population analysis, frontier molecular orbital (FMO) analysis, and molecular electrostatic potential surfaces were carried out to understand the nonlinear optical (NLO) characteristics of the synthesized compounds. Additionally, a comparative study was carried out between DFT and experimental results (UV-vis study), and a good agreement was observed in the results. The energy gap calculated through FMOs was found to be in decreasing order as 4.505 (FHCT2) > 4.499 (HBCT6) > 4.497 (BHCT1) = 4.497(HMCT5) > 4.386 (CHCT3) > 4.241(AHCT4) in eV. The global reactivity parameters (GRPs) were attained through E HOMO and E LUMO, which described the stability and hardness of novel compounds. The NBO approach confirmed the charge delocalization and stability of the molecules. Among all the investigated compounds, a larger value (557.085 a.u.) of first hyperpolarizability (ßtot) was possessed by CHCT3. The NLO response (ßtot) of BHCT1-HBCT6 was found to be 9.145, 9.33, 13.33, 5.43, 5.68, and 10.13 a.u. times larger than that of the standard para-nitroaniline molecule. These findings ascertained the potential of entitled ligands as best NLO materials for a variety of applications in modern technology.

Synthesis of Fluorinated Hydrazinylthiazole Derivatives: A Virtual and Experimental Approach to Diabetes Management.

A novel series of fluorophenyl-based thiazoles was synthesized following the Hanztsch method. All of the compounds were initially verified with physical parameters (color, melting point, retardation factor (R f)), which were further confirmed by several spectroscopic methods, including ultraviolet-visible (UV-visible), Fourier-transform infrared (FTIR), 1H, 13C, 19F NMR, and high-resolution mass spectrometry (HRMS). The binding interactions of all compounds were studied using a molecular docking simulation approach. Furthermore, each compound was evaluated for its alpha(α)-amylase, antiglycation, and antioxidant potentials. The biocompatibility of all compounds was checked with an in vitro hemolytic assay. All synthesized scaffolds were found biocompatible with minimal lysis of human erythrocytes as compared to the standard Triton X-100. Among the tested compounds, the analogue 3h (IC50 = 5.14 ± 0.03 µM) was found to be a highly potent candidate against α-amylase as compared to the standard (acarbose, IC50 = 5.55 ± 0.06 µM). The compounds 3d, 3f, 3i, and 3k exhibited excellent antiglycation inhibition potential with their IC50 values far less than the standard amino guanidine (IC50 = 0.403 ± 0.001 mg/mL). The antidiabetic potential was further supported by docking studies. Docking studies revealed that all synthesized compounds exhibited various interactions along enzyme active sites (pi-pi, H-bonding, van der Waals) with varied binding energies.

Efficient Synthesis of Imine-Carboxylic Acid Functionalized Compounds: Single Crystal, Hirshfeld Surface and Quantum Chemical Exploration.

Two aminobenzoic acid based crystalline imines (HMBA and DHBA) were synthesized through a condensation reaction of 4-aminobenzoic acid and substituted benzaldehydes. Single-crystal X-ray diffraction was employed for the determination of structures of prepared Schiff bases. The stability of super molecular structures of both molecules was achieved by intramolecular H-bonding accompanied by strong, as well as comparatively weak, intermolecular attractive forces. The comparative analysis of the non-covalent forces in HMBA and DHBA was performed by Hirshfeld surface analysis and an interaction energy study between the molecular pairs. Along with the synthesis, quantum chemical calculations were also accomplished at M06/6-311G (d, p) functional of density functional theory (DFT). The frontier molecular orbitals (FMOs), molecular electrostatic potential (MEP), natural bond orbitals (NBOs), global reactivity parameters (GRPs) and natural population (NPA) analyses were also carried out. The findings of FMOs found that Egap for HMBA was examined to be smaller (3.477 eV) than that of DHBA (3.7933 eV), which indicated a greater charge transference rate in HMBA. Further, the NBO analysis showed the efficient intramolecular charge transfer (ICT), as studied by Hirshfeld surface analysis.

Synthesis, characterization and exploration of photovoltaic behavior of hydrazide based scaffolds: a concise experimental and DFT study.

Solar energy being a non-depleting energy resource, has attracted scientists' attention to develop efficient solar cells to meet energy demands. Herein, a series of hydrazinylthiazole-4-carbohydrazide organic photovoltaic compounds (BDTC1-BDTC7) with an A1-D1-A2-D2 framework was synthesized with 48-62% yields, and their spectroscopic characterization was accomplished using FT-IR, HRMS, 1H and 13C-NMR techniques. Density functional theory (DFT) and time dependent DFT analyses were performed utilizing the M06/6-31G(d,p) functional to calculate the photovoltaic and optoelectronic properties of BDTC1-BDTC7via numerous simulations of the frontier molecular orbitals (FMOs), transition density matrix (TDM), open circuit voltage (V oc) and density of states (DOS). Moreover, the conducted analysis on the FMOs revealed efficient transference of charge from the highest occupied to the lowest unoccupied molecular orbitals (HOMO → LUMO), further supported by TDM and DOS analyses. Furthermore, the values of binding energy (E b = 0.295 to 1.150 eV), as well as reorganization energy of the holes (-0.038-0.025 eV) and electrons (-0.023-0.00 eV), were found to be smaller for all the studied compounds, which suggests a higher exciton dissociation rate with greater hole mobility in BDTC1-BDTC7. V oc analysis was accomplished with respect to HOMOPBDB-T-LUMOACCEPTOR. Among all the synthesized molecules, BDTC7 was found to have a reduced band gap (3.583 eV), with a bathochromic shift and absorption maximum at 448.990 nm, and a promising V oc (1.97 V), thus it is regarded as a potential candidate for high performance photovoltaic applications.

Multitarget Potential of Phytochemicals from Traditional Medicinal Tree, Terminalia arjuna (Roxb. ex DC.) Wight & Arnot as Potential Medicaments for Cardiovascular Disease: An In-Silico Approach.

Cardiovascular diseases (CVDs) are the leading cause of mortality worldwide. Terminalia arjuna (Roxb. ex DC.) Wight & Arnot of the Combretaceae family is one of the most frequently approved and utilized medicinal trees in the traditional medicinal system, which was used for the treatment of a variety of diseases, including cardiovascular disorders. The present study aims to identify phytochemicals from T. arjuna, that do not exhibit any toxicity and have significant cardioprotective activity using an in-silico technique. Four different cardiovascular proteins, namely human angiotensin receptor (PDB ID: 4YAY), P38 mitogen-activated protein kinase (MAPK, PDB ID: 4DLI), 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-Co A) reductase (PDB ID: 1HW9), and human C-reactive protein (PDB ID: 1B09), were used as target proteins to identify potential inhibitors using a virtual screening of the phytochemicals in T. arjuna revealed casuarinin as a potential inhibitor of all selected target proteins with strong binding energy. Furthermore, MD simulations for a 100 ns time scale also revealed that most of the key protein contacts of all target proteins were retained throughout the simulation trajectories. Binding free energy calculations using the MM-GBSA approach also support a strong inhibitory effect of casuarinin on target proteins. Casuarinin's effective binding to these proteins lays the groundwork for the development of broad-spectrum drugs as well as the understanding of the underlying mechanism against cardiovascular diseases through in vivo and clinical studies.

Role of gibberellins, neem leaf extract, and serine in improving wheat growth and grain yield under drought-triggered oxidative stress.

The foliar application of gibberellins (GA3), neem leaf extract (NLE) and serine can be proven as effective growth regulating agents to counter drought stress-related deleterious effects. The literature about the collaborative role of these substances in foliar spray application under drought stress is not available to this date. No single report is available in literature on combine foliar application of GA3, NLE, and serine in improving wheat growth and yield under drought-triggered oxidative stress. The objective of this study was to induct tolerance against drought stress in order to sustain maximum growth and yield of wheat varieties (Anaj-2017 and Galaxy-2013) with foliar applications of GA3, NLE, and serine. The current field trial was designed to disclose the protective role of these substances in wheat varieties (Anaj-2017 and Galaxy-2013) under water-deficit stress. Two irrigation levels, i.e., control (normal irrigation) and water stress (water deficit irrigation), and 5 levels of GA3, NLE and serine i.e., control (water spray), GA3 (10.0 ppm), NLE (10.0%), serine (9.5 mM), and mixture (GA3 + NLE + serine) in a 1:1:1 ratio was applied. Application of these substances improved the pigments (Chlorophyll a, b), carotenoids, growth, biomass, and grain yield traits of both wheat varieties under water-deficit stress. Activities of antioxidant enzymes (POD, CAT and SOD), and non-enzymatic antioxidants (proline, total phenolic contents, anthocyanin and free amino acids) were up-regulated under drought stress and with foliar spray treatments. The foliar applications of these substances reduced the drought triggered overproduction of lipid peroxidation (MDA) and H2O2. The study found that Galaxy-2013 variety is more tolerant to drought stress than Anaj-2017, while co-applied treatments (GA3 + NLE + serine) were shown to be the most effective among all applications. Supplementary Information: The online version contains supplementary material available at 10.1007/s12298-023-01402-9.

Evaluation of the Antifungal, Antioxidant, and Anti-Diabetic Potential of the Essential Oil of Curcuma longa Leaves from the North-Western Himalayas by In Vitro and In Silico Analysis.

Essential oils (EOs) have gained immense popularity due to considerable interest in the health, food, and pharmaceutical industries. The present study aimed to evaluate the antimicrobial and antioxidant activity and the anti-diabetic potential of Curcuma longa leaf (CLO) essential oil. Further, major phytocompounds of CLO were analyzed for their in-silico interactions with antifungal, antioxidant, and anti-diabetic proteins. CLO was found to have a strong antifungal activity against the tested Candida species with zone of inhibition (ZOI)-11.5 ± 0.71 mm to 13 ± 1.41 mm and minimum inhibitory concentration (MIC) was 0.63%. CLO also showed antioxidant activity, with IC50 values of 5.85 ± 1.61 µg/mL using 2,2-diphenyl-1-picrylhydrazyl (DPPH) scavenging assay and 32.92 ± 0.64 µM using ferric reducing antioxidant power (FRAP) assay. CLO also showed anti-diabetic activity with an IC50 of 43.06 ± 1.24 µg/mL as compared to metformin (half maximal inhibitory concentration, IC50-16.503 ± 0.66 µg/mL). Gas chromatography-mass spectrometry (GC-MS) analysis of CLO showed the presence of (-)-zingiberene (17.84%); 3,7-cyclodecadien-1-one, 3,7-dimethyl-10-(1-methylethylidene)-(15.31%); cyclohexene, 4-methyl-3-(1-methylethylidene) (12.47%); and (+)-4-Carene (11.89%) as major phytocompounds. Molecular docking of these compounds with antifungal proteins (cytochrome P450 14 alpha-sterol demethylase, PDB ID: 1EA1, and N-myristoyl transferase, PDB ID: 1IYL), antioxidant (human peroxiredoxin 5, PDB ID: 1HD2), and anti-diabetic proteins (human pancreatic alpha-amylase, PDB ID: 1HNY) showed strong binding of 3,7-cyclodecadien-1-one with all the selected protein targets. Furthermore, molecular dynamics (MD) simulations for a 100 ns time scale revealed that most of the key contacts of target proteins were retained throughout the simulation trajectories. Binding free energy calculations using molecular mechanics generalized born surface area (MM/GBSA), and drug-likeness and toxicity analysis also proved the potential for 3,7-cyclodecadien-1-one, 3,7-dimethyl-10-(1-methylethylidene) to replace toxic synthetic drugs and act as natural antioxidants.

Design, Synthesis, and Biological Evaluation of Novel Dihydropyridine and Pyridine Analogs as Potent Human Tissue Nonspecific Alkaline Phosphatase Inhibitors with Anticancer Activity: ROS and DNA Damage-Induced Apoptosis.

Small molecules with nitrogen-containing scaffolds have gained much attention due to their biological importance in the development of new anticancer agents. The present paper reports the synthesis of a library of new dihydropyridine and pyridine analogs with diverse pharmacophores. All compounds were tested against the human tissue nonspecific alkaline phosphatase (h-TNAP) enzyme. Most of the compounds showed excellent enzyme inhibition against h-TNAP, having IC50 values ranging from 0.49 ± 0.025 to 8.8 ± 0.53 µM, which is multi-fold higher than that of the standard inhibitor (levamisole = 22.65 ± 1.60 µM) of the h-TNAP enzyme. Furthermore, an MTT assay was carried out to evaluate cytotoxicity against the HeLa and MCF-7 cancer cell lines. Among the analogs, the most potent dihydropyridine-based compound 4d was selected to investigate pro-apoptotic behavior. The further analysis demonstrated that compound 4d played a significant role in inducing apoptosis through multiple mechanisms, including overproduction of reactive oxygen species, mitochondrial dysfunction, DNA damaging, and arrest of the cell cycle at the G1 phase by inhibiting CDK4/6. The apoptosis-inducing effect of compound 4d was studied through staining agents, microscopic, and flow cytometry techniques. Detailed structure-activity relationship (SAR) and molecular docking studies were carried out to identify the core structural features responsible for inhibiting the enzymatic activity of the h-TNAP enzyme. Moreover, fluorescence emission studies corroborated the binding interaction of compound 4d with DNA through a fluorescence titration experiment.