Strong Inhibition Research Articles

Fabrication, Structural, DFT, Biological and Molecular Docking Studies of Fe(III), Ni(II), and Cu(II) Complexes Based on Schiff-base derived from benzene-1,4-diamine and 2-hydroxy-1-naphthaldehyde

This study presents the design & comprehensive characterization of three novel metal complexes derived from a Schiff base compound (H2PDN) synthesized from benzene-1,4-diamine and 2-hydroxy-1-naphthaldehyde, coordinated with Fe (III) (FePDN), Ni (II) (NiPDN), & Cu (II) (CuPDN). Structures of both the H2PDN ligand & its metal complexes were proposed utilizing various analytical methods, having elemental analysis, ultraviolet-visible spectroscopy, mass spectrospcopy, infrared spectroscopy, magnetic properties, conductivity measurement, & thermal analysis. The obtained data revealed octahedral geometries for both FePDN and CuPDN complexes, denoted as [Fe2(PDN)(H2O)4(Cl)4] and [Cu2(PDN)(H2O)6(Cl)2], respectively, while the NiPDN complex exhibited a distorted tetrahedral structure, represented as [Ni2(PDN)(H2O)2(Cl)2]. Density functional theory (DFT) computations were employed to validate the molecular structures & explore quantum chemical parameters of both H2PDN & its metal complexes. The synthesized H₂PDN Schiff base and its metal complexes (FePDN, NiPDN, CuPDN) showcased significant antimicrobial, anti-inflammatory, and antioxidant activities. NiPDN exhibited the highest inhibition zone against P. aeruginosa (21.44±0.28 mm) and S. aureus (19.37±0.40 mm), while CuPDN showed strong inhibition against E. coli (18.42±0.13 mm). NiPDN demonstrated excellent antibacterial efficacy with a low MIC against B. cereus (21.00±0.98 μM), and CuPDN displayed potent anti-inflammatory (IC50: 121.65 μM) and antioxidant activity (IC50: 84.7±0.77 μM). These results indicate the therapeutic potential of the H₂PDN complexes. Molecular docking studies targeting specific proteins (2VF5 for Escherichia coli, 3CKU for Aspergillus flavus, 5IKT for Human Cyclooxygenase-2, & 5IJT for human peroxiredoxin 2) were performed to assess the binding affinities & interactions of H2PDN & its metal complexes. The results propose promising potential for the application of H2PDN and its metal complexes as novel therapeutic agents with diverse biological activities.

Novel benzenesulfonamide-aroylhydrazone conjugates as carbonic anhydrase inhibitors that induce MAPK/ERK-mediated cell cycle arrest and mitochondrial-associated apoptosis in MCF-7 breast cancer cells

A series of novel 4-alkylthio-2-chloro-5-[(2-arylmethylidene)hydrazinecarbonyl]benzenesulfonamide derivatives 3–22 were synthesized and evaluated for their inhibitory activity against human carbonic anhydrase isozymes hCA I, hCA II, hCA IX, and hCA XII. These compounds showed varying degrees of activity against the studied isoenzymes. However, the importance of substituent choice in designing potent carbonic anhydrase inhibitors is highlighted by the strong inhibition profiles of compounds 3 and 10 against hCA IX and the low average KI values for compounds 9 and 10 (134 nM and 77 nM, respectively). All the synthesized compounds were evaluated for their antiproliferative activity toward HeLa, HCT-116, and MCF-7 cell lines. Compounds 9 and 19 exhibited significant activity, particularly against the MCF-7 cell line (IC50 values of 4 μM and 6 μM, respectively). Notably, compound 9 demonstrated a high selectivity index (SI = 8.2) for MCF-7 cells. The antiproliferative effects of compounds 9 and 19 were linked to the induction of cell cycle arrest and apoptosis via the mitochondrial pathway and involved the activation of the MAPK/ERK signaling pathway. Inhibition of MAPK/ERK activity reduced the compounds’ ability to induce cell cycle arrest and apoptosis, indicating the critical role of this pathway. These findings suggest that compounds 9 and 19 are promising candidates for further development as specific and potent anticancer agents targeting the MAPK/ERK pathway.

Degradation of norfloxacin by the synergistic effect of micro-nano bubbles and sodium hypochlorite: kinetics, influencing factors and pathways.

This study thoroughly investigated the degradation of norfloxacin (NOR) under the influence of micro-nanobubbles (MNBs) and sodium hypochlorite (NaClO), focusing on their synergistic effects. The impact of various environmental factors, including NaClO concentration, pH, inorganic anions, and surfactants, on NOR degradation efficiency within the MNBs/NaClO system was systematically assessed. The basic properties of the MNBs/NaClO system and the degradation kinetics of NOR were explored. The degradation products and pathways of NOR were explored to reveal the degradation mechanism of antibiotics in the MNBs/NaClO system by employing density functional theory (DFT) and high-performance liquid chromatography-mass spectrometry (HPLC-MS). The redox potential of the MNBs/NaClO system exhibited significantly superior properties than the single system, with bubble sizes predominantly in the nanoscale. The degradation kinetics of NOR adhered to a pseudo-first-order reaction model, with optimal degradation occurring at a 0.025% NaClO volume concentration. Acidic conditions promoted the degradation of NOR, and alkaline conditions inhibited the degradation of NOR. Inorganic anions PO43-, HCO3-, and CO32- in the water matrix led to strong inhibition of NOR degradation. Cationic surfactants accelerated the degradation process of NOR, while anionic and nonionic surfactants had a consistent inhibitory effect on the degradation of NOR. Based on the degradation behavior, three potential pathways for NOR degradation were proposed: quinolone group transformation, defluorination reaction, piperazine ring cracking and quinolone ring decomposition. This research contributes a novel technical approach for addressing antibiotic pollution and offers a theoretical framework for understanding the fate of antibiotics in the environment.

Design, synthesis, QSAR modelling and molecular dynamic simulations of N-tosyl-indole hybrid thiosemicarbazones as competitive tyrosinase inhibitors

Tyrosinase is an enzyme crucial for the progression of melanogenesis. Immoderate production of melanin may be the cause of hyperpigmentation and darkening leading to skin diseases. Tyrosinase is the most researched target for suppressing melanogenesis since it catalyzes the rate-limiting stage of melanin production. Thiosemicarbazones have been reported to possess strong inhibition capability against tyrosinase. We have designed and synthesized eighteen N-tosyl substituted indole-based thiosemicarbazones as competitive tyrosinase inhibitors in the current work. All the compounds exhibited outstanding to good potency with half maximal inhibitory concentration in the range of 6.40 ± 0.21 µM to 61.84 ± 1.47 µM. The compound 5r displayed the top-tier inhibition amongst the entire series with IC50 = 6.40 ± 0.21 µM. Compounds, 5q and 5r exhibited competitive inhibitions in concentration dependent manner with Ki = 3.42 ± 0.03 and 10.25 ± 0.08 µM respectively. The binding mode of 5r was evaluated through in silico molecular dynamics simulations and molecular docking, while ADME assessment studies predicted the drug-like characteristics of the derivatives. The newly synthesized derivatives may serve as a structural guide for designing and developing novel tyrosinase inhibitors.

In vitro antifungal activity of extracts and alkaloid compounds from Piper arboreum against dermatophytes

Piper is widely distributed in subtropical regions and species of this genus are known for their potent pharmacological activities. Piper arboreum Aubl. is a traditional medicinal plant popularly known as "pau-de-angola", "jaborandi", and chili pepper, demonstrating antifungal, trypanocidal, antibacterial, and antioxidant activities. The leaves of P. arboreum were extracted using Soxhlet and dichloromethane to obtain the extract, which was then fractionated using solvents of different polarities. Samples were analyzed using ultra-high-performance liquid chromatography coupled with mass spectrometry equipped with an electrospray ionization source. Antifungal microdilution assays were performed, and scanning and transmission electron microscopy were used to assess the invasion of the pretreated nail. The minimum inhibitory concentration (MIC) values of the extract and a dichloromethane fraction were, respectively, 62.5 μg/ml and 16.0 μg/ml against Trichophyton rubrum, and 125 μg/ml and 62.5 μg/ml, and 500 μg/ml and 500 μg/ml against T. mentagrophytes, and Microsporum gypseum, respectively. No growth was observed on nail fragments exposed to the extract (at concentrations > 64 µg/ml and then inoculated with spore suspension. Transmission electron microscopy revealed strong inhibition of hyphal growth and an irregular growth pattern following treatment with the extract and the dichloromethane fraction. Results demonstrated the antifungal properties of the P. arboreum extract and its dichloromethane fraction against dermatophytes, with the identification of three different alkaloid compounds. The cytotoxicity was specific towards the fungal cells, and morphological and ultrastructural analyses indicated damage to the cell wall and cytoplasmic membrane as the potential mechanism of action. The leaf material used to generate the extract can be taken from the plant without any detrimental effect thus enabling strategies to be implemented for the exploitation of this species.

CAMP/PKA-mediated in vitro angiogenesis: A novel interplay between PKA, RhoA/ROCK, and VEGFR2 signalling

Abstract Background and Aims Others and we have previously demonstrated that cAMP/PKA signalling stabilise endothelial cell (EC) barrier function via modulating the activities of Rho GTPases, mainly RhoA and Rac1. In the present study we analysed whether cAMP/PKA also modulates EC angiogenesis capacity and whether Rho GTPases are involved in this function. Methods The study was carried out on cultured human umbilical vein ECs (HUVECs). RhoA and Rac1 activities were genetically manipulated by lentiviral-mediated over expression of dominant negative (DN) and constitutive active (CA) forms of RhoA and Rac1. Pharmacologically, specific activation and inhibition of PKA was achieved by using cAMP analogue N6-Benzoyl-cAMP (5 mM) and PKI (1 µM), respectively. Pharmacologically, Rac1 was inhibited using NSC 23766 (10 µM) and RhoA was activated using Rho activator I (Cytoskeleton Inc.). In vitro angiogenesis was analysed by 3-D spheroid assay and matrigel tube formation assay. Results Pharmacologically, specific activation of PKA induced EC migration (Wound healing assay), tube formation, and 3-D spheroids and potentiated the VEGF-induced in vitro angiogenesis. These pro-angiogenesis activities were abrogated by highly specific cell-permeable peptide inhibitor (PKI) of PKA. Activation of cAMP/PKA-signalling resulted in an increased VEGFR2 and Akt phosphorylation, increased Rac1 activity, and a strong inhibition of RhoA/Rock pathway. Pharmacological activation of RhoA but not inhibition of Rac1 abrogated PKA-induced VEGFR2 phosphorylation, tube formation and 3-D spheroids. Lentiviral mediated over-expression of constitutive active form of RhoA but not Rac1 abrogated PKA-induced VEGFR2 and Akt phosphorylation and angiogenesis. Moreover, pharmacological inhibition of Akt also abrogated PKA-mediated VEGFR2 phosphorylation and angiogenesis. Likewise, over expression of either dominant negative RhoA or pharmacological inhibitors of Rho kinase (ROCK) promoted basal and potentiated PKA-mediated VEGFR2 and Akt phosphorylation and angiogenesis. Conclusion We describe for the first time a novel interplay between PKA, RhoA/ROCK, Akt, and VEGFR2 signalling and angiogenesis. Inhibition of RhoA/ROCK plays an important role in mediating PKA-induced angiogenesis and activation of RhoA/ROCK signalling may offer an important target to intervene therapeutic angiogenesis.

Deciphering the Metabolic Basis and Molecular Circuitry of the Warburg Paradox in Lymphoma

Background/Objectives: Warburg’s metabolic paradox illustrates that malignant cells require both glucose and oxygen to survive, even after converting glucose into lactate. It remains unclear whether sparing glucose from oxidation intersects with TCA cycle continuity and if this confers any metabolic advantage in proliferating cancers. This study seeks to understand the mechanistic basis of Warburg’s paradox and its overall implications for lymphomagenesis. Methods: Using metabolomics, we first examined the metabolomic profiles, glucose, and glutamine carbon labeling patterns in the metabolism during the cell cycle. We then investigated proliferation-specific metabolic features of malignant and nonmalignant cells. Finally, through bioinformatics and the identification of appropriate pharmacological targets, we established malignant-specific proliferative implications for the Warburg paradox associated with metabolic features in this study. Results: Our results indicate that pyruvate, lactate, and alanine levels surge during the S phase and are correlated with nucleotide synthesis. By using 13C1,2-Glucose and 13C6, 15N2-Glutamine isotope tracers, we observed that the transamination of pyruvate to alanine is elevated in lymphoma and coincides with the entry of glutamine carbon into the TCA cycle. Finally, by using fludarabine as a strong inhibitor of lymphoma, we demonstrate that disrupting the transamination of pyruvate to alanine correlates with the simultaneous suppression of glucose-derived nucleotide biosynthesis and glutamine carbon entry into the TCA cycle. Conclusions: We conclude that the transamination of pyruvate to alanine intersects with reduced glucose oxidation and maintains the TCA cycle as a critical metabolic feature of Warburg’s paradox and lymphomagenesis.

Insights into Citrus limon (L.) Osbeck peel essential oil from NE India: A study of its pharmacological properties and chemical composition

Citrus limon (L.) Osbeck is considered as one of the most significant horticultural as well as essential oil crop. However, the significance of the fruit peels left after the utilization of the sour fruit find limited importance and these leftover peels are rich in essential oil. Lemon peel essential oil (LPEO) finds used in the fragrance, food, cosmetic, and pharmaceutical industries. In this study lemon peel were used for isolation of essential oil by hydro-distillation, analyzed by GC-FID and GC-MS and was further subjected to in vitro anti-oxidant (DPPH, ABTS), anti-inflammatory, anti-tyrosinase, genotoxicity and anti-diabetic assays. The essential oil analysis has revealed limonene as major compound (38.08%) along with other minor compounds namely, α-citral (12.02%), decanal (8.14%) and neral (7.36%). The total amount of citral (α-citral and neral) was found to be 19.38%, comparatively higher compared to previous reports. LPEO was found to exhibit very strong tyrosinase inhibition activity along with good alpha-amylase inhibition. The results from this study further strengthen the immense potential of LPEO as an anti-diabetic and skin whitening agent. The results framed from this study will further strengthen the position of earlier works on biological activities of C. limon besides providing a descriptive work on the potential of Assam LPEO.

Lecithin-based mixed polymeric micelles for activity improvement of curcumin against Staphylococcus aureus

Considering cellular uptake promotion of lecithin and high expression of phospholipase in S. aureus, we designed curcumin (Cur)-loaded soy lecithin-based mPEG-PVL copolymer micelles (MPPC). The effect of soy lecithin on the anti-S. aureus activity of the formulation was studied with cur-loaded mPEG-PVL micelles (MPC without soy lecithin) as control. It was found that MPPC enhanced the water-solubility of Cur, and showed slow and sustained release behavior of Cur. Although MPPC had the same anti-S. aureus activity as Cur, its activity was significantly higher than MPC due to the cellular uptake promotion of soybean lecithin. It was noted that MPPC had good inhibition or destruction effect on biofilm, significant cell membrane damage, strong inhibition effect on protease or lipase production, and obvious induction effect on ROS expression when compared with Cur and MPC. So, the introduction of soy lecithin could improve the antibacterial activity of Cur. The lecithin-based micelles would offer potential to deliver antibacterial drugs for improved therapeutic action.

A Synthetic Route Towards Spiro Indanone Fused Pyrano[2,3‐c]Chromene Derivatives via Oxa–Diels–Alder Reaction: Computational Investigation, Antibacterial Evaluation and Molecular Docking Studies as Potential DNA Gyrase Inhibitors

ABSTRACTA highly efficient method for the synthesis of 2′H‐spiro[indene‐2,3′‐pyrano[2,3‐c]chromene] derivatives 20(a–s) has been developed involving oxa–Diels–Alder reaction as the key step under conventional conditions in good to excellent yields. The compounds were all characterized using 1H, 13C NMR, HRMS, and X‐ray crystallography. The present study employs DFT to validate the reaction pathway. In vitro antibacterial assay of all the synthesized derivatives was evaluated against Gram‐negative Escherichia coli and Gram‐positive Staphylococcus aureus bacterial strains. Compound 20e was found to be the most potent molecule with ZI of 19 mm and MIC of 16 μg mL−1 in E. coli and ZI of 14 mm and MIC of 32 μg mL−1 in S. aureus. Additionally, 20e demonstrated a strong inhibition of DNA gyrase in silico, with a binding affinity of −9.3 and − 9.0 kcal/mol in E. coli and S. aureus respectively. Also, significant pharmacokinetic, physicochemical, and drug‐like properties of the spirocyclic compounds were further corroborated by ADME investigations. Hence, these new series of spiro indanone fused pyrano[2,3‐c]chromene derivatives may be potent druggable antibacterial agents in future.

Oxidative stress mechanism by gold compounds: a close look at total ROS increase and the inhibition of antioxidant enzymes.

The antitumor activity of various gold compounds is a promising field of investigation, attracting researchers seeking potential clinical candidates. To advance this research, they explore the complex mechanisms of action of these compounds. Since the discovery of the strong inhibition of thioredoxin reductase by auranofin, the primary mechanism explored has been the inhibition of this enzyme. This inhibition disrupts the redox balance in cells, promoting oxidative stress and triggering cell death. In this review, we analyzed studies from the past decade that measured cellular ROS increase and examined the coordination structures of gold compounds. We also correlate ROS increase with the inhibition of redox-regulating enzymes, thioredoxin reductase and glutathione reductase, to elucidate the relationship between these cellular effects and chemical structures. Our data compilation reveals that different structures exhibit varying efficacy: some significantly increase ROS production and inhibit thioredoxin reductase or glutathione reductase, while others elevate ROS levels without affecting these target enzymes, suggesting alternative mechanisms of action. This review consolidates critical evidence, enhancing our understanding of the mechanisms by which these gold complexes act and providing valuable insights for developing new therapeutic strategies against tumor cells.

Building Confidence in Physiologically Based Pharmacokinetic Modeling of CYP3A Induction Mediated by Rifampin: An Industry Perspective.

Physiologically-based pharmacokinetic (PBPK) modeling offers a viable approach to predict induction drug-drug interactions (DDIs) with the potential to streamline or reduce clinical trial burden if predictions can be made with sufficient confidence. In the current work, the ability to predict the effect of rifampin, a well-characterized strong CYP3A4 inducer, on 20 CYP3A probes with publicly available PBPK models (often developed using a workflow with optimization following a strong inhibitor DDI study to gain confidence in fraction metabolized by CYP3A4, fm,CYP3A4, and fraction available after intestinal metabolism, Fg), was assessed. Substrates with a range of fm,CYP3A4 (0.086-1.0), Fg (0.11-1.0) and hepatic availability (0.09-0.96) were included. Predictions were most often accurate for compounds that are not P-gp substrates or that are P-gp substrates but that have high permeability. Case studies for three challenging DDI predictions (i.e., for eliglustat, tofacitinib, and ribociclib) are presented. Along with parameter sensitivity analysis to understand key parameters impacting DDI simulations, alternative model structures should be considered, for example, a mechanistic absorption model instead of a first-order absorption model might be more appropriate for a P-gp substrate with low permeability. Any mechanisms pertinent to the CYP3A substrate that rifampin might impact (e.g., induction of other enzymes or P-gp) should be considered for inclusion in the model. PBPK modeling was shown to be an effective tool to predict induction DDIs with rifampin for CYP3A substrates with limited mechanistic complications, increasing confidence in the rifampin model. While this analysis focused on rifampin, the learnings may apply to other inducers.

Exploring Teucrium aureo-candidum Essential Oil as a Promising Alternative to Triclosan for Targeting Enoyl-Acyl Carrier Protein Reductase: Chemical Composition, Antibacterial Activity, and Molecular Docking Study.

The chemical composition of the essential oil isolated from the aerial parts of Teucrium aureo-candidum, an endemic aromatic shrub collected from Moghrar and Djeniene Bourezg in the Nâama region (Algeria), was determined for the first time using GC/FID and GC/MS. A total of 45 constituents were identified, representing 87.73% of the oil. Characterized by unique chemical variability, it was primarily composed of sesquiterpene hydrocarbons (29.53%) and oxygenated sesquiterpenes (30.06%), with the major compounds being γ-cadinene (5.24%), δ-cadinene (4.24%), α-muurolene (4.04%), τ-muurolol (11.35%), and α-cadinol (3.30%). However, monoterpene hydrocarbons and oxygenated monoterpenes accounted for 23.98% and 1.64%, respectively, contributing to a relatively low fraction. The essential oil demonstrated notable antibacterial activity, particularly against Gram-positive bacteria. Due to safety concerns associated with triclosan, a known inhibitor of the Enoyl-Acyl Carrier Protein Reductase (FabI) enzyme, the essential oil components from this plant were explored as alternatives through a combination of experimental approaches and in silico molecular docking studies. The results revealed that α-cadinol, spathulenol, caryophyllene, and α-muurolene exhibited strong FabI inhibition, with better bioavailability and lower toxicity than triclosan, highlighting their potential in combating antibiotic-resistant bacteria.

Inhibitory effects characteristics of polysaccharide of Polygonati Rhizome on cytochrome P450 enzymes.

As the major active ingredient of Polygonatum sibriricum Red., polysaccharide of Polygonati Rhizome (PSP) has been reported to possess various pharmacological activities, especially for the treatment of chronic disorders in the elderly. This study evaluated the effect of PSP on the activities of major cytochrome P450 enzymes (CYP450) isoforms, aiming to provide theoretical reference for its co-prescription with other drugs and prevent the risk of adverse drug-drug interaction. The activities of CYP450 isoforms were assessed in human liver microsomes with specific probe substances. Through Lineweaver-Burk fitting models, the effect of PSP on the activity of inhibited CYP450 isoforms was characterized by competitive and non-competitive models. Dose-dependent and time-dependent experiments were also performed to completely understand the inhibition. Among experimental isoforms, PSP significantly inhibited the activities of CYP2C9, 2D6, and 3A4 in a concentration-dependent manner with IC50 values of 14.01, 17.63, and 5.33 μM. The inhibition of CYP2C9 and 2D6 was best fitted with the competitive model with the Ki values of 7.15 and 8.92 μM, respectively, while the inhibition of CYP3A4 was non-competitive with the Ki value of 2.63 μM. Additionally, the inhibition of CYP3A4 by PSP also showed time-dependent characteristics with the inhibition parameters, KI of 1.273 μM-1 and Kinact of 0.036 min-1. PSP exerted moderate inhibition on CYP2C9 and 2D6 and strong inhibition of CYP3A4. The dosage of CYP2C9-, 2D6-, and 3A4-metabolized drugs should be adjusted when co-administrated with PSP and its sourced herbs.

Decoupling relationship between logistics growth and carbon emissions and driving factors in Chongqing: A novel decomposition framework

A comprehensive understanding of the logistics decoupling status and driving factors is of immense theoretical and practical importance for rationally formulating low-carbon logistics policies and accelerating the realization of high-quality development. Present study introduces the logarithmic mean Divisia index method (LMDI) decomposition technique into Tapio index model, extends traditional decoupling model, and establishes a new analytical framework for the decoupling relationship between logistics growth and carbon emissions. Using long-term data from Chongqing (1997–2021), this study investigated the Chongqing logistics decoupling relationship and driving factors. The study found the following: (1) Chongqing logistics carbon emissions show phased changes and face greater pressure to reduce emissions. (2) The decoupling status of logistics growth and carbon emissions is predominantly expansive and weak decoupling, with an overall evolutionary trend of “expansive decoupling–weak decoupling–strong decoupling. The average decoupling index in 2013–2021 was 0.5523, indicating a decreasing trend; however, there was still a large gap in realizing a strong decoupling goal. (3) The energy consumption intensity effect facilitates logistics carbon decoupling, the economic scale effect has a strong inhibiting effect, and the industrial structure effect and transportation intensity effect are staged. Finally, targeted policy recommendations are proposed to expedite logistics carbon emissions decoupling in Chongqing.

Asymmetric winter warming reduces microbial carbon use efficiency and growth more than symmetric year-round warming in alpine soils

Asymmetric seasonal warming trends are evident across terrestrial ecosystems, with winter temperatures rising more than summer ones. Yet, the impact of such asymmetric seasonal warming on soil microbial carbon metabolism and growth remains poorly understood. Using 18O isotope labeling, we examined the effects of a decade-long experimental seasonal warming on microbial carbon use efficiency (CUE) and growth in alpine grassland ecosystems. Moreover, the quantitative stable isotope probing with 18O-H2O was employed to evaluate taxon-specific bacterial growth in these ecosystems. Results show that symmetric year-round warming decreased microbial growth rate by 31% and CUE by 22%. Asymmetric winter warming resulted in a further decrease in microbial growth rate of 27% and microbial CUE of 59% compared to symmetric year-round warming. Long-term warming increased microbial carbon limitations, especially under asymmetric winter warming. Long-term warming suppressed the growth rates of most bacterial genera, with asymmetric winter warming having a stronger inhibition on the growth rates of specific genera (e.g., Gp10, Actinomarinicola, Bosea, Acidibacter, and Gemmata) compared to symmetric year-round warming. Bacterial growth was phylogenetically conserved, but this conservation diminished under warming conditions, primarily due to shifts in bacterial physiological states rather than the number of bacterial species and community composition. Overall, long-term warming escalated microbial carbon limitations, decreased microbial growth and CUE, with asymmetric winter warming having a more pronounced effect. Understanding these impacts is crucial for predicting soil carbon cycling as global warming progresses.

Synthesis of Novel Indolyl Aryl Sulfone-clubbed Hydrazone Derivatives as Potential HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitors: Molecular Modeling and QSAR Studies.

Non-Nucleoside Reverse Transcriptases Inhibitors (NNRTIs) are among the most extensively studied enzymes for understanding the biology of Human Immunodeficiency Viruses (HIV) and designing inhibitors for managing HIV infections. Indolyl aryl sulfones (IASs), an underexplored class of potent NNRTIs, require further exploration for the development of newer drugs for HIV. In this context, we synthesized a series of novels by Indolyl Aryl Sulfones with a hydrazone moiety at the carboxylate site of the indole nucleus. A 2D-QSAR model was developed to predict Reverse Transcriptase inhibitory activity against wild-type RT (WT-RT) enzyme. The model was successfully applied to predict the HIV-1 inhibitory activity of known Indolyl Aryl Sulfones. Considering the reliability, robustness, and reproducibility of the 2D-QSAR model, we made an in-silico prediction of the RT inhibition for our synthesized compounds (1-14). Molecular docking and dynamics simulations established our synthesized Indolyl Aryl Sulfones, particularly compounds 23, 24, and 28, as effective NNRTIs by stabilizing HIV reverse transcriptase's structure. Binding energy calculations revealed compound 28 as the strongest inhibitor (-43.21 ± 0.09 kcal/mol), followed by 23 (-40.94 ± 0.10 kcal/mol) and 24 (-39.18±0.08 kcal/mol), emphasizing their binding affinity towards HIV reverse transcriptase. In summary, the synthesized Indolyl Aryl Sulfones, particularly compounds 23, 24, and 28, demonstrate significant potential as Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) against HIV. These results highlight the promising role of these compounds in developing novel NNRTIs for managing HIV infections.

Assessment of the Antioxidant and Photoprotective Properties of Cornus mas L. Extracts on HDF, HaCaT and A375 Cells Exposed to UVA Radiation.

The influence of UV radiation on skin discoloration, skin aging and the development of skin cancer is widely known. As a part of this study, the effect of extracts from three varieties of Cornus mas L. (C. mas L.) on skin cells exposed to UVA radiation was assessed. The analyses were performed on both normal and cancer skin cells. For this purpose, the potential photoprotective effects of the obtained extracts (aqueous and ethanolic) was assessed by performing two cytotoxicity tests (Alamar blue and Neutral red). Additionally, the antioxidant capacity was compared using three different assays. The 2',7'-dichlorodihydrofluorescein diacetate (H2DCFDA) probe was used to evaluate the intracellular level of free radicals in cells exposed to the simultaneous action of UVA radiation and dogwood extracts. Additionally, the ability to inhibit excessive pigmentation was determined by assessing the inhibition of melanin formation and tyrosinase activity. The obtained results confirmed the strong antioxidant properties of dogwood extracts and their photoprotective effect on normal skin cells. The ability to inhibit the viability of melanoma cells was also observed. Additionally, a reduction in oxidative stress in skin cells exposed to UVA radiation and a strong inhibition of melanin formation and tyrosinase activity have been demonstrated. This study shows that dogwood extract could be a valuable cosmetic raw material that can play both a photoprotective and antihyperpigmentation role in cosmetic preparations.

Molecular Dynamics Unveils Multiple-Site Binding of Inhibitors with Reduced Activity on the Surface of Dihydrofolate Reductase.

The sensitivity to protein inhibitors is altered by modifications or protein mutations, as represented by drug resistance. The mode of stable drug binding to the protein pocket has been experimentally clarified. However, the nature of the binding of inhibitors with reduced sensitivity remains unclear at the atomic level. In this study, we analyzed the thermodynamics and kinetics of inhibitor binding to the surface of wild-type and mutant dihydrofolate reductase (DHFR) using molecular dynamics simulations combined with Markov state modeling. A strong inhibitor of methotrexate (MTX) showed a preference for the active site of wild-type DHFR with minimal binding to unrelated (secondary) sites. Deletion of a side-chain fragment in MTX largely destabilized the active site-bound state, with clear evidence of binding to secondary sites. Similarly, the F31V mutation in DHFR diminished the specificity of MTX binding to the active site. These results reveal the presence of multiple-bound states whose stabilities are comparable to or higher than those of the unbound state, suggesting that a reduction in the binding affinity for the active site significantly elevates the fractions of these states. This study presents a theoretical model that more accurately interprets the altered drug sensitivity than the traditional two-state model.

Consumer skepticism towards organic beauty products Cross-country research

Based on the attitude–behaviour–context (ABC) theory, the present study addressed consumer skepticism as one of the inhibitors of organic purchasing behaviour. More specifically, it investigated the role of environmental concern and environmental knowledge as a mediator, in the organic cosmetics background. Data gathered from consumers in Tunisia (N = 736), Italy (N = 720) and France (N = 715) and analysed using a structural equation modelling approach. The findings revealed that green skepticism is a strong inhibitor towards adoption of organic cosmetic products among consumers in the three countries. On the other hand, findings revealed that environmental knowledge and environmental concern fully mediate the relationship between green skepticism and organic purchasing behaviour. The ultimate goal is to provide valuable insights for business leaders, policymakers and marketers fully understand consumers’ resistance to organic cosmetic products. Further, it offers a comprehensive framework to support strategies to reduce consumers’ skepticism towards organic products, in different market segments.