Mode Of Action Research Articles

Investigation of the Roles of Phosphatidylinositol 4-Phosphate 5-Kinases 7,9 and Wall-Associated Kinases 1-3 in Responses to Indole-3-Carbinol and Biotic Stress in Arabidopsis Thaliana.

Indole-3-carbinol (I3C), a hydrolysis product of indole-3-methylglucosinolate, is toxic to herbivorous insects and pathogens. In mammals, I3C is extensively studied for its properties in cancer prevention and treatment. Produced in Brassicaceae, I3C reversibly inhibits root elongation in a concentration-dependent manner. This inhibition is partially explained by the antagonistic action of I3C on auxin signaling through TIR1. To further elucidate the mode of action of I3C in plants, we have employed a forward-genetic amiRNA screen that circumvents functional redundancy. We identified and characterized two amiRNA lines with impaired I3C response. The first line, ICT2, targets the phosphatidylinositol 4-phosphate 5-kinase family (PIP5K), exhibiting tolerance to I3C, while the second line, ICS1, targets the Wall-Associated Kinases (WAK1-3) family, showing susceptibility to I3C. Both lines maintain I3C-induced antagonism of auxin signaling, indicating that their phenotypes are due to auxin-independent mechanisms. Transcript profiling experiments reveal that both lines are transcriptionally primed to respond to I3C treatment. Physiological, metabolomic, and transcriptomic analysis reveal that these kinases mediate numerous developmental processes and are involved in abiotic and biotic stress responses.

Essential oils from Cuminum cyminum and Laurus nobilis and their principal constituents: evaluation of antifungal and antimycotoxigenic potential in Aspergillus species.

The antifungal and antimycotoxigenic activities of the essential oils (EO) from Cuminum cyminum and Laurus nobilis, and their respective principal compounds, cuminaldehyde and 1,8-cineole, were evaluated against fungi of the genus Aspergillus: A.carbonarius, A.niger, A.ochraceus and A.westerdijkiae. The antifungal activity was determined by the contact method and the mycelial growth of the fungi was evaluated. Scanning Electron Microscopic (SEM) images were obtained to suggest modes of action of the compounds analyzed. The antimycotoxigenic activity was determined by HPLC. A.carbonarius was completely inhibited by cumin EO (500 µL L-1), by laurel EO and by cuminaldehyde (5000 µL L-1). The cumin EO (500 µL L-1) completely inhibited the growth of A.niger. All the samples inhibited the mycelial growth of A.ochraceus, especially cumin EO and cuminaldehyde (250 µL L-1). A.westerdijkiae was completely inhibited by cumin EO and cuminaldehyde (1000 µL L-1), by laurel EO and 1,8-cineole (10000 µL L-1). A decrease in the production of ochratoxin A (OTA) was observed post-treatment, except in A. ochraceus, only inhibited by laurel EO. SEM images showed morphological changes in fungal structures and spore inhibition post-treatment. The results confirmed the antifungal and antimycotoxigenic effect of EO and their principal constituents on fungi evaluated.

The effect of Traumeel LT ad us. vet. on the perioperative inflammatory response after castration of stallions: a prospective, randomized, double-blinded study.

Stallion castration is a standard procedure with a risk of post-surgical complications. Castration induces an acute phase response (APR). Serum Amyloid-A (SAA) is a well-studied major acute phase protein (APP), that has been shown to be a good marker for the development of post-surgical complications. The current gold standard for reducing the APR after castration is Flunixin-Meglumin, which is a non-steroidal anti-inflammatory drug (NSAID) inhibiting COX1/2. In contrast, Traumeel LT ad us. vet. can modulate the APR by induction of the inflammation resolution. The aim of this study was to compare the effect of Flunixin-Meglumin and Traumeel LT ad us. vet. on the acute phase response. A total of 60 stallions were recruited and 54 stallions entered the study with 27 stallions in each treatment group. The stallions were treated pre- and postoperatively with either Flunixin-Meglumin (FL) or with Traumeel LT ad us. vet. (TR). Blood was taken before and 24 h, 48 h and 72 h after castration. The following main parameters were assessed: SAA, fibrinogen, iron, white blood cells, neutrophils, Interleukin1ß, and cortisol. Wound healing and pain were assessed at 8 time points. The main variable SAA was increased after surgery reaching a mean value of 122 µg/ml in the FL group and a mean SAA of 226 µg/ml in the TR group 48 h after surgery, reaching a significant difference only at the 24 h timepoint (p = 0.03). All stallions had the highest pain summary score 8 hours after surgery, with decreasing values thereafter. The pain scores were not statistically different at any time point. In the FL group five stallions developed a suture dehiscence compared to only one stallion in the TR group (p = 0.001). Within the limitations of this study, Traumeel LT ad us. vet. seems to have proresolving effects on the inflammation induced by surgery making it a valuable treatment to reduce the APR induced by castration. Due to its different mode of action, Traumeel LT ad us. vet. might be an alternative treatment option if gastrointestinal side effects or renal side effects of NSAIDs should be avoided. Further studies are needed combining Traumeel LT ad us. vet. and Flunixin.

Exploring novel antitubercular agents: Innovative design of 2,3-diaryl-quinoxalines targeting DprE1 for effective tuberculosis treatment

Abstract The rising instances of drug resistance in Mycobacterium tuberculosis strains pose a significant global health challenge. Conventional tuberculosis (TB) treatments, which typically involve multiple antibiotics, face hurdles like drug resistance, reduced effectiveness, and heightened toxicity. Consequently, there is a pressing need for innovative anti-TB agents with new modes of action. Decaprenyl-phosphoryl-β-d-ribose 2′-epimerase 1(DprE1), a crucial enzyme in Mycobacterium tuberculosis, plays a vital role in cell wall biosynthesis – a critical aspect for the bacterium’s survival. Building on the success of diarylquinolines like bedaquiline, targeting DprE1 presents a promising avenue for developing anti-TB drugs, especially against drug-resistant strains. Our research focused on discovering novel DprE1 inhibitors using a ligand-based drug design strategy, starting with the established non-covalent inhibitor Ty38c. We assembled a library of 16 molecules, modifying them based on factors like drug-like properties, chemical accessibility, and synthetic feasibility. Molecular docking analyses of this library identified three molecules with binding affinities comparable to Ty38c. Among these, KS_QD_05 and KS_QD_04 are promising candidates, which were further validated through molecular dynamics simulation studies where root-mean-square deviation (RMSD) values of all three complexes reached a plateau, measuring around 0.3 nm, indicating that the apoprotein and all complexes stabilized during the simulation. The ligands KS_QD_04 and KS_QD_05 displayed significantly stable deviation. KS_QD_05 reached about 0.1 nm equilibrium value. However, the ligand KS_QD_04 reached an RMSD value of 0.17 nm and showed distress at 70 nm. KS_QD_04 and KS_QD_05 showed an average value of 1-3 H-bond interaction and regarding the RMSF values, both the compounds showed fluctuations less than 0.5 nm in the case of Mtb. DprE1 enzyme. This indicates the potential of both compounds to become lead compounds in the pursuit of DprE1 inhibitors for TB treatment.

A dual-targeted small-molecule photosensitizer with enhanced dual antitumor and anti-vascular effect for metastatic advanced prostate cancer photodynamic therapy

Advanced prostate cancer is regarded as a fatal disease, characterized by limited treatment options, poor prognosis and considerable tumor metastasis closely related to angiogenesis. Photodynamic therapy emerges as a promising and safe therapeutic modality for advanced prostate cancer with high metastasis and high fatality rate due to its focal damage to tumor cells, as well as its anti-angiogenesis and antitumor immunity capabilities. Herein, a tumor-targeting vascular disrupting agent ASA-404 was introduced to conjugate with a photosensitizer ZnPc for targeted prostate cancer treatment and enhanced vascular-disrupting efficiency. Notably, this novel organic small-molecule photosensitizer Pc-ASA possess a well-defined chemical structure and purity, as well as good photophysical and photochemical properties, which are of benefit for clinical approval and application. Pc-ASA prefers to accumulate in both prostate cancer cells and vascular endothelial cells. Moreover, the conjugation of ASA-404 boosts the photodynamic anticancer effect of Pc-ASA towards both prostate cancer cells and vascular endothelial cells. Ultimately, PC-ASA can successfully inhibit the migration and metastasis of prostate cancer cells, offering significant advantages in advanced prostate cancer management. Our study might open a window in the development of the tumor and vascular dual-targeted small-molecule photosensitizers, with the potential to achieve safe and efficient treatment of metastatic advanced prostate cancer through dual mode of antitumor and anti-vascular action.

Entangling roles of cholesterol-dependent interaction and cholesterol-mediated lipid phase heterogeneity in regulating listeriolysin O pore-formation.

Cholesterol-dependent cytolysins (CDCs) are the distinct class of β-barrel pore-forming toxins (β-PFTs) that attack eukaryotic cell membranes, and form large, oligomeric, transmembrane β-barrel pores. Listeriolysin O (LLO) is a prominent member in the CDC family. As documented for the other CDCs, membrane cholesterol is essential for the pore-forming functionality of LLO. However, it remains obscure how exactly cholesterol facilitates its pore formation. Here, we show that cholesterol promotes both membrane-binding and oligomerization of LLO. We demonstrate cholesterol not only facilitates membrane-binding, it also enhances the saturation threshold of LLO-membrane association, and alteration of the cholesterol-recognition motif in the LLO mutant (LLOT515G-L516G) compromises its pore-forming efficacy. Interestingly, such defect of LLOT515G-L516G could be rescued in the presence of higher membrane cholesterol levels, suggesting cholesterol can augment the pore-forming efficacy of LLO even in the absence of a direct toxin-cholesterol interaction. Furthermore, we find the membrane-binding and pore-forming abilities of LLOT515G-L516G, but not those of LLO, correlate with the cholesterol-dependent rigidity/ordering of the membrane lipid bilayer. Our data further suggest that the line tension derived from the lipid phase heterogeneity of the cholesterol-containing membranes could play a pivotal role in LLO function, particularly in the absence of cholesterol binding. Therefore, in addition to its receptor-like role, we conclude cholesterol can further facilitate the pore-forming, membrane-damaging functionality of LLO by asserting the optimal physicochemical environment in membranes. To the best of our knowledge, this aspect of the cholesterol-mediated regulation of the CDC mode of action has not been appreciated thus far.

Molecular and functional landscape of malignant serous effusions for precision oncology

Personalized treatment for patients with advanced solid tumors critically depends on the deep characterization of tumor cells from patient biopsies. Here, we comprehensively characterize a pan-cancer cohort of 150 malignant serous effusion (MSE) samples at the cellular, molecular, and functional level. We find that MSE-derived cancer cells retain the genomic and transcriptomic profiles of their corresponding primary tumors, validating their use as a patient-relevant model system for solid tumor biology. Integrative analyses reveal that baseline gene expression patterns relate to global ex vivo drug sensitivity, while high-throughput drug-induced transcriptional changes in MSE samples are indicative of drug mode of action and acquired treatment resistance. A case study exemplifies the added value of multi-modal MSE profiling for patients who lack genetically stratified treatment options. In summary, our study provides a functional multi-omics view on a pan-cancer solid tumor cohort and underlines the feasibility and utility of MSE-based precision oncology.

Heterocyclic phytometabolites formononetin and arbutin prevent in vitro oxidative and alkylation-induced mutagenicity

Phenolic phytometabolites are promising bioactive compounds for management of genomic instability related diseases. Formononetin (FMN) and arbutin (ARB) are found in several plant sources. Our goal was to investigate the safety and efficacy of FMN and ARB using in vitro both standardized and alternative toxicogenetic methods. FMN and ARB were evaluated through the OECD’S guidelines No. 471 (Bacterial Reverse Mutation Test –Salmonella/microsome) and No. 487 (In vitro Mammalian Micronucleus Test – CBMN assay), accordingly to the mentioned recommendations. Also, antimutagenicity of FMN and ARB was assessed in S. Typhimurium strains TA98, TA100 and TA1535, following pre-, co- and post- treatment protocols. Liver human lineages HepG2 and F C3H were assayed for cytotoxicity after exposure to FMN and ARB (24, 48 and 72 h) using in vitro WST-1 test. ARB showed no mutagenicity in the Salmonella/microsome test under both metabolic conditions (in presence or absence of 4 % S9 mix), but FMN was cytotoxic to the TA97 and TA100 strains after metabolic activation. Under this same condition, FMN induced an increase in the mutagenic index of strain TA1535 at two of the highest tested concentrations. Even so, ARB and FMN exhibited protection against the induced alkylation of DNA in multiple action modes. In the antimutagenicity assay, FMN reached the maximum of 80 % of oxidative-provoked mutagenicity reduction in TA98 strain in co-treatment with known mutagen, besides 69 % of reduction in TA100 in the same exposure condition. ARB showed up to reduce induced mutagenicity in strains TA100 and TA1535, reaching percentages from 55 % to 100 % of antimutagenicity in all of the tested exposure models against alkylating agent. In the CBMN assay, no increase in micronuclei formation was observed. The results suggest that FMN and ARB prevent DNA from mutation using multi-targeted antimutagenic roles. Finally, our data suggests that FMN and ARB are not genotoxic and presented encouraging antimutagenicity action in vitro, being promising compounds for use in genomic instability-related diseases therapeutics.

Degradation of Natural Undaria pinnatifida into Unsaturated Guluronic Acid Oligosaccharides by a Single Alginate Lyase.

Here, we report on a bifunctional alginate lyase (Vnalg7) expressed in Pichia pastoris, which can degrade natural Undaria pinnatifida into unsaturated guluronic acid di- and trisaccharide without pretreatment. The enzyme activity of Vnalg7 (3620.00 U/mL-culture) was 15.81-fold higher than that of the original alg (228.90 U/mL-culture), following engineering modification. The degradation rate reached 52.75%, and reducing sugar reached 30.30 mg/mL after combining Vnalg7 (200.00 U/mL-culture) and 14% (w/v) U. pinnatifida for 6 h. Analysis of the action mode indicated that Vnalg7 could degrade many substrates to produce a variety of unsaturated alginate oligosaccharides (AOSs), and the minimal substrate was tetrasaccharide. Site-directed mutagenesis showed that Glu238, Glu241, Glu312, Arg236, His307, Lys414, and Tyr418 are essential catalytic sites, while Glu334, Glu344, and Asp311 play auxiliary roles. Mechanism analysis revealed the enzymatic degradation pattern of Vnalg7, which mainly recognizes and attacks the third glycosidic linkage from the reducing end of oligosaccharide substrate. Our findings provide a novel alginate lyase tool and a sustainable and commercial production strategy for value-added biomolecules using seaweeds.

Positive impact of early-probiotic administration on performance parameters, intestinal health and microbiota populations in broiler chickens

Minimizing the utilization of antibiotics in animal production is crucial to prevent the emergence of antimicrobial resistances. Thus, research on alternatives is needed to maintain productivity, sustainability, and animal health. To gain a comprehensive understanding of probiotics' modes of action on performance, intestinal microbiota, and gut health in poultry, 3 probiotic strains (Enterococcus faecalis CV1028 [EntF], Bacteroides fragilis GP1764 [BacF], and Ligilactobacillus salivarius CTC2197 [LacS]) were tested in 2 in vivo trials. Trial 1 comprised of a negative control group fed basal diet (BD) and 3 treatment groups that received BD with EntF, BacF and LacS. Trial 2 included a negative control group, a positive control group with Zinc-Bacitracin as antibiotic growth promoter (AGP), and 2 groups treated with a blend of probiotics (EntF+BacF+LacS) during 0 to 10 or 0 to 35 d, respectively. Wheat-soybean-rye based diets without exogenous enzymes were used as a challenge model to induce intestinal mild- or moderate-inflammatory process in the gut. In Trial 1, individually administered probiotics improved FCR at 8 d compared to Control, but these positive effects were lost in the following growing periods probably due to the high grade of challenging diet and a too low dose of probiotics. In Trial 2, both Probiotic treatments, administered only 10 or 35 d, significantly improved FCR to the same extent as of the Antibiotic group at the end of the trial. Although the performance between antibiotic and probiotic mixture showed similar values, microbiota analysis revealed different microbial composition at 7 d, but not at 21 d. This suggests that modes of action of the AGP and the tested probiotic blend differ on their effects on microbiome, and that the changes observed during the first days' posthatch are relevant on performance at the end of the study. Therefore, the probiotics administration only during the first 10 d posthatch was proven sufficient to induce similar performance improvements to those observed in birds fed antibiotic growth promoters throughout the whole experimental trial.

The mode of toxic action of ionic liquids: Narrowing down possibilities using high-throughput, in vitro cell-based bioassays

Growing concerns about the environmental impact of ionic liquids (ILs) have spurred research into their (eco)toxic effects, but studies on their mode of toxic action (MOA) still remain limited. However, understanding the MOA and identifying structural features responsible for enhanced toxicity is crucial for characterising the hazard and designing safer alternatives. Therefore, 45 ILs, with systematically varied chemical structures, were tested for cytotoxicity and two specific endpoints in reporter gene assays targeting the Nrf2-ARE mediated oxidative stress response (AREc32) and aryl hydrocarbon receptor activation (AhR-CALUX). While none of the ILs activated the reporter genes, cytotoxicity was high and markedly different between cell lines. Seven and 25 ILs proved more cytotoxic than predicted by baseline toxicity model in the AREc32 and the AhR-CALUX assays, respectively. The length of the side chain and headgroup structures of ILs altered the MOA of ILs. Cellular metabolism of the ILs, investigated by LC-MS/MS, showed side-chain oxidation of the long-chain quaternary ammonium compounds in AhR-CALUX cells and, to a lower extent, in AREc32 cells, however, this transformation could not explain the high cytotoxicity. Effect data for 72 ILs for ten endpoints retrieved from the Tox21 database identified the inhibition of aromatase activity and of mitochondrial membrane potential as potential MOAs. However, in vitro fluorimetric assays for these endpoints demonstrated that effects were activated in a non-specific manner, probably through cytotoxicity. Although many of the ILs tested induced cytotoxicity at concentrations lower than baseline toxicity, the specific MOAs responsible could not be identified. Alternatively, we suggest that the descriptors currently used may fail to define the affinity of ILs for cells. Testing of the affinity of ILs for a diverse range of biomolecules is needed to accurately describe their interactions with cells.

A green approach coupled with molecular dynamics simulations and toxicity assays to infer the mode of action for organophosphate esters

Organophosphate esters (OPEs) have attracted extensive attention due to their toxic effects on human health and biological systems as plasticizers and flame retardants. This study focused on exploring a green approach to get toxicity mechanisms that used less solvents or organisms. The toxicity values of selected organophosphate esters including tri (2-chloroethyl) phosphate (TCEP), tri (1, 3-dichloro-2-propyl) phosphate (TDCP), tripropyl phosphate (TPrP), tri-n-butyl phosphate (TnBP), and tritolyl Phosphate (TCrP) to Photobacterium phosphoreum were determined. Their EC50 range was between 7.27 × 10−8–5.12 × 10−6 mol/L. Based on molecular dynamics simulation the data of binding affinity between OPEs and n-octanol / phospholipid bilayer were calculated respectively. Coupling with binding affinity energies and toxicity values, the mode of action (MOA) of OPEs including types of reactive or anesthetic mechanism could be fast deduced. The proposed hypothesis of n-octanol (C8H18O) as a virtual biofilm to replace phospholipid bilayer was verified. The alternative green approach could simplify toxicity assay and realize fast predicting MOA for different chemicals and model organisms.

Investigation of Antimicrobial Compounds Produced by Endolichenic Fungi in Different Culture Media.

Continuous use of synthetic fungicides has led to explosive emergence of fungicide-resistant microbes. Therefore, there are urgent needs for environmentally friendly antimicrobial agents with novel modes of action. This study investigated endolichenic fungi (ELF) as a source of antimicrobial compounds against various plant pathogens. We utilized an One Strain MAny Compounds (OSMAC) approach to enhance the chemical diversity of fourteen ELF. This involved cultivation of ELF in four growth media and subsequently assessing antimicrobial activities of culture extracts. Nearly half of the culture extracts exhibited antimicrobial activity against a Gram-positive bacterium, but showed minimal activity against Gram-negative bacteria tested. Notably, culture extracts from two ELF, Chaetomium globosum and Nodulisporium sp., demonstrated significant inhibitory effects against plant pathogenic fungi. LC-MS/MS-based metabolome profiling confirmed the presence of known bioactive compounds like cyclic dipeptides and chaetoglobosins. These findings highlight the effectiveness of combining OSMAC and metabolomics for identifying antimicrobial agents for agricultural use.

Structural characterization and bioactivity profiling of the fungal peptaibiotic tolypin reveal protective effects against influenza viruses.

In a bioprospection for new antivirals, we tested nonribosomally biosynthesized polypeptide antibiotics in MDCK II cells for their actions on influenza A and B viruses (IAV/IBV). Only tolypin, a mixture of closely related 16-residue peptaibiotics from the fungus Tolypocladium inflatum IE 1897, showed promising activity. It was selected for further investigation and structural characterization byultrahigh performance liquid chromatography coupled to high-resolution mass spectrometry (UHPLC-HR-MS/MS) and ultrahigh performance liquid chromatography coupled to in-source collision-induced dissociation tandem mass spectrometry (UHPLC-isCID-HR-MS/MS), revealing 12 partially co-eluting individual peptides that were fully sequenced. Since tolypin-related efrapeptins are potent inhibitors of F1/Fo-ATPase, we screened tolypin for its toxicity against MDCK II cells and larvae of the greater wax moth Galleria mellonella. We found that a nontoxic concentration of tolypin (1 µg/mL) reduced the titer of two IBV strains by 4-5 log values, and that of an H3N2 strain by 1-2 log values, but the H1N1pdm strain was not affected. The higher concentrations of tolypin were cytostatic to MDCK II cells, shifted their metabolism from oxidative phosphorylation to glycolysis, and induced paralysis in G. mellonella, supporting the inhibition of F1/Fo-ATPase as the mode of action. Our results lay the foundations for future work to investigate the interplay between viral replication and cellular energy metabolism, as well as the development of drugs that target host factors.

Nonylphenol Toxicity: Exposure, Mode of Action, Toxic Effects

Nonylphenol Toxicity: Exposure, Mode of Action, Toxic Effects

Enhanced Antibacterial and Anti‐Biofilm Functions of Black Bean Skin Anthocyanins Against V. parahaemolyticus

ABSTRACTBlack bean skin anthocyanins (BBSAs), as by‐products of black beans, have not been fully exploited. BBSAs are rich in anthocyanins and have a wide range of health benefits. In this study, the antibacterial and antibiofilm action mode of BBSAs against Vibrio parahaemolyticus (V. parahaemolyticus) was evaluated. The antibacterial and antibiofilm efficiency was evaluated under different conditions, shedding light on their mode of action against V. parahaemolyticus. The results showed that the inactivation efficacy of BBSAs on V. parahaemolyticus was positively correlated with its concentration and incubating time. The MIC value for BBSAs was determined to be 10 μg/mL. The formation of V. parahaemolyticus biofilm was hindered by the presence of the BBSAs, especially at higher concentrations of BBSAs and during the early intervention stage. After exposure to 1 MIC of BBSA, the inhibition rate of biofilm reached 91.94%. The release of cellular components and alterations in membrane morphology indicated that BBSAs can damage the integrity of V. parahaemolyticus cell membrane. Furthermore, BBSAs may interact with membrane proteins, causing a notable conformational change in membrane proteins. HPLC and UPLC‐MS analysis confirmed that the major antibacterial compound in BBSAs was Cyanidin‐3‐O‐glucoside (C3G), which can form a stable complex with LolB protein in the outer membrane via hydrogen bonding. This study can provide strong technical support for the accurate control of V. parahaemolyticus and pave the way for the application of natural antibacterial agents in the realm of food‐borne bacterial control.

Biologic and targeted synthetic disease-modifying anti-rheumatic drugs improve body composition in rheumatoid arthritis patients more than conventional synthetic disease-modifying anti-rheumatic drugs: Results from the PRESENT study.

The effects of biologic and targeted synthetic disease-modifying anti-rheumatic drugs (b/tsDMARDs) and conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) on body composition and muscle function in rheumatoid arthritis (RA) patients requiring treatment enhancement were compared. This multicenter, prospective, observational study (PRESENT Study) divided RA patients non-randomly into a csDMARD group (n = 100) and a b/tsDMARD group (n = 100). Changes in body composition and muscle function were examined in 80 patients in each group followed for 52 weeks. The percentages of new-onset and improved sarcopenia over 1 year were investigated. Patients in the b/tsDMARD group were divided into three groups by drug type: TNF inhibitors (n = 30), non-TNF inhibitors (n = 23), and JAK inhibitors (n = 27). Baseline median age and disease duration were 70.0 and 4.0 years, respectively. Changes in weight (24 and 52 weeks) and muscle mass (52 weeks) were significantly higher in the b/tsDMARD group (p = .035, p < .001, and p = .002, respectively). On multivariate logistic regression analysis, b/tsDMARD treatment (OR 3.21, p = .002), DAS28-ESR (OR 0.65 p = .011), and muscle mass (OR 0.90, p = .023) were independently associated with increased muscle mass at 52 weeks. The percentages of new-onset and improved sarcopenia were almost equal. There were no significant differences in the time-dependent changes (52 weeks) of clinical status, body composition, muscle function, and status of sarcopenia among TNF inhibitors, non-TNF inhibitors, and JAK inhibitors. Weight and muscle mass increased significantly more with b/tsDMARD than with csDMARD treatment. There were no differences in body composition changes by mode of action with b/tsDMARDs.

Current scenario of pyrazole hybrids with anti-breast cancer therapeutic applications.

Breast cancer stands as the leading cause of cancer-related deaths among women globally, but current therapy is restricted to the serious adverse effects and multidrug resistance, necessitating the exploration of novel, safe, and efficient anti-breast cancer chemotherapeutic agents. Pyrazoles exhibit excellent potential for utilization as effective anti-breast cancer agents due to their ability to act on various biological targets. Particularly, pyrazole hybrids demonstrated the advantage of targeting multiple pathways, and some of them, which are exemplified by larotrectinib (pyrazolo[1,5-a]pyrimidine hybrid), can be applied for breast cancer therapy. Thus, pyrazole hybrids hold great promise as useful therapeutic interventions for breast cancer. The aim of this review is to summarize the current scenario of pyrazole hybrids with in vitro and/or in vivo anti-breast cancer potential, along with the modes of action and structure-activity relationships, covering articles published from 2020 to the present, to streamline the development of rational, effective and safe anti-breast cancer candidates.

Coumarin-imidazopyridine hybrids and their first-in-class ZnII metal complexes as potent dual entry and replication inhibitors of Zika viral infection

In this study, we synthesized and characterized a series of coumarin-imidazopyridine hybrid ligands (HL1-HL4) and their corresponding Zn(II) complexes (C1-C4). The ligands were synthesized via a two-step process in 56–90 % yields. The resulting ligands, were utilized to form Zn(II) complexes, characterized by conductivity measurements, HRMS, IR, 1H NMR spectroscopy and X-ray diffractions. Biological evaluations revealed that these compounds exhibited potent antiviral activity against Zika virus (ZIKV), with EC50 values ranging from 0.55 to 4.8 µM and SI of up to 1490. Notably, the complexes (the first-in-class Zn(II) anti-ZIKV complexes) generally displayed enhanced activity compared to their respective ligands, with some compounds outperforming the reference antiviral, ribavirin. The Time of Addition assay suggested that while some compounds interfere with both viral entry (with a virucidal component) and replication phases, other only acted in replication phases. These results together with molecular modeling studies on ZIKV Envelope protein and ZIKV NS2B-NS3 offered insights for their mode of actions and further optimizations.

Pesticides and Heavy Metal Toxicity in Fish and Possible Remediation – A Review

Abstract Pesticides and heavy metals are considered as potent contaminants in aquatic environment. Both contaminants are sourced into the aquatic ecosystems by various types of anthropogenic as well as natural practices. Such types of aquatic contamination drastically affect the normal activity of associated living organisms particularly fish. Both the pesticides and heavy metals toxicity cause several negative effects on fish growth, physiology, immune response, reproduction, embryonic and larval development as well as different histopathology of major organs including fish gill, kidney, liver, gonads, and intestine. Besides, the consumption of contaminated fish poses a serious health concern to associated consumers. Considering these serious issues, the current review is designed to investigate the toxic effects of pesticides and heavy metals on different aspects of fishes along with their possible sources, major types, and mode of action as well as role of medicinal herbs to mitigate their toxicity.