Plausible Mechanism Of Action Research Articles

Beneficial effects of Saccharomyces cerevisiae fermentation postbiotic products on calf and cow health and plausible mechanisms of action

Supplementation of cattle diets with Saccharomyces cerevisiae fermentation products (SCFP) has been shown to improve health and performance of calves and cows in both the dairy and feedlot. Numerous studies have shown SCFP supplementation is beneficial in the context of production- and infection-related stressors, promoting resilience, accelerated resolution of inflammation or oxidative stress, and enabling the cow or calf to maintain homeostasis. SCFPs, derived from yeast fermentation, encompass a rich array of bioactive compounds, including vitamins, minerals, amino acids, and metabolites, which likely influence the host through both distinct and overlapping processes. Understanding the mechanisms by which SCFPs exert their beneficial effects is crucial for optimizing their utilization in cattle production systems. In this review, we focused not only on the beneficial effects of SCFPs on health and performance but also on their influence on host microbiota, epithelial barrier integrity, and the host immune system, providing mechanistic insights. Previous studies have suggested that SCFPs impact host metabolism, modulate rumen and hindgut microbial populations, exert antioxidant and immunomodulatory effects, and stimulate the expression of genes involved in maintaining tissue barrier integrity. However, there are still gaps in understanding certain mechanistic pathways, particularly those involving the nervous system, as well as the paradoxical effects of SCFPs in enhancing immune responses while simultaneously mitigating excessive inflammation. This review summarizes several recent reports describing the health benefits of SCFP supplementation in cattle and considers the available evidence on the mode of action.

Discovery of New 3-(Benzo[b]Thiophen-2-yl)Pyrrolidine-2,5-Dione Derivatives as Potent Antiseizure and Antinociceptive Agents-In Vitro and In Vivo Evaluation.

Background/Objectives: To address the unmet clinical needs in the treatment of epilepsy and pain, the continued development of more effective and safer anticonvulsants and analgesics is still necessary. Therefore, herein we report synthesis and antiseizure/antinociceptive evaluation of a focused series of 3-(benzo[b]thiophen-2-yl)pyrrolidine-2,5-dione derivatives. Methods: The anticonvulsant properties were investigated in acute models of seizures, namely the maximal electroshock (MES), the 6 Hz (32 mA), and subcutaneous pentylenetetrazole (scPTZ) seizure models, whereas analgesic activity was tested in the model of a tonic pain/formalin test and oxaliplatin-induced neuropathic pain (in CD-1-mice, i.p.). In addition, a number of in vitro assays were performed, aiming at the evaluation of the drug-like properties of the compounds disclosed herein. Results: We identified 33 as a lead compound with the most promising antiseizure properties, i.e., ED50 (MES) = 27.4 mg/kg and ED50 (6 Hz, 32 mA) = 30.8 mg/kg. Furthermore, 33 at a dose of 100 mg/kg significantly prolonged the latency time to the first seizure episode in the scPTZ model and at high doses did not impaire coordination of mice in the rotarod test (TD50 > 200 mg/kg). Apart from broad antiseizure protection, 33 demonstrated a significant analgesic effect in the formalin test (45 mg/kg, i.p.), and effectively alleviated allodynia in the oxaliplatin-induced neuropathic pain model (30 and 45 mg/kg). The binding assays suggest that the most plausible mechanism of action relies on interaction with the neuronal voltage-sensitive sodium channel (site 2). Furthermore, the drug-like potential of 33 supports favorable in vitro results, i.e., no hepatocytotoxicity and neurocytotoxicity at a high concentration of 100 μM, as well as a lack of mutagenicity at a concentration as high as 500 μM. Conclusions: Compound 33 identified in the current studies is proposed to be an interesting candidate for further preclinical development as therapy for epilepsy and neuropathic pain.

Development of Novel Alaninamide Derivatives with Anticonvulsant Activity and Favorable Safety Profiles in Animal Models.

In our current study, we developed a focused series of original ((benzyloxy)benzyl)propanamide derivatives that demonstrated potent activity across in vivo mouse seizure models, specifically, maximal electroshock (MES) and 6 Hz (32 mA) seizures. Among these derivatives, compound 5 emerged as a lead molecule, exhibiting robust protection following intraperitoneal (i.p.) injection, as follows: ED50 = 48.0 mg/kg in the MES test, ED50 = 45.2 mg/kg in the 6 Hz (32 mA) test, and ED50 = 201.3 mg/kg in the 6 Hz (44 mA) model. Additionally, compound 5 displayed low potential for inducing motor impairment in the rotarod test (TD50 > 300 mg/kg), indicating a potentially favorable therapeutic window. In vitro toxicity assays further supported its promising safety profile. We also attempted to identify a plausible mechanism of action of compound 5 by applying both binding and functional in vitro studies. Overall, the data obtained for this lead molecule justifies the more comprehensive preclinical development of compound 5 as a candidate for a potentially broad-spectrum and safe anticonvulsant.

Experimental Models in Unraveling the Biological Mechanisms of Mushroom-Derived Bioactives against Aging- and Lifestyle-Related Diseases: A Review.

Mushrooms have garnered considerable interest among researchers due to their immense nutritional and therapeutic properties. The presence of biologically active primary and secondary metabolites, which includes several micronutrients, including vitamins, essential minerals, and other dietary fibers, makes them an excellent functional food. Moreover, the dietary inclusion of mushrooms has been reported to reduce the incidence of aging- and lifestyle-related diseases, such as cancer, obesity, and stroke, as well as to provide overall health benefits by promoting immunomodulation, antioxidant activity, and enhancement of gut microbial flora. The multifunctional activities of several mushroom extracts have been evaluated by both in vitro and in vivo studies using cell lines along with invertebrate and vertebrate model systems to address human diseases and disorders at functional and molecular levels. Although each model has its own strengths as well as lacunas, various studies have generated a plethora of data regarding the regulating players that are modulated in order to provide various protective activities; hence, this review intends to compile and provide an overview of the plausible mechanism of action of mushroom-derived bioactives, which will be helpful in future medicinal explorations.

Marine-derived Anti-Tuberculosis compounds

Tuberculosis (TB), which is caused primarily by Mycobacterium tuberculosis, is the largest cause of death among all infectious diseases, accounting for more than two million fatalities each year. Marine natural products and some of their derivatives have been found to have potent antitubercular activity against Mycobacterium TB, and some of them have been chosen as prototype molecules for the development of novel anti-tubercular drugs. Because of their strong medicinal qualities, a variety of marine natural products such as terpenoids, alkaloids, pyrones, sterols, and quinones derived from marine sources have piqued interest in recent decades. In this review study, we present current discoveries on the anti-tubercular action of marine natural products, emphasizing their medicinal potential for the treatment of tuberculosis. Based on the research from the last decade, this review provides a full grasp of marine natural products as anti-tubercular agents, as well as a plausible mechanism of action.

Abstract CT287: LINNOVATE: A Phase 1/2 study of safety/efficacy using lurbinectedin, combined with ipilimumab, and nivolumab for advanced soft tissue sarcomas (NCT05876715)

Abstract Background: Sarcoma cells are most immunogenic earlier in the course of the disease. Therefore, immune checkpoint inhibitors such as ipilimumab (ipi) and nivolumab (nivo), that promote sustained T-cell activation by suppressing T regs would be most effective when given as first line therapy, together with a tumoricidal agent, such as lurbinectedin, whose plausible mechanism of action is not only to destroy the cancer cells and expose the tumor neoantigens for immune recognition, but also to destroy growth promoting factors in the tumor microenvironment. In the SAINT phase 2 study using ipi, nivo and trabectedin as first line therapy for advanced soft tissue sarcomas (STS; n=79), there were 6 complete responses, 14 partial responses, 49 stable disease, 25.3% best response rate, 87.3% disease control rate; median PFS, 6.7 months, median OS, 24.6 months (Gordon et al, Cancers vol. 15, 906, 2023). Lurbinectedin is a synthetic marine-derived agent and an analog of trabectedin. Therefore, we expect that lurbinectedin will be as effective as trabectedin when used together with ipi and nivo as first line therapy for advanced STS. Methods: Objective 1: Assess MTD of lurbinectedin. Objective 2: Evaluate PFS, OS, incidence and severity of adverse events; Correlative: Correlate response with ctDNA using Signatera. This is an open label, dose-seeking phase 1/2 study. The phase 1 part employs standard “cohort of three” design with a DLT window of 6 weeks. Treatment schedule: Ipi 1 mg/kg IV q 12 weeks; Nivo 3 mg/kg IV q 2 weeks; escalating doses of lurbinectedin from 2.6 mg/m2 to 3.2 mg/m2 IV q 3 weeks. Phase 2 part follows completion of phase 1 part wherein additional 28-34 participants will receive lurbinectedin at the MTD with fixed doses of Ipi and Nivo. Participants may continue treatment until significant disease progression or unacceptable toxicity occurs. Eligible patients are 18 years of age or older, previously treated in phase 1 and previously untreated in phase 2 with confirmed diagnosis of advanced STS, adequate hematologic and organ function, and no history of autoimmune disorder. To date, 6 patients in phase 1 have been dosed. Citation Format: Erlinda M. Gordon, Nadezhda Omelchenko, Samantha Jeffrey, Vaishali Kumar, Neal S. Chawla, Mahesh Seetharam, Victoria Chua, Ania Moradkhani, Doris Quon, Steven Wong, Sant Chawla. LINNOVATE: A Phase 1/2 study of safety/efficacy using lurbinectedin, combined with ipilimumab, and nivolumab for advanced soft tissue sarcomas (NCT05876715) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT287.

Nitroprusside and metal nitroprusside nano analogues for cancer therapy.

Sodium nitroprusside (SNP), U.S approved drug has been used in clinical emergency as a hypertensive drug for more than a decade. It is well established for its various biomedical applications such as angiogenesis, wound healing, neurological disorders including anti-microbial applications etc. Apart from that, SNP have been considered as excellent biomedical materials for its use as anti-cancer agent because of its behavior as NO-donor. Recent reports suggest that incorporation of metals in SNP/encapsulation of SNP in metal nanoparticles (metal nitroprusside analogues) shows better therapeutic anti-cancer activity. Although there are numerous reports available regarding the biological applications of SNP and metal-based SNP analogue nanoparticles, unfortunately there is not a single comprehensive review which highlights the anti-cancer activity of SNP and its derivative metal analogues in detail along with the future perspective. To this end, the present review article focuses the recent development of anti-cancer activity of SNP and metal-based SNP analogues, their plausible mechanism of action, current status. Furthermore, the future perspectives and challenges of these biomedical materials are also discussed. Overall, this review article represents a new perspective in the area of cancer nanomedicine that will attract a wider spectrum of scientific community.

19 Schiff bases as antimycobacterial agents: synthesis, molecular docking and a plausible mechanism of action.

Aim: To discover novel anti-Mycobacterium tuberculosis (Mtb) drugs, 19 compounds were synthesized; their anti-Mtb effects were evaluated and mechanisms of action were preliminarily explored. Materials & methods: The compounds were synthesized and their anti-Mtb activity was elucidated using resazurin microtiter assays. The plausible target of the potential compound was investigated by microimaging techniques, gas chromatography-mass spectrometry analysis and molecular docking. Results: 19compounds inhibited Mtb growth with minimum inhibitory concentrationsranging from 1 to 32μg/ml. Compounds 1-17 showed inhibition of Mtb KatG enzyme. Compound 19, the most potent, might be an inhibitor of Pks13 polyketide synthase. Conclusion: This study suggests that 2-((6-fluoropyridin-3-yl)methylene) hydrazine-1-carbothioamide (19) is a potential anti-Mtb lead compound with a novel mechanism of action.

Synthesis, antibiofilm activity and molecular docking of N-acylhomoserine lactones containing cinammic moieties

We prepared a series of cinnamoyl-containing furanones by an affordable and short synthesis. The nineteen compounds hold a variety of substituents including electron-donating, electron-withdrawing, bulky and meta-substituted phenyls, as well as heterocyclic rings. Compounds showed antibiofilm activity in S. aureus, K. pneumoniae and, more pronounced, against P. aeruginosa. The disruption of quorum sensing (QS) was tested using the violacein test and molecular docking predicted the antagonism of LasR as a plausible mechanism of action. The trimethoxylated and diene derivatives showed the best antibiofilm and anti-QS properties, thus becoming candidates for further modifications.

Evidence and possible mechanism of Scutellaria baicalensis and its bioactive compounds for hepatocellular carcinoma treatment

Background Traditional Chinese medicines have been reported to have outstanding effects in the treating of hepatocellular carcinoma. Scutellaria baicalensis (S. baicalensis) has demonstrated anti-tumor, anti-angiogenic, and anti-inflammatory properties. Baicalein, wogonin, and baicalin are the main pharmacologically bioactive compounds of S. baicalensis. Methods Eight electronic databases were searched to select articles published from their inception to 30 May 2022. For selected articles, clinical and preclinical data was obtained on the use of S. baicalensis and its bioactive compounds in hepatocellular carcinoma therapy. Statistical analyses were performed using RevMan version 5.3 and Stata software. Quality assessment of the studies was performed using Cochrane and Systematic Review Centre for Laboratory Animal Experimentation (SYRCLE)’s risk of bias tools. Results Seven clinical and 17 preclinical in vivo studies along with 31 in vitro studies were included in this research. Meta-analysis showed that a Chinese herbal medicine preparation, with S. baicalensis as the sovereign herb, combined with Transcatheter arterial chemoembolization (TACE) or primary treatment, could lead to a significantly improved tumor objective response rate (Risk ratio (RR) = 1.57, 95% confidence interval (CI): [1.30, 1.90], p < 0.00001). Scutellaria baicalensis-based extracts (standard mean difference (SMD) = –0.86, 95%CI: [–1.20, −0.53], p < 0.00001), baicalein (SMD = –4.80, 95%CI: [–6.66, − 2.95], p < 0.00001), baicalin (SMD = –2.28, 95%CI [–3.26, −1.30], p < 0.00001) and wogonin (SMD = –1.41, 95%CI [–2.26, −0.57], p < 0.00001) slowed tumor growth in vivo. These outcomes might be linked to the mechanism by which S. baicalensis promotes apoptosis, induces autophagy, and blocks the expression of vascular endothelial growth factor (p < 0.05). Conclusion Based on experimental and clinical evidence, we believe that S. baicalensis and its bioactive compounds have therapeutic potential and plausible mechanisms of action against hepatocellular carcinoma, in terms of efficacy and safety.

Converging thiolactone and quinoline scaffolds: New potential antitubercular conjugates

Tuberculosis infections pose a serious challenge, particularly because of the emergence of drug resistant mycobacterial strains, highlighting the need of development of new drugs. We report twenty-four new compounds that are designed and synthesized by converging thiolactone and quinoline scaffolds as potential antitubercular entities. Bacterial assay demonstrated one of the conjugates, 4f to be a highly potent molecule with minimum inhibitory concentration (MIC) value of 0.5 μg/mL, comparable to first line drugs. Remarkably, the conjugate 4f demonstrated similar potency against rifampicin and multidrug resistant mycobacterial strains while exhibiting little toxicity against normal cells. In vivo studies demonstrated the promising potential of the conjugate for further development. Finally, a molecular docking study was conducted on four different targets to elucidate the plausible mechanism of action.

Bioactive Pyrrolo[2,1-f][1,2,4]triazines: Synthesis, Molecular Docking, In Vitro Cytotoxicity Assay and Antiviral Studies

A series of 2,4-disubstituted pyrrolo[2,1-f][1,2,4]triazines containing both aryl and thienyl substituents were synthesized by exploiting the 1,3-cycloaddition reaction of N(1)-ethyl-1,2,4-triazinium tetrafluoroborates with dimethyl acetylenedicarboxylate. The antiviral activity of the synthesized compounds against influenza virus strain A/Puerto Rico/8/34 (H1N1) was studied in experiments on Madin-Darby canine kidney (MDCK) cell culture. Among the pyrrolo[2,1-f][1,2,4]triazine derivatives, compounds with low toxicity and high antiviral activity were identified. Dimethyl 4-(4-methoxyphenyl)-7-methyl-2-p-tolylpyrrolo[2,1-f][1,2,4]triazine-5,6-dicarboxylate was found to demonstrate the best antiviral activity (IC50 4 µg/mL and selectivity index 188). Based on the results of in vitro tests and molecular docking studies performed, a plausible mechanism of action for these compounds was suggested to involve inhibition of neuraminidase.

Exploration of antiproliferative potential of modified triazole-benzohydrazone scaffold: Multitarget approach.

A novel series of triazole-benzohydrazone hybrids was efficiently designed and synthesized as antiproliferative agents, targeting different kinases. All compounds were screened via the National Cancer Institute (NCI) against 60 cancer cell lines, where compounds 16, 17, and 18 exhibited growth inhibition percent(GI%)of various leukemia subpanels with values of 70.33%, 64.13%, and 76.03%, respectively. Compound 18 showed broad-spectrum antiproliferative efficacy towardmost cancer cells, with outstanding potency regarding melanoma (MALME-3M GI% = 101.82%) and breast cancer cell lines (MCF7 GI% = 85.87%), while proving safe towardthe WI-38 normal cell line, compared to doxorubicin. Multikinase investigation including vascular endothelial growth factor receptor 2 (VEGFR-2), mesenchymal epithelial transition factor (c-Met), proto-oncogene B-Raf, mitogen-activated protein kinase kinase, extracellular signal-regulated kinase, and phosphoinositide 3-kinase was accomplished to reveal its plausible mechanism of action, giving the ultimate potency against both VEGFR-2 and c-Met with IC50 values of 0.055and 0.042 μM, respectively, while displaying moderate to good inhibition concerning the remaining kinases. DNA binding capability was excluded using the methyl green colorimetric assay. Further, it exhibited both early and late apoptotic induction by about 16- and 9.4-fold over the control, respectively, triggering cell cycle arrest in the G2/M phase. Physicochemical properties and bioavailability radar plot inferred drug-likeness characteristics for compound 18. The molecular docking study assessed the binding pattern with the active sites of c-Met and VEGFR-2.

Updated Perspectives on the Diagnosis and Management of Familial Adenomatous Polyposis.

Familial adenomatous polyposis (FAP) is an autosomal dominant cancer predisposition syndrome marked by extensive colorectal polyposis and a high risk of colorectal cancer (CRC). Having access to screening and enrollment programs can improve survival for patients with FAP by enabling them to undergo surgery before the development of colorectal cancer. Provided that there are a variety of surgical options available to treat colorectal polyps in patients with adenomatous polyposis, the appropriate surgical option for each patient should be considered. The gold-standard treatment to reduce this risk is prophylactic colectomy, typically by the age of 40. However, colectomy is linked to morbidity and constitutes an ineffective way at preventing extra-colonic disease manifestations, such as desmoid disease, thyroid malignancy, duodenal polyposis, and cancer. Moreover, extensive studies have been conducted into the use of chemopreventive agents to prevent disease progression and delay the necessity for a colectomy as well as the onset of extracolonic disease. The ideal chemoprevention agent should demonstrate a biologically plausible mechanism of action and provide safety, easy tolerance over an extended period of time and a lasting and clinically meaningful effect. Although many pharmaceutical and non-pharmaceutical products have been tested through the years, there has not yet been a chemoprevention agent that meets these criteria. Thus, it is necessary to develop new FAP agents that target novel pathways, such as the mTOR pathway. The aim of this article is to review the prior literature on FAP in order to concentrate the current and future perspectives of diagnosis and treatment. In conclusion, we will provide an update on the diagnostic and therapeutic options, surgical or pharmaceutical, while focusing on the potential treatment strategies that could further reduce the risk of CRC.

MicroRNA sequencing for biomarker detection in the diagnosis, classification and prognosis of Diffuse Large B Cell Lymphoma

Despite being considered a single disease, Diffuse Large B Cell Lymphoma (DLBCL) presents with variable backgrounds, which results in heterogeneous outcomes among patients, with 40% of them still having primary refractory disease or relapse. Thus, novel biomarkers are needed. In addition, multiple factors regarding its pathogenesis remain unclear. In this context, recent investigations point to the relevance of microRNAs (miRNAs) in cancer. However, regarding DLBCL, there is inconsistency in the data reported. Therefore, in this work, the main goals were to determine a miRNA set with utility as biomarkers for DLBCL diagnosis, classification, prognosis and treatment response, as well as to decipher the mechanism of action of deregulated miRNAs in the origin of the disease. We analyzed miRNA expression in a cohort of 78 DLBCL patients and 17 controls using small RNA sequencing and performed a miRNA-mRNA interaction network analysis. This way, we were able to define new miRNA expression signatures for diagnosis, classification, treatment response and prognosis, and we identified plausible mechanisms of action by which deregulated miRNAs could be involved in DLBCL pathogenesis. In summary, our study remarks that miRNAs could play an important role in DLBCL.

Antimalarial Drugs Induce the Selective Folding of Human Telomeric G-Quadruplex in a Cancer-Mimicking Microenvironment.

Regulating the equilibrium between the duplex form of DNA and G-quadruplex (Gq) and stabilizing the folded Gq are the critical factors for any drug to be effective in cancer therapy due to the direct involvement of Gq in controlling the transcription process. Antimalarial drugs are in the trial stage for different types of cancer diseases; however, the plausible mechanism of action of these drug molecules is not well known. Hence, we investigate the plausible role of antimalarial drugs in the folding and stabilization of Gq-forming DNA sequences from the telomere and promoter gene regions by varying the salt (KCl) concentrations, mimicking the in vitro cancerous and normal cell microenvironments. The study reveals that antimalarial drugs fold and stabilize specifically to telomere Gq-forming sequences in the cancerous microenvironment than the DNA sequences located in the promoter region of the gene. Antimalarial drugs are not only able to fold Gq but also efficiently protect them from unfolding by their complementary strands, hence significantly biasing the equilibrium toward the Gq formation from the duplex. In contrast, in a normal cell microenvironment, K+ controls the folding of telomeres, and the role of antimalarial drugs is not prominent. This study suggests that the action of antimalarial drugs is sensitive to the cancer microenvironment as well as selective to the Gq-forming region.

Novel pyrimidine – Imines against tuberculosis: Rationale, in vitro, in silico studies and mechanistic insights

Two series of novel multifunctional pyrimidine–imine hybrids were synthesized and evaluated for their antitubercular and antimicrobial properties. A novel synthetic methodology utilizing water as a green solvent and a catalytic amount of HCl resulted in the isolation of barbituric acid – uracil – imine hybrids in moderate to good yields. The in vitro antitubercular activity of the compounds revealed exceptional activity, with D16 showing MIC100 at 6 µM, which is comparable to the commercial drug ethambutol with MIC100 at 7.63 µM. Compounds D7, D12, D18, D19, and D20 also showed MIC100 at concentrations ranging from 10.60 µM to 50.86 µM. The compounds were also noncytotoxic in the mouse macrophage cell line (RAW 264.7) at 25 µg/ml concentration. Molecular docking studies were carried out against M.tb thymidylate kinase to gain insights into the binding modes of the compounds and understand the plausible mechanism of action. The compound D16 outperformed all compounds with a MIC100 of 6 µM, attributed to its strong binding affinity with thymidylate kinase valued at -9.1 kcal/mol. Compounds also showed promising activity against pathogenic bacterial and fungal strains, with the M series being more active. Even though the compounds showed broad-spectrum antibacterial activity against Gram-positive and Gram-negative bacteria, the inhibitory effect on the growth of Gram-positive bacteria was more significant. This may be due to the structural difference in the cell wall composition of both bacteria. Compound M9 displayed moderate to good activity against bacteria and various species of Candida. This is the first-ever report on the synthesis and biological evaluation of uracil–imine hybrids as antitubercular and antimicrobial agents.

A mononuclear N,N,N,O donor schiff base Cu(II) complex inhibits bacterial biofilm formation and promotes apoptosis and cell cycle arrest in prostate cancer cells

In this work, we report a distorted square pyramidal mononuclear copper(II) complex [Cu(L)(NCS)] (1) which was obtained by the reaction of the aqueous solution of ammonium thiocyanate to a methanolic solution of copper nitrate trihydrate and corresponding Schiff-base ligands. Schiff bases, HL (C12H19N3O) act as a tetradentate Schiff base, derived from 1:1 condensation of o-hydroxyacetophenone and diethylenetriamine. The synthesized complex has been successfully characterized based on elemental analysis and Infrared (IR) spectroscopy. The structure of complex 1 was confirmed by single-crystal X-ray diffraction study. In our study, we investigated synthesis, structural characterization, antimicrobial, anti-biofilm, and anti-cancer activity, and plausible mechanism of action of a novel mononuclear copper(II) schiff base complex. Increasing microbial resistance to several commercially available or traditional antimicrobial compounds has become a major global health concern at present time. The mononuclear copper(II) complex exhibited potential antibacterial activity against two strains of the gram-negative pathogen Pseudomonas aeruginosa. The copper compound dependent damage of bacterial cell membrane and inhibition of bacterial biofilm formation were also identified. Moreover, complex 1 inhibited prostate cancer cell growth, and migration by inducing apoptosis and arresting the cell cycle at the G2/M phase. Based on the results, we are suggesting our novel mononuclear copper(II) compound as a potential candidate for the development of new antibacterial and anti-cancer drugs.

4-Thiazolidinone Based 5-Arylidene Hybrids: Design, Synthesis, Antimicrobial Activity, and Molecular Docking Studies

In recent years, the most pressing challenge in drug development has been the fight against bacterial drug resistance. Microbes have developed resistance against the present classes of antibiotics, necessitating the development of new antibiotics capable of replacing less effective drugs commercially accessible in the market. In order to achieve this, a straightforward technique for the synthesis of 4-thiazolidinone-based pyrazole-pyridine hybrids was designed (5a–o). The hybrids were characterized using spectroscopic techniques and tested for antimicrobial efficacy against a variety of bacterial and fungal species. The MIC value of compounds 5d, 5f, 5j, 5 l, 5 m, and 5o against tested bacterial strains was 62.5 μg/mL. Compound 5i showed a MIC value of 250 μg/mL against Candida albicans, which is twice the activity of the standard drug. Furthermore, to rationalize the antimicrobial finding and to gain an insight into the plausible mechanism of action, molecular docking study was performed against microbial DNA gyrase. A very significant correlation obtained between the in silico binding affinity and the antimicrobial activity could set an excellent platform for structure based drug design.

Long noncoding RNA00324 is involved in the inflammation of rheumatoid arthritis by targeting miR-10a-5p via the NF-κB pathway.

Altered expressions of genes in immune cells and synovial tissues are involved in the pathology of rheumatoid arthritis (RA). Long noncoding RNAs act as competing endogenous RNAs and can cause immune disorders. The goal of this study was to reveal the association between noncoding RNA linc00324 and RA, and a plausible action mechanism was proposed. RT-qPCR was used to evaluate the expression of linc00324 in peripheral blood mononuclear cellsisolated from 50 RA patients and 50 healthy controls, and the correlations between linc00324 level and the clinical indicators were analyzed. Flow cytometry was used to characterize CD4+ T cells. The effects of linc00324 on cytokine production and cell proliferation of CD4+ T cells were evaluated by ELISA assay and Western blot. The interaction between linc00324 and miR-10a-5p was investigated by RNA immunoprecipitationand dual-luciferase assays. The linc00324 expression was significantly enhanced in RA patients, and linc00324 expression was positively correlated with rheumatoid factor and CD4+ T cells. Overexpression of linc00324 promoted CD4+ T cells proliferation, and enhanced chemokine MIP-1α secretion and NF-κB phosphorylation level, whereas knockout of linc00324 blocked CD4+ T cell proliferation and NF-κB phosphorylation. Overexpression of miR-10a-5p led to the decrease of CD4+ T cells proliferation and NF-κB phosphorylation, and reversed the effects of linc00324 on cell proliferation and NF-κB activity. Linc00324 was upregulated in RA and may exaggerate inflammation by targeting miR-10a-5p through NF-κB signaling pathway.