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A pivotal pathway of photodynamic therapy (PDT) is to prompt mitochondrial damage by reactive oxygen species (ROS) generation, thus leading to cancer cell apoptosis. However, mitochondrial autophagy is induced during such a PDT process, which is a protective mechanism for cancer cell homeostasis, resulting in undermined therapeutic efficacy. Herein, we report a series of meticulously designed donor (D)-π-acceptor (A) photosensitizers (PSs), characterized by the strategic modulation of thiophene π-bridges, which exhibit unparalleled mitochondrial targeting proficiency. Notably, TTBI within this series possesses remarkable ROS generation capability, which can directly trigger mitochondrial depolarization, thus effectively inducing apoptosis in cancer cells. Meanwhile, the damaged mitochondria activate the mitophagy process, which further boosts the ROS generation of the TTBI owing to the acidic environment in the lysosome, ultimately inducing lysosomal membrane permeability (LMP), thereby blocking the protective autophagy route and promoting extra apoptotic cell death. Accordingly, TTBI disrupts the integrity of mitochondrial and lysosome, leveraging a synergistic interplay between cellular compartments to achieve more potent apoptosis. This work provides new insights to overcome the limitation of PDT efficacy imposed by mitochondrial autophagy., Competing Interests: Declaration of competing interest The authors declare that they have no financial and personal relationships with other people or organizations that can inappropriately influence our work, there is no professional or other personal interest of any nature or kind in any product, company., (Copyright © 2025. Published by Elsevier B.V.)

Alzheimer's disease (AD) is primarily caused by oxidative stress, hyperphosphorylated τ-protein aggregation, and amyloid-β deposition. Changes in dopaminergic and serotoninergic neurotransmitter pathways are linked to certain symptoms of AD. Derivatives of bicyclic and tricyclic cyclohepta[b]thiophene were developed to identify new potential candidates as acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitors for the treatment of AD. All synthesized compounds exhibited AChE inhibition with IC 50 values below 15 μM, while all compounds exhibited BChE inhibition with IC 50 values below 25 μM. Compounds 9 and 12 exhibited AChE inhibitory activities with IC 50 values of 0.51 μM and 0.55 μM, respectively. Compounds 5 and 9 demonstrated excellent inhibitory activity against BChE with IC 50 values of 2.9 μM and 2.48 μM, respectively. Compounds 9, 13, and 14 were found to be the most active in terms of the decrease in the escape latency time, with values comparable to that of Donepezil. Compounds 10, 11, and 12 exhibited promising effects on learning and memory. Compounds 5, 10, 11, and 12 exhibited promising SAP values of 70.67 %, 71.5 %, 74.33 % and 73.83 %, respectively. Other biomarkers were evaluated in rat brains including TAC, MDA, SOD, BDNF, IL-β and TNF-α. Fundamental features of ADMET have been computed in-silico for synthesized compounds. Molecular docking was performed to confirm the binding of the novel compounds to the targets., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Ischemic stroke leads to disability and death worldwide and evidence suggests that stroke severity is affected by the time dimension of the stroke. Rev-Erbα regulates the core circadian clock through repression of the positive clock element Bmal1. However, it remains unclear if a Rev-Erbα agonist (SR9009) alleviates stroke pathology in mice. We found that stroke reduces the level of Rev-Erbα and elevates neuroinflammation and stroke severity at zeitgeber time (ZT) ZT06. Therefore, we hypothesized that SR9009 treatment may reduce neuroinflammation and stroke severity in a mouse suture occlusion model. At 12 to 14 weeks, C57BL/6 J (Wild Type, n = 5-10 mice/group) mice were randomly assigned to undergo MCAO stroke for 60 min at either zeitgeber time ZT06 (MCAO-ZT06-sleep phase) or ZT18 (MCAO-ZT18-awake phase). Stroked mice were treated with SR9009 (100 mg/kg) or vehicle at 1 h and 24 h after MCAO. After forty-eight hours of stroke, TTC staining, Western blot, and qRT-PCR were performed. We found that SR9009 treatment alleviates neuroinflammation and infarct volume by Rev-Erb remodeling in ZT06 stroke mice but not in ZT18 stroke mice. Additionally, monocytic and neutrophilic NLRP3 as well as brain NLRP3 levels were reduced by SR9009 treatment in ZT06 stroke though no effects were observed at ZT18 stroke. SR9009 also reduced TNFα expression and increased IL-10 expression in blood and brain in ZT06 stroke mice and no differences were observed at ZT18. There were no significant effects of SR9009 on neurological deficit score and sensorimotor function at ZT06 or ZT18 at 48 h. Our study demonstrates that SR9009 treatment reduces stroke volume, circulating immune response, circadian expression, and that the protection was circadian- and treatment time-dependent., Competing Interests: Declaration of competing interest All authors in this manuscript declare that they have no known competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The escalating prevalence of antibiotic-resistant bacteria has led to a serious global public health problem; therefore, there is an urgent need for the development of structurally innovative antibacterial agents. In our study, different series of tetra-substituted thiophene derivatives were designed and synthesized by multi-component reactions (MCRs) in moderate to excellent yields. Some of the designed final compounds were synthesized by both microwave assisted method and traditional synthesis. Thirteen compounds were evaluated against antibiotic resistance bacteria ESKAPE, among which compounds 11, 13 and 17 showed the most potent inhibitory activities against multidrug-resistant Enterococcus faecalis with MIC (minimum inhibitory concentration) values as low as 15.62, 7.61 and 15.62 µg/mL, respectively. Two potent candidates 11 and 13 not only showed rapid bactericidal properties and impeded E. faecalis biofilm formation to effectually relieve the development of drug resistance, but also performed low toxicity toward human normal cells. Moreover, time dependent killing assay was performed that showed the reduction of the concentration of bacteria by 5.0 Log (CFU/mL) within 6 h, stronger than reference drug, ampicillin at the same concentration. Additionally, mechanistic investigation demonstrated that both compounds 11 and 13 could exert inhibitory activity against DHPS with IC 50 value of 1.73 and 4.67 µM, respectively and against DNA gyrase enzyme with IC 50 value of 0.07 and 0.04 µM, respectively. Moreover, the cytotoxic activity of the most active compound was crucial to be determined that showed IC 50 value of 75.42 µM. Molecular docking indicated that the binding of both compounds 11 and 13 to DHPS and DNA gyrase enzymes could hinder their function. These results can provide novel structures of antibacterial drugs chemically different from currently known antibiotics and broaden prospects for the development of effective antibiotics against antibiotic-resistant bacteria., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Circadian rhythm disruption is thought to be associated with periodontitis, and molecular clock genes play critical roles in regulating bone homeostasis. However, the specific contribution of molecular clock genes to alveolar bone resorption caused by periodontitis is poorly understood. In this study, we introduced a novel Periodontitis Circadian Rhythm Score (PeriCRS) model that was established through machine learning using periodontal transcriptomic data from periodontitis clinical cohorts in the Gene Expression Omnibus (GEO) database. This approach revealed the potential regulatory role of circadian rhythm disruption in periodontitis and identified key molecular clock genes associated with alveolar bone destruction. Moreover, we established an experimental periodontitis model with circadian rhythm disturbance via periodontal ligation in mice exposed to a 6-h advanced LD12:12 cycle every 2 d. Our bioinformatics analysis revealed that NR1D1 , which encodes REV-ERBα, is a pivotal factor in the impact of circadian rhythm disruption on periodontitis in periodontal tissues. Next, we confirmed the abnormal expression of the molecular clock gene Rev-erbα in inflammatory periodontal tissue in mice and confirmed that circadian rhythm disruption altered REV-ERBα expression. Furthermore, the activation of REV-ERBα with the agonist SR9009 notably decreased RANKL-induced osteoclast differentiation and suppressed the expression of osteoclast-related factors. Subsequent in vivo experiments demonstrated that SR9009 mitigated alveolar bone loss caused by periodontitis. Mechanistically, we found that the IL-22-STAT3 pathway inhibited REV-ERBα expression and modulated RANKL-induced osteoclast differentiation in vitro. Our results elucidate the role of REV-ERBα in osteoclastogenesis and suggest a potential new therapeutic avenue for addressing alveolar bone resorption associated with periodontitis., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

The clinical efficacy of combination drug regimens containing the first-generation diarylquinoline (DARQ) bedaquiline in the treatment of multidrug-resistant tuberculosis has validated ATP synthesis as a vulnerable pathway in Mycobacterium tuberculosis . New DARQs in clinical development may be even more effective than bedaquiline, including against emerging bedaquiline-resistant strains. Telacebec (T) is a novel cytochrome bc 1 :aa 3 oxidase inhibitor that also inhibits ATP synthesis. Based on its demonstrated efficacy as a monotherapy in mice and in a phase 2a clinical trial, we tested the contribution of T to novel combination therapies against two strains of M. tuberculosis (H37Rv and HN878) in an established BALB/c mouse model of tuberculosis in an effort to find more effective regimens. Overall, T was more effective in regimens against the HN878 strain than against the H37Rv strain, a finding supported by the greater vulnerability of the former strain to T and to genetic depletion of QcrB. Against both strains, combinations of a DARQ, clofazimine, and T were highly bactericidal. However, only against HN878 did T contribute synergistically, whereas an antagonistic effect was observed against H37Rv. These results demonstrate the therapeutic potential of T and highlight how differences in the susceptibility of M. tuberculosis strains could lead to different conclusions about a drug's potential contribution to novel drug regimens.CLINICAL TRIALSThis study is registered with Clinicaltrials.gov as NCT04890535 and NCT06058299., Competing Interests: Todd Black and Nader Fotouhi are employees of the TB Alliance.

In recent years, a number of synthetic potentiators of antibiotics have been discovered. Their action can significantly enhance the antibacterial effect and limit the spread of antibiotic resistance through inhibition of bacterial cystathionine-γ-lyase. To expand the known set of potentiators, we developed methods for the synthesis of five new representatives of 6-bromoindole derivatives-potential inhibitors of bacterial cystathionine-γ-lyase-namely potassium 3-amino-5-((6-bromoindolyl)methyl)thiophene-2-carboxylate ( MNS2 ) and its 6-bromoindazole analogs ( MNS3 and MNS4 ), along with two 6-broindazole analogs of the parent compound NL2 . Their syntheses are based on 6-bromoindole, 6-bromoindazole and methyl 5-(bromomethyl)-3-((ethoxycarbonyl)amino)thiophene-2-carboxylate as the main building blocks, assembling the rest of the heterocyclic system on their basis at the nitrogen atom. We assessed the ability of the new inhibitors to potentiate the antimicrobial activity of gentamicin.

Dorzolamide (DZD), a Carbonic anhydrase (CA) inhibitor clinically used to lower intraocular pressure, exhibits anti-inflammatory effects owing to the drug's ability to inhibit the TIR domain-containing adaptor protein (TIRAP)-mediated signalling in macrophages. Here, we investigated whether DZD intermediates also demonstrate any anti-inflammatory property like DZD but with a reduced inhibition of CA. We found that several intermediates of DZD show increased binding to TIRAP at the common interface of kinases, such as Protein kinase C-delta (PKCδ) and Bruton's tyrosine kinase (BTK). Such binding results in a decreased activity of TIRAP, p38 Mitogen-activating protein kinases (MAPK), and p65, which are essential for major inflammatory signaling pathways. Remarkably, the DZD intermediates were more effective than DZD in decreasing the mRNA expression levels of pro-inflammatory cytokines in Lipopolysaccharide (LPS)-stimulated RAW 264.7 cells. The DZD intermediates also exhibit a reduced binding energy to CA II and CA IV, highlighting their improved specificity as anti-inflammatory compounds with decreased unwanted biological effects. Furthermore, we validated the anti-inflammatory effect of the most efficient DZD intermediate, DRZ V, in a model of mouse sepsis. DRZ V-treated septic mice exhibited improved survival compared to DZD-treated septic mice. Our data indicate that the tested DZD intermediates are more effectual in dampening TIRAP-mediated inflammatory signaling as compared to DZD. Thus, DZD intermediates may be a promising option for developing novel anti-inflammatory therapeutics., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The circadian clock protein reverse erythroblastosis virus (REV)-ERBα is implicated in the pathogenesis of various diseases, including cancer and myocardial infarction. Emerging evidence suggests that SR9009, an agonist of REV-ERBα, regulates multiple signaling molecules independent or dependent of REV-ERBα. However, the impact of SR9009 on renal fibrosis remains largely unevaluated. In this study, we investigated the effects of SR9009 on transforming growth factor (TGF)-β1-induced fibrotic responses and elucidated the mechanisms involved. Masson's trichome staining revealed that in the unilateral ureteral obstruction groups, there was a decrease in REV-ERBα expression, accompanied by increased levels of the profibrotic factor TGF-β1 and the fibrosis marker α-smooth muscle actin (α-SMA). REV-ERBα knockdown significantly increased α-SMA expression in NRK-49F cells. SR9009 significantly attenuated unilateral ureteral obstruction-induced fibrosis and TGF-β1-induced fibrotic responses in normal rat kidney fibroblasts (NRK-49F cells). Conversely, the REV-ERBα antagonist SR8278 did not affect TGF-β1-induced fibrotic responses. Mechanistic studies revealed that SR9009 significantly inhibited the phosphorylation of ERK and p38, concomitant with reduced α-SMA levels, suppressing TGF-β1-induced NADPH oxidase 4 (NOX4) mRNA expression in NRK-49F cells. Notably, SR9009 did not influence the expression of dual specificity phosphatase 4, which dephosphorylates MAPKs, including p38. Furthermore, REV-ERBα knockdown did not affect the ability of SR9009 to inhibit TGF-β1-induced fibrotic responses and NOX4 expression in NRK-49F cells. In conclusion, SR9009 exerts a protective role against renal fibrosis independent of REV-ERBα. Therefore, SR9009 is a promising therapeutic agent for the prevention and treatment of renal fibrosis associated with renal failure., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

As a biological macromolecule, the coat protein (CP) of potato virus Y (PVY) mediates the virus' primary pathogenic behaviors. It has been gradually realized that certain residues on the CP are crucial for functions such as virus particle movement and assembly. However, there are few reports of potential drugs successfully targeting these key residues with unique mechanisms of action. Here, we disclose the first new phytovirucide that acts on the key site Arg157 (R 157 ) on the PVY CP. In this investigation, we developed a series of benzo[b]thiophene-based compounds, strategically introducing sulfonamide functionalities to enhance their antiviral performance. Through bio-screening, derivative C54 (EC 50  = 69.2 μg/mL for inactive activity) emerged as notably more effective against PVY than the established antiviral agent ningnanmycin (EC 50  = 79.6 μg/mL). Mechanistic studies revealed that C54 is an inhibitor of viral particle assembly by specifically binding to the CP residue R 157 , thereby disrupting its interaction with RNA. These results underscore the promise of C54 as a potent antiviral lead and provide a fresh perspective on the strategic design of inhibitors focusing on viral assembly processes., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Methicillin-resistant Staphylococcus aureus (MRSA) is a major contributor to hospital-acquired infections and is highly resistant to treatment. Ongoing research focuses on developing new antimicrobial medications to prevent the spread of resistance. A facile method was employed to efficiently synthesize new pyrazolo[1,5-a]pyrimidines in 84-93 % yields by reacting 4-benzyl-1H-pyrazole-3,5-diamine with the respective α,β-unsaturated ketones. The reaction was carried out in ethanol containing 1.2 equivalents of potassium hydroxide at reflux for 5-6 h. The new products are attached to a para-substituted aryl group with variable electronic properties at pyrazolopyrimidine-C5, in addition to one of three units at C7, namely phenyl, thiophen-2-yl, or furan-2-yl units. A wide spectrum of antibacterial activity was displayed by the new pyrimidines against six different bacterial strains. In general, pyrimidines attached to furan-2-yl units at C7, in addition to another aryl unit at C5, attached to 4-Me or 4-OMe groups, demonstrate significant antibacterial activity, particularly against S. aureus strain. They had MIC/MBC of 2.5/5.1 and 2.4/4.9 μM, respectively, which exceeded that of ciprofloxacin. Moreover, they demonstrate more effective MRSA inhibitory activity than linezolid, with MIC/MBC values up to 4.9/19.7 and 2.4/19.7 μM against MRSA ATCC:33591 and ATCC:43300 strains, respectively., (© 2024 Wiley-VHCA AG, Zurich, Switzerland.)

Due to the inadequate photothermal conversion efficiency (PCE), most photothermal agents (PTAs) have to be used under high-power near-infrared (NIR) irradiation, which significantly exceeds medical safety standards, for achieving effective photothermal therapy (PTT) in antitumor treatment. This significantly hinders practical PTT application. Herein, three acceptor-donor-acceptor(A-D-A)-type molecules are synthesized based on cyclopentadithiophene unit to develop effective PTAs. By incorporating the large-size Si atom in the A-D-A molecules, the photosensitizer displays an increased packing distance in the aggregate state, leading to a blue-shifted absorption spectrum that better matches the medial laser wavelength. Also, the Si incorporation strategy elevates the nonradiative decay rate constants (k nr ) of the A-D-A photosensitizer, and thereby a further enhancement in PCE is achieved for the PTA. Consequently, the SiO-4F-based nanoparticles exhibited 64.23% PCE, with excellent biosafety and photothermal stability. Under NIR irradiation with medical safety (808 nm, 0.33 W cm -2 ), SiO-4F nanoparticles with 100 µg mL -1 yield a death rate of over 91% for diverse tumor cells. Moreover, in vivo experiments, SiO-4F-based PTT effectively inhibited and eliminated tumors. These findings suggest that the Si-incorporated CDPT is promising for constructing effective A-D-A photosensitizers, enabling the PTT under NIR irradiation that meets medical safety standards., (© 2024 Wiley‐VCH GmbH.)

Chronic obstructive pulmonary disease (COPD) is a major health burden globally and in India. Oxidative stress plays a pivotal role in the pathogenesis of COPD, causing mucus hypersecretion, bronchoconstriction, and accelerated lung function decline. An important class of pharmacological agents that are often less discussed are the thiol mucolytic agents, which have a two-pronged effect of serving as both a mucolytic and an antioxidant. One of these agents which has reignited interest lately is erdosteine, with recent evidence demonstrating advantages over traditionally used N-acetylcysteine. In this review, we have summarized the key available evidence for the role of erdosteine in COPD, with takeaways on its place in therapy., (© Journal of The Association of Physicians of India 2025.)

SIRT2 (sirtuin2) is a NAD + -dependent deacetylase implicated in fibrosis and inflammation of the liver, kidney, and heart. In this study, we designed and synthesized a series of 3-naphthylthiophene derivatives and evaluated their inhibitory activity against the SIRT2 enzyme. Among them, Z18 demonstrated outstanding SIRT2 inhibitory activity and selectivity. It significantly inhibited both the proliferation of cardiac fibroblasts (CFs) and the activity and expression of SIRT2 in CFs. Moreover, compound Z18 effectively suppressed TGF-β1-induced increases in α-SMA and CoL-1A1 protein expression, as well as hydroxyproline levels. Pharmacological mechanism tests demonstrated that Z18 inhibited SIRT2, thereby suppressing the TGF-β1-induced autocrine production of TGF-β1 and the phosphorylation of Smad2/3 in CFs. In MTT assays, Z18 exhibited a significant inhibitory effect on the proliferation of CFs induced by TGF-β1. In vivo, Z18 effectively ameliorated TAC- and ISO-induced declines in cardiac function, histopathological morphological changes, and collagen deposition. It also inhibited SIRT2 activity and reduced the expression of α-SMA and p-Smad2/3. In hepatorenal toxicity assays, Z18 exhibited an excellent safety profile. These results support the further development of the selective SIRT2 inhibitor Z18 as a potential lead compound for the treatment of myocardial fibrosis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Objectives: Thiophene is one of the most important heterocyclic scaffolds with notable pharmacological properties. Thiophene and its derivatives are of particular interest among sulphurcontaining heterocycles because of their similarities to numerous natural and synthetic compounds with identified potential. The purpose of this study is to extensively analyse the synthetic pathways adopted for synthesising thiophene derivatives and investigate their various biological functions., Methods: A comprehensive review of the existing literature was conducted to collect data pertaining to the methods that are employed for the synthesis of thiophene derivatives. A comprehensive search was carried out through relevant databases, including work published in 2024. A variety of synthesis procedures were identified and arranged, encompassing both traditional approaches like the Gewald reaction and contemporary ones like microwave-assisted synthesis and green synthesis. In addition, a comprehensive compilation of in vitro and in vivo studies was conducted to investigate the biological effects of 50 distinct thiophene derivatives. The primary focus of the studies was on various activities such as anti-cancer, anti-inflammatory, antiprotozoal, antibacterial, antioxidant, and antiviral functions., Results: Diverse methodologies have been employed in the synthesis of thiophene derivatives, encompassing both conventional and modern methods. Furthermore, the biological potential of thiophene derivatives was investigated, demonstrating a broad range of actions. Key structural elements necessary for biological activity were clarified by investigations of the structure-activity relationship., Conclusion: The biological potential and flexible synthesis pathways of thiophene derivatives make them attractive candidates for use in medicinal and pharmaceutical chemistry. Understanding the different synthesis methods and biological actions of thiophene derivatives may assist rational design and create novel treatments for a variety of conditions. The potential for these compounds to be further explored and optimised is considerable for the next drug development initiatives., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Phototherapy, including photodynamic therapy (PDT) and photothermal therapy (PTT), has attracted wide attention in tumor treatment. However, the hypoxic tumor microenvironment and the heat shock proteins produced by tumor cells significantly reduce their efficacy. Developing effective phototherapy agents that have high reactive oxygen species generation efficiency and photothermal conversion efficiency (PCE) while simultaneously utilizing the hypoxic tumor microenvironment is of great importance. Here, a thienothiophene-benzopyran derivative, BTPIC4F-C10 is designed and synthesized, with near-infrared (NIR) absorption and fluorescence. Then the lipid nanoparticles (LipBFCA NPs) which encapsulated BTPIC4F-C10 in a phospholipid bilayer together with hypoxia-activated prodrug banoxanthrone (AQ4N) are constructed for NIR-II fluorescence imaging-guided synergistic PDT/PTT/chemotherapy and immune activation. Under 808 nm laser irradiation, LipBFCA NPs is a high singlet oxygen quantum yield of 20.2% and PCE of 78.8%. With ultra-high photon energy utilization efficiency of 99%, LipBFCA NPs is an excellent phototherapy effect. The hypoxic environment caused by phototherapy can further activate AQ4N to transform into chemically toxic AQ4 radicals to kill tumor cells. Moreover, phototherapy can induce immunogenic cell death, release tumor-associated antigens, and activate immune responses. This work provides a new way for the clinical application of fluorescence imaging in guiding tumor diagnosis and treatment., (© 2024 Wiley‐VCH GmbH.)

Xanomeline/trospium chloride (COBENFY™), formerly KarXT, is a first-in-class, oral, fixed-dose muscarinic agonist/antagonist combination being developed for use in schizophrenia and Alzheimer's disease psychosis. Xanomeline is thought to confer efficacy by acting as an agonist at M 1 and M 4 muscarinic acetylcholine receptors in the brain, and trospium chloride reduces the peripheral cholinergic adverse events associated with xanomeline. Xanomeline/trospium chloride received its first approval on 26 September 2024 in the USA for the treatment of schizophrenia in adults. This article summarizes the milestones in the development of xanomeline/trospium chloride leading to this first approval for schizophrenia., Competing Interests: Declarations. Funding: The preparation of this review was not supported by any external funding. Authorship and Conflict of interest: During the peer review process the manufacturer of the agent under review was offered an opportunity to comment on the article. Changes resulting from any comments received were made by the authors on the basis of scientific completeness and accuracy. Yahiya Y. Syed is a salaried employee of Adis International Ltd/Springer Nature, and declares no relevant conflicts of interest. All authors contributed to this article and are responsible for its content. Ethics approval, Consent to participate, Consent to publish, Availability of data and material, Code availability: Not applicable., (© 2024. Springer Nature Switzerland AG.)

The genetic recombination and antigenic variation of influenza viruses may decrease the efficacy of antiviral vaccines, highlighting the imperativeness of developing novel anti-influenza agents. Herein, a series of thiophene-based compounds were designed and synthesized as potent anti-influenza agents. Among them, ATV2301 exhibited an excellent anti-influenza activity (EC 50 , H1N1 = 1.88 nM, H3N2 = 4.77 nM), a higher safety index (SI, H1N1 = 18218, H3N2 = 7180), and a remarkably improved oral bioavailability ( F = 71.60%). The prodrug ATV2301A demonstrated strong therapeutic efficacy and protection in H1N1-infected BALB/c mice, with low toxicity and broad tissue distribution. ATV2301 also exhibited high stability in both human and mouse liver microsomes. Mechanistic studies indicated that ATV2301 's anti-influenza activity was due to its effects on polymerase acid protein (PA), nuclear protein (NP), and RNA-dependent RNA polymerase (RdRp). Additionally, ATV2301 showed potent activities against clinical isolates of anti-influenza A virus (IAV) and anti-influenza B virus (IBV), positioning it as a promising cap-dependent endonuclease inhibitor for further clinical research.

Multiple signaling pathways have been reported to be altered in Myotonic Dystrophy type 1 (DM1) skeletal muscle, contributing to pathogenicity. In particular, previous work established that AMPK signaling, a key sensor of energy metabolism, is repressed in DM1 mouse muscle and that activating AMPK through exercise and/or with pharmacological activators is beneficial for the DM1 muscle phenotype. Here, we explored the effects of a newer, more specific allosteric AMPK activator acting directly on AMPK. We treated male and female HSA LR mice for 1 and 4 weeks with a daily injection of the allosteric activator MK-8722, the AMP mimetic AICAR, or vehicle. Our results show that 1 and 4 weeks of treatment with MK-8722 improves alternative splicing toward wild-type levels in male and female HSA LR muscle. However, the effects of MK-8722 were more modest compared to AICAR. In contrast, 4 weeks of treatment with MK-8722 improved muscle histology to a greater extent than AICAR. As expected with AMPK activation, 4 weeks of treatment with MK-8722 and AICAR promoted the expression of slower, more oxidative fibers. Finally, acute injections of MK-8722 and AICAR triggered the rapid and transient increase in phospho-AMPK in muscle. However, the peak of AMPK phosphorylation was lower with MK-8722 compared to AICAR, thereby explaining the more modest effects of AMPK allosteric activation. Altogether, our data demonstrate that chronic activation of AMPK with specific pharmacological activators is beneficial for the DM1 muscle. They further indicate that at least a portion of the beneficial effects seen following the administration of these drugs occurs through AMPK., (© 2024 Federation of American Societies for Experimental Biology.)

Purpose: Oltipraz has various applications, including for treating cancer, liver fibrosis, and cirrhosis. However, its role in regulating metabolic processes, inflammation, oxidative stress, and insulin resistance in STZ-induced T2DM remains unclear. Hence, a comprehensive understanding of how oltipraz ameliorates diabetes, particularly inflammation and oxidative stress, is imperative., Methods: The negative control (NC), T2DM model (T2DM), and T2DM models treated with oltipraz (OLTI) and metformin (MET) were constructed. The RNA sequencing (RNA-Seq) was performed on the pancreatic tissues. H&E staining was conducted on the liver and pancreatic tissues. The intraperitoneal glucose tolerance test (IPGTT), blood glucose and lipids, inflammatory factors, and oxidative stress indexes were measured. qPCR and Western blotting examined the nuclear factor erythroid-derived 2-like 2 (Nrf2) / hemoglobin-1 (HO-1) signaling pathway, cell apoptosis-related genes, and Reg3g levels. Immunofluorescence (IF) analysis of the pancreas was performed to measure insulin secretion., Results: A total of 256 DEGs were identified in OLTI_vs_T2DM, and they were mainly enriched in circadian rhythm, cAMP, AMPK, insulin, and MAPK signaling pathways. Moreover, Reg3g exhibits reduced expression in T2DM_vs_NC, and elevated expression in OLTI_vs_T2DM, yet remains unchanged in MET_vs_T2DM. OLTI reduced fasting blood glucose and alleviated T2DM-induced weight loss. It improved blood glucose and insulin resistance, decreased blood lipid metabolism, reduced inflammation and oxidative stress through the Nrf2/HO-1 signaling pathway, mitigated pancreatic and liver tissue injury, and enhanced pancreatic β-cell insulin secretion. OLTI exhibited anti-apoptosis effects in T2DM. Moreover, OLTI exhibits superior antioxidant activity than metformin., Conclusion: In summary, OLTI improves blood glucose and insulin resistance, decreases blood lipid metabolism, reduces inflammation and apoptosis, suppresses oxidative stress through the Nrf2/HO-1 signaling pathway, mitigates pancreatic and liver tissue injury, and enhances pancreatic β-cell insulin secretion, thereby mitigating T2DM symptoms. Moreover, Reg3g could be an important target for OLTI treatment of T2DM., Competing Interests: No competing financial interests exist., (© 2024 Luo et al.)

In this study, a series of novel thieno [3, 2-b]pyridinone derivatives were designed and synthesized using a scaffold hopping strategy. Six compounds showed potent anti-mycobacterial activity (minimum inhibitory concentration (MIC) ≤ 1 μg/mL) against Mycobacterium tuberculosis (Mtb) UAlRa. Compound 6c displayed good activity against Mtb UAlRv (MIC = 0.5-1 μg/mL). Compounds 6c and 6i also showed activity against Mtb UAlRa in macrophages and exhibited low cytotoxicity against LO-2 cells. The selected compounds displayed a narrow antibacterial spectrum, with no activity against representative Gram-positive, Gram-negative bacteria, as well as fungi. Furthermore, compound 6c demonstrated favorable oral pharmacokinetic properties with a T 1/2 value of 47.99 h and exhibited good in vivo activity in an acute mouse model of tuberculosis (TB). The target of compound 6c was identified as a NADH-dependent enoyl-acyl carrier protein reductase (InhA) by genome sequencing of spontaneously compound 6c-resistant Mtb mutants, indicating that compound 6c may not require activation and can directly target InhA. In vitro antimicrobial assays against a recombinant M. smegmatis overexpressing the Mtb-InhA, along with InhA inhibition assays, confirmed that InhA is the target of thieno [3, 2-b]pyridinone derivatives. Overall, this study identified thieno [3, 2-b]pyridinone scaffold as a novel chemotype that is promising for the development of anti-TB agents., Competing Interests: Declaration of competing interest There are no conflicts to declare., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Background: Alzheimer's disease (AD) is a progressive and irreversible neurological disorder that gradually deteriorates an individual's ability to carry out even the simplest tasks., Objective: This study was undertaken to investigate the potential therapeutic efficacy of a novel bithiophene in a rat model of aluminum-induced AD pathology., Methods: A total of 108 adult male albino rats weighing 160 ± 20 g, were randomly assigned to six groups: (1) a control group administered DMSO, (2) group receiving a high dose of bithiophene (1 mg/kg), (3) a model group received AlCl 3 (100 mg/kg), those rats were then treated by either (4) bithiophene low dose (0.5 mg/kg), (5) high dose (1 mg/kg), or (6) memantine (20 mg/kg)., Results: Low dose bithiophene treatment was a promising strategy for mitigating oxidative stress and improving synaptic plasticity. This was demonstrated by reductions in malondialdehyde level, and increased activities of superoxide dismutase and catalase, and elevated glutathione content. Likewise, low dose bithiophene enhanced synaptic plasticity through a reduction in excitatory glutamate and norepinephrine levels, while increasing dopamine. Moreover, bithiophene significantly downregulated the expression of GSAP , GSK3 - β , and p53 , which are implicated in AD progression. This treatment also decreased caspase 3 and amyloid-β (Aβ 1-42 ) accumulation in the hippocampus. Finally, behavioral assessments revealed that low dose bithiophene significantly enhanced learning abilities, as proved by Morris water maze., Conclusions: Low dose bithiophene mitigated AD through ameliorating oxidative stress, promoting synaptic plasticity, inhibiting the Aβ accumulation, and enhancing the cognitive functions in a rat model., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Heteromeric Tandem pore domain Acid Sensitive (TASK)-1/3 channels are critical to oxygen-sensing by carotid body type 1 cells, where hypoxia-induced inhibition of TASK-3 and/or TASK-1/3 potassium currents leads to voltage-gated calcium entry, exocytotic transmitter release and increases in carotid body afferent input responses that initiate corrective changes in breathing patterns. It was proposed that, in response to hypoxia, the AMP-activated protein kinase (AMPK) might directly phosphorylate and inhibit TASK channels, in particular TASK-3, but studies on rat type I cells questioned this view. However, sequence alignment identified a putative AMPK recognition motif in human (h) TASK-3, but not hTASK-1, with Ser 55 representing a potential phosphorylation site. We therefore studied the effects of five different AMPK activators on recombinant hTASK-3 potassium channels expressed in human embryonic kidney (HEK)-293 cells. Two structurally unrelated AMPK activators, the thienopyridine A-769662 (100-500 µM) and the benzimidazole 991 (3-30 µM) inhibited hTASK-3 currents in a concentration-dependent manner, while the 4-azabenzimidazole MK-8722 (3-30 µM) partially inhibited hTASK-3 at concentrations above those required for maximal AMPK activation. By contrast, the 4-azabenzimidazole, BI-9774 (10-100 µM; a closely related analogue of MK8722) and the pro-drug AICA-riboside (1 mM; metabolised to ZMP, an AMP-mimetic) had no significant effect on hTASK-3 currents at concentrations sufficient to maximally activate AMPK. Importantly, A-769662 (300 µM) also inhibited hTASK-3 channel currents in HEK-293 cells that stably over-expressed an AMPK-β1 subunit mutant (S108A) that renders AMPK insensitive to activators that bind to the Allosteric Drug and Metabolite site, such as A-769662. We therefore identify A-769662 and 991 as novel hTASK-3 channel inhibitors and provide conclusive evidence that AMPK does not regulate hTASK-3 channel currents., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Background: Protein kinases are a type of transferase enzyme that catalyze the phosphorylation of protein substrates, including receptor proteins. Testis-specific serine/threonine kinases (TSSKs) are a highly conserved group of protein kinases found in various organisms. They play an essential role in male reproduction by influencing sperm development and function., Results: In this study, we report on the characterization of BmTSSK3, a TSSK from the silkworm, Bombyx mori. We found that BmTSSK3 is specifically expressed in the testis and localized to the sperm flagella, particularly in the sperm tail cyst. Furthermore, we developed BmTSSK3 inhibitors through molecular docking and binding assays. Small molecules 5-(4-Fluorophenyl)-2-ureidothiophene-3-carboxamide (TPCA-1) and Imidurea were identified to bind to BmTSSK3. Using site-specific mutation technology, we identified amino acid residues R134 and S184 as crucial binding sites for small molecules. RNA interference assay and Western blot analysis showed that knockdown of BmTSSK3 significantly decreased histone 3 phosphorylation. To confirm the inhibitory effect of these small molecules, we treated silkworm testes with TPCA-1 and observed a strong inhibitory effect., Conclusion: TPCA-1 is an inhibitor of BmTSSK3, which raises its potential as a future candidate for male sterility of the silkworm. Thus, this study may offer a novel strategy for sterile silkworms as well as insects. © 2024 Society of Chemical Industry., (© 2024 Society of Chemical Industry.)

Tissue specificity can render mitochondrial uncouplers more promising as leading compounds for creating drugs against serious diseases. In search of tissue-specific uncouplers, we address anilinothiophenes as possible glutathione-S-transferase substrates (GST). Earlier, 'cyclic' uncoupling activity was reported for 5-bromo-N-(4-chlorophenyl)-3,4-dinitro-2-thiophenamine (BDCT) in isolated rat liver mitochondria (RLM). The mechanism by which BDCT induced two-phase changes in mitochondrial respiration (stimulation followed by deceleration) was unknown. To clarify this issue, we synthesized BDCT and its two analogues. Among these, 5-bromo-3,4-dinitro-N-(4-nitrophenyl)-2-thiophenamine (BDNT) appeared to be the most effective as a mitochondrial uncoupler, decreasing membrane potential and stimulating respiration at submicromolar concentrations. Importantly, BDNT exerted two-phase changes in both mitochondrial membrane potential and respiration rate of RLM, which were enhanced by the addition of glutathione (GSH) but inhibited by the compounds capable of GSH depleting, such as 1-chloro-2,4-dinitrobenzene (CDNB). By contrast, the phase of recoupling was not observed in rat heart mitochondria (RHM). Remarkably, BDNT elicited mitochondrial depolarization in primary human fibroblasts but not in cultured human liver (HepG2) cells. By detecting proton-selective electrical current through planar bilayer lipid membranes, we demonstrated the ability of BDCT and BDNT to transfer protons across membranes. BDNT proved to be an anionic protonophore with a pK a of 7.38. By using LC-MS and capillary electrophoresis, we directly showed the formation of BDNT conjugates with GSH upon incubation with RLM but not RHM. Therefore, we hypothesize that GST is involved in the disappearance of the anilinothiophene uncoupling activity in RLM, ensuring the tissue-specific behavior of the uncoupler., (© 2024 Federation of European Biochemical Societies.)

Rho family GTPases regulate cellular processes and promote tumour growth and metastasis; thus, RhoA is a potential target for tumour metastasis inhibition. However, limited progress has been made in the development of RhoA targeting anticancer drugs. Here, we synthesised benzo[ b ]thiophene-3-carboxylic acid 1,1-dioxide derivatives based on a covalent inhibitor of RhoA (DC-Rhoin), reported in our previous studies. The observed structure-activity relationship (contributed by carboxamide in C-3 and 1-methyl-1 H -pyrazol in C-5) enhanced the anti-proliferative activity of the derivatives. Compound b19 significantly inhibited the proliferation, migration, and invasion of MDA-MB-231 cells and promoted their apoptosis. The suppression of myosin light chain phosphorylation and the formation of stress fibres confirmed the inhibitory activity of b19 via the RhoA/ROCK pathway. b19 exhibited a different binding pattern from DC-Rhoin, as observed in molecular docking analysis. This study provides a reference for the development of anticancer agents targeting the RhoA/ROCK pathway.

The surge of drug-resistant Mycobacterium tuberculosis (DR-TB) impedes the World Health Organization's efforts in ending TB and calls for new therapeutic formulations. M. tuberculosis sirtuin-like protein Rv1151c is a bifunctional enzyme with both deacetylation and desuccinylation activities, which plays an important role in M. tuberculosis drug resistance and stress responses. Thus, it appears to be a promising target for the development of new TB therapeutics. In this study, we screened 31,057 ligand compounds from seven compound libraries in silico to identify inhibitors of Rv1151c. Ipragliflozin can bind to Rv1151c and interact stably. Ipragliflozin can change the acylation level of M. tuberculosis by inhibiting Rv1151c and effectively inhibit the growth of M. tuberculosis H37Rv and M. smegmatis. It can potentiate the first-front anti-TB drug isoniazid. As an antidiabetic drug, Ipragliflozin can be potentially included in the regimen to treat diabetes-tuberculosis comorbidity., Competing Interests: Declaration of competing interest The authors have no relevant financial or non-financial interests to disclose., (Copyright © 2024 Elsevier B.V. All rights reserved.)

α,β-unsaturated carbonyl compounds have extensive applications in various fields, such as organic, inorganic, analytical, and biological. In the modern era, they offer excellent pharmacological application prospects and find widespread use in the pharmaceutical industry. The current study revealed the synthesis and characterization of a novel 3-(2-bromo-5-fluorophenyl)-1-(thiophen-2-yl) prop-2-en-1-one (CY3). In vitro their antimicrobial (Pseudomonas aeruginosa, Klebsiella pneumonia, Escherichia coli, Staphylococcus aureus, and Acinetobacter baumannii), antifungal ( Candida parapsilosis, Candida tropicalis, and Candida albicans), cytotoxicity (VERO and Hep-G2 cells), in silico, and molecular docking analysis were also performed. The in-silico analysis evaluated the drug-likeness properties of the compound CY3 using various filtering rules, including Lipinski's, Ghose filter, Veber, Egan, Muegge, and Medicinal Chemistry alerts such as Pan Assay Interference Structures (PAINS), Brenk, and Lead-likeness. Then, molecular docking studies performed using the AutoDock (AD4), Vina, and iGEMDOCK tools to determine the mechanism by which the CY3 compound interact with the bacterial strains. Here, five different receptors were selected, such as DNA gyrase, glucose 6-phosphate synthase (GlmS), dihydrofolate reductase (DHFR), dehydrosqualene synthase (DHSS), and undecaprenyl pyrophosphate synthase (UDPPS), for molecular docking analysis. The CY3 compound showed a good binding affinity with the two target proteins, DHFR and DHSS, respectively, with maximum binding energies of about - 7.07 and - 7.05 kcal/mol. The synthesized CY3 compound exhibited moderate antibacterial activity with a MIC value > 100 µg/mL against all five bacterial strains and moderate antifungal activity with a MIC value > 50 µg/mL against all three fungal strains. Drug-likeness analyses also support their favourable bioavailability., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Eight Novel chalcones were synthesized and their structures were confirmed by different spectral tools. All the prepared compounds were subjected to SRB cytotoxic screening against several cancer cell lines. Compound 5c exerted the most promising effect against MCF7 and HEP2 cells with IC 50 values of 9.5 and 12 µg/mL, respectively. Real-time PCR demonstrated the inhibitory effect of compound 5c on the expression level of Antigen kiel 67 (KI-67), Survivin, Interleukin-1beta (IL-1B), Interleukin-6 (IL-6), Cyclooxygenase-2 (COX-2) and Protein kinase B (AKT1) genes. Flow-cytometric analysis of the cell cycle indicated that compound 5c stopped the cell cycle at the G0/G1 and G2/M phases in MCF7 and HEP2 treated cells, respectively. ELISA assay showed that Caspase 8, Caspase 9, P53, BAX, and Glutathione (GSH) were extremely activated and Matrix metalloproteinase 2 (MMP2), Matrix metalloproteinase 9 (MMP9), BCL2, Malondialdehyde (MDA), and IL-6 were deactivated in 5c treated MCF7 and HEP2 cells. Wound healing revealed that chalcone 5c reduced the ability to close the scrape wound and decreased the number of migrating MCF7 and HEP2 cells compared to the untreated cells after 48 h. Theoretical molecular modeling against P53 cancer mutant Y220C and Bcl2 showed binding energies of -22.8 and -24.2 Kcal/mole, respectively, which confirmed our ELISA results., Competing Interests: Declarations. Ethics approval: Not applicable. Consent to participate: Not applicable. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Altered polycystin-mediated endothelial flow mechanosensitivity contributes to the development of hypertension and cardiovascular complications in patients with autosomal dominant polycystic kidney disease (ADPKD). Stimulation of endothelial type 5 dopamine receptors (DR5) can acutely compensate for the endothelial consequences of polycystin deficiency, but the chronic impact of this approach must be evaluated in ADPKD. Nineteen patients with ADPKD on standard of care therapy were randomized to receive a 2-month treatment with the DR agonist rotigotine using transdermal patches, nine at 2 mg/24hours and ten at 4 mg/24hours or while ten were untreated. Rotigotine at the dose of 4 mg/24hours significantly increased nitric oxide release (nitrite levels from 10±30 to 46±34 nmol/L) and radial artery endothelium-dependent flow-mediated dilatation (from 16.4±6.3 to 22.5±7.3%) in response to hand skin heating. Systemic hemodynamics were not significantly modified but aplanation tonometry showed that rotigotine at 4 mg/24hours reduced aortic augmentation index and pulse pressure without affecting carotid-to femoral pulse wave velocity. Plasma creatinine and urea, urinary cyclic AMP, which contributes to cyst growth in ADPKD and copeptin, a surrogate marker of vasopressin, were not affected by rotigotine. In mice with a specific deletion of polycystin-1 in endothelial cells, chronic infusion of the peripheral DR5 agonist fenoldopam also improved mesenteric artery flow-mediated dilatation and reduced blood pressure. Thus, our study demonstrates that in patients with ADPKD, chronic administration of rotigotine improves conduit artery endothelial function through the restoration of flow-induced nitric oxide release as well as hemodynamics suggesting that endothelial DR5 activation may represent a promising pharmacological approach to prevent cardiovascular complications of ADPKD., (Copyright © 2024 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Addition of dopamine (DA)/serotonin (5-HT) partial agonists to 5-HT/norepinephrine (NE) reuptake inhibitors are commonly used to enhance the antidepressant response. The simultaneous inhibition of 5-HT and NE transporters with venlafaxine and its combination of brexpiprazole, which blocks the α 2 -adrenergic autoreceptor on NE terminals, could constitute a superior strategy. Anesthetized rats received venlafaxine and brexpiprazole for 2 and 14 days, then the firing activity of dorsal raphe nucleus 5-HT, locus coeruleus NE, and ventral tegmental area DA neurons were assessed. Net 5-HT and NE neurotransmissions were evaluated by assessing the tonic activation of 5-HT 1A , and α 1 - and α 2 -adrenergic receptors in the hippocampus. The combination of brexpiprazole with venlafaxine resulted in normalized 5-HT and NE neuron activity, which occurred earlier than that with venlafaxine alone. A significant enhancement of the tonic activation of 5-HT 1A receptors and α 2 -adrenoceptors in the hippocampus was observed following administration of the combination for 14 days. The combination more than doubled the number of DA neurons per electrode descent, after both 2 and 14 days, while this increase was observed only after 14 days of venlafaxine administration. This increase in population activity was prevented by NBQX, an AMPA receptor antagonist. In conclusion, early during administration, the combination of venlafaxine with brexpiprazole normalized firing activity of 5-HT and NE neurons, and increased the population activity of DA neurons through AMPA receptors. In the hippocampus, there was an overall increase in both 5-HT and NE transmissions. These results imply that this strategy could be a rapid-acting approach to treat depression., (© 2024. The Author(s).)

Candida species resistant to fluconazole have raised concern in the scientific medical community due to high mortality in patients with invasive disease. In developing countries, such as Brazil, fluconazole is the most commonly used antifungal, and alternative treatments are expensive or not readily available. Furthermore, the occurrence of biofilms is common, coupled with their inherent resistance to antifungal therapies and the host's immune system, these microbial communities have contributed to making infections caused by these yeasts an enormous clinical challenge. Therefore, there is an urgent need to develop alternative medicines, which surpass the effectiveness of already used therapies, but which are also effective against biofilms. Therefore, the present study aimed to describe for the first time the antifungal and antibiofilm action of the derivative 2-amino-5,6,7,8-tetrahydro-4 H-cyclohepta[b]thiophene-3-isopropyl carboxylate (2AT) against clinical strains of Candida spp. resistant to fluconazole (FLZ). When determining the minimum inhibitory concentrations (MIC), it was found that the compound has antifungal action at concentrations of 100 to 200 µg/mL, resulting in 100% inhibition of yeast cells. Its synergistic effect with the drug FLZ was also observed. The antibiofilm action of the compound in subinhibitory concentrations was detected, alone and in association with FLZ. Moreover, using scanning electron microscopy, it was observed that the compound 2AT in isolation was capable of causing significant ultrastructural changes in Candida. Additionally, it was also demonstrated that the compound 2AT acts by inducing characteristics compatible with apoptosis in these yeasts, such as chromatin condensation, when visualized by transmission electron microscopy, indicating the possible mechanism of action of this molecule. Furthermore, the compound did not exhibit toxicity in J774 macrophage cells up to a concentration of 4000 µg/mL. In this study, we identify the 2AT derivative as a future alternative for invasive candidiasis therapy, in addition, we highlighted the promise of a strategy combined with fluconazole in combating Candida infections, especially in cases of resistant isolates., Competing Interests: Declarations. Conflict of interest: The authors declare no conflict of interest., (© 2024. The Author(s) under exclusive licence to Sociedade Brasileira de Microbiologia.)

Invasive fungal infections have high morbidity and mortality rates and have become one of the most serious threats to human health. In the present study, a series of triazole antifungal derivatives with phenylthiophene backbone were obtained by structural modification of the lead compound using Iodiconazole as the lead compound. Among them, compound 19g is a triazole antifungal compound with 4-chloro-2-fluoro phenylthiophene backbone, which showed optimal antifungal activity against Candida albicans, Cryptococcus neoformans, and Aspergillus, with a MIC 80 value of 0.0625 μg/mL. In addition, compounds 19e, 19f, 19g, 19h, 19i and 19k exhibited different levels of inhibitory activity against fluconazole-resistant strains with MIC 80 values ranging from 0.0625 μg/mL to 32 μg/mL. Since compound 19g had optimal in vitro antifungal activity, we selected 19g for human liver microsomal stability and CYP enzyme inhibition assays as well as further evaluated the inhibitory activity of compound 19g on normal and cancerous cells in humans. Finally, we verified the inhibitory effect of compound 19g on the filamentation of Candida albicans and determined the mechanism of action by sterol composition analysis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Current treatments for acute myeloid leukemias (AMLs) cure fewer than 30 % of patients. This low efficacy is due, in part, to the inter-patient and intra-patient heterogeneity of AMLs; accordingly, all current AML treatment regimens involve drug combinations (polypharmacy). A recently-completed clinical trial in relapsed/refractory AML using a combination of two newer targeted antileukemics, the BCL-2 inhibitor venetoclax (VEN) plus the FLT3 inhibitor gilteritinib (GIL), yielded highly promising results for this two-drug polypharmacy combination. Polypharmacology - wherein a single drug molecule that inhibits two or more biological targets is created - has been proposed to offer superior therapeutic results, as compared to the corresponding polypharmacy approach. Herein, we designed and synthesized several polypharmacologic dual BCL-2/FLT3 hybrid single-molecule inhibitors by tethering VEN to GIL, through their solvent-exposed domains. While the in vitro antileukemic activity of the two-drug VEN + GIL polypharmacy combination proved superior to our focused library of VEN-GIL hybrids, alternative grafting points on GIL may yield improved results for future hybrid compounds., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Masson SAS.)

This study explores the intricacies of dopamine receptor-ligand interactions, focusing on the D1R and D5R subtypes. Using molecular modeling techniques, we investigated the binding of the pan-agonist rotigotine, revealing a universal binding mode at the orthosteric binding pocket. Additionally, we analyze the stability of antagonist-receptor complexes with SKF83566 and SCH23390. By examining the impact of specific mutations on ligand-receptor interactions through computational simulations and thermostability assays, we gain insights into binding stability. Our research also delves into the structural and energetic aspects of antagonist binding to D1R and D5R in their inactive states. These findings enhance our understanding of dopamine receptor pharmacology and hold promise for drug development in central nervous system disorders, opening doors to future research and innovation in this field.

Background: Dopaminergic signaling in the Central Nervous System (CNS) has been observed in the pathophysiology of memory deficits. Rotigotine belongs to a non-ergot-based dopamine receptor agonist possessing anti-inflammatory properties. However, it is uncertain if it has a role in ameliorating cognitive decline. Here, we evaluated the actions of rotigotine on neuroinflammation and memory impairment., Methodology: Rotigotine 1, 3, and 5 mg/kg were administered to mice subcutaneously once a day for fifteen days. Lipopolysaccharide (LPS) 750 µg/kg was administered intraperitoneally for seven days to produce cognitive impairment in mice. Morris water maze and Passive avoidance step-down tests were performed to evaluate memory function. Further, tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and amyloid-beta (Aβ) were estimated by ELISA. The mouse brain was analyzed for acetylcholinesterase (AChE) activity, lipid peroxidation, catalase, and reduced glutathione levels., Results: LPS elevated IL-6, Aβ, TNF-α, and AChE activity, promoted oxidative stress, and caused memory decline in mice. Lower doses of rotigotine 1 and 3 mg/kg significantly reduced neuroinflammation, oxidative stress, and AChE activity, followed by improved cognitive impairment., Conclusion: Our data suggest that rotigotine 1 and 3 mg/kg could reverse the neuroinflammation-associated memory impairment., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

A group of N-phenylbenzofuran-2-carboxamide and N-phenylbenzo[b]thiophene-2-carboxamide derivatives were designed and synthesized as a novel class of Aβ42 aggregation modulators. In the thioflavin-T based fluorescence aggregation kinetics study, compounds 4 a, 4 b, 5 a and 5 b possessing a methoxyphenol pharmacophore were able to demonstrate concentration dependent inhibition of Aβ42 aggregation with maximum inhibition of 54 % observed for compound 4 b. In contrast, incorporation of a 4-methoxyphenyl ring in compounds 4 d and 5 d led to a significant increase in Aβ42 fibrillogenesis demonstrating their ability to accelerate Aβ42 aggregation. Compound 4 d exhibited 2.7-fold increase in Aβ42 fibrillogenesis when tested at the maximum concentration of 25 μM. These results were further confirmed by electron microscopy studies which demonstrates the ability of compounds 4 a, 4 b, 4 d, 5 a, 5 b and 5 d to modulate Aβ42 fibrillogenesis. Compounds 5 a and 5 b provided significant neuroprotection to mouse hippocampal neuronal HT22 cells against Aβ42-induced cytotoxicity. Molecular docking studies suggest that the orientation of the bicyclic aromatic rings (either benzofuran or benzo[b]thiophene) plays a major role in moderating their ability to either inhibit or accelerate Aβ42 aggregation. Our findings support the application of these novel derivatives as pharmacological tools to study the mechanisms of Aβ42 aggregation., (© 2024 The Authors. ChemMedChem published by Wiley-VCH GmbH.)

We discovered novel neuroprotective compounds by phenotypic screening using SOD1-mutant amyotrophic lateral sclerosis (ALS) patient induced pluripotent stem cell (iPSC)-derived motor neurons. Mechanistic analysis showed that the protective effect of initial hit compound 1 was likely due to the inhibition of MAP4Ks, including MAP4K4, a member of the MAP4K kinase family. Structural transformation led to compound 15f, which showed improved MAP4K4 inhibitory activity and superior neuroprotective effects compared to 1 in motor neurons. The results suggest that structural optimization based on MAP4K4 inhibitory activity might improve the neuroprotective effect of this series of compounds., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Introduction: Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer with limited treatment options. This study explores the potential of novel 5-nitro-thiophene-thiosemicarbazone derivatives as therapeutic agents for PDAC., Methods: We evaluated the cytotoxicity of seven derivatives in peripheral blood mononuclear cells (PBMCs) and PDAC cell lines. Promising candidates (PR12 and PR17) were further analyzed for their effects on colony formation, cell cycle progression, and reactive oxygen species (ROS) production. PR17, the most promising derivative, was subjected to additional investigation, including analysis of autophagy-related genes and protein kinase inhibition., Results: Three derivatives (PR16, PR19, and PR20) displayed cytotoxicity towards PBMCs. PR12 reduced colony formation and G0/G1 cell cycle arrest in PDAC cells. Notably, PR17 exhibited potent activity in MIA PaCa-2 cells, inducing S-phase cell cycle arrest, downregulating autophagy genes, and inhibiting key protein kinases., Conclusion: PR17, a 5-nitro-thiophene-thiosemicarbazone derivative, demonstrates promising antineoplastic activity against PDAC cells by potentially modulating cell cycle progression, autophagy, and protein kinase signaling. Further studies are warranted to elucidate the detailed mechanism of action and explore its efficacy in vivo., Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Bacterial pneumonia has garnered significant attention in the realm of infectious diseases owing to a surge in the incidence of severe infections coupled with the growing scarcity of efficacious therapeutic modalities. Antibiotic treatment is still an irreplaceable method for bacterial pneumonia because of its strong bactericidal activity and good clinical efficacy. However, the mucus layer forming after a bacterial infection in the lungs has been considered as the "Achilles' heels" facing the clinical application of such treatment. Herein, traceable biomimetic nanoantibiotics (BioNanoCFPs) were developed by loading indacenodithieno[3,2- b ]thiophene (ITIC) and cefoperazone (CFP) in nanoplatforms coated with natural killer (NK) cell membranes. The BioNanoCFP exhibited excellent demonstrated mucus-penetrating abilities, facilitating their arrival at the infection site. The presence of Toll-like receptors in the NK cell membrane rendered the BioNanoCFP with the capability to recognize pathogen-associated molecular patterns within bacteria, allowing precise targeting of bacterial colonization sites and achieving substantial therapeutic efficacy. Overall, our findings demonstrate the viability and desirability of using NK cell membrane-mediated drug delivery as a promising strategy for precision treatment.

Herein, 2-amino-6-(tert-butyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbonitrile (1) was synthesized in excellent yield through gewald reaction in multi components one pot reaction. Compound 1 was utilized as a building block to synthesize a new group of tetrahydro benzo[b] thiophene congeners. The chemical structure of all the novel tetrahydro benzo[b]thiophene derivatives were elucidated through the melting point, elemental analysis, FT-IR, 1 H-NMR, and mass spectroscopy. Furthermore, the total antioxidant capacity (TAC) of all the newly synthesized heterocyclic derivatives was evaluated according to the phosphomolybdenum method using ascorbic acid as standard. The findings revealed that compounds 1, 16, and 17 demonstrated significant antioxidant potency comparable to that of ascorbic acid. This suggests the potential of these heterocycles as promising candidates for antioxidant drugs in the treatment of oxidative stress-related diseases. Finally, molecular docking was conducted to study the binding affinity for the most potent antioxidant compounds 1, 16, 17 and ascorbic acid inside the interactions of compounds 1, 16, and 17 with the Keap1 (Kelch-like ECH-associated protein 1) protein (PDB: 7C5E), compared to the co-crystallized ligand triethylene glycol (PGE) and ascorbic acid as a reference drug for antioxidants. DFT calculations and global descriptors were calculated for the most potent compounds to correlate the relation between chemical structure and reactivity., (© 2024. The Author(s).)

Herein, we designed and synthesized a series of novel 2-methylthieno [3,2-d]pyrimidine analogues as tubulin inhibitors with antiproliferative activities at low nanomolar levels. Among them, compound DPP-21 displayed the most potent anti-proliferative activity against six cancer cell lines with an average IC 50 of ∼6.23 nM, better than that of colchicine (IC 50  = 9.26 nM). DPP-21 exerted its anti-cancer activity by suppressing the polymerization of tubulin with an IC 50 of 2.4 μM. Furthermore, the crystal structure of DPP-21 in complex with tubulin was solved by X-ray crystallography to 2.94 Å resolution, confirming the direct binding of DPP-21 to the colchicine site. Moreover, DPP-21 arrested the cell cycle in the G2/M phase of mitosis, subsequently inducing tumor cell apoptosis. Additionally, DPP-21 was able to effectively inhibit the migration of cancer cells. Besides, DPP-21 exhibited significant in vivo anti-tumor efficacy in a B16-F10 melanoma tumor model with a TGI of 63.3 % (7 mg/kg) by intraperitoneal (i.p.) injection. Notably, the combination of DPP-21 with NP-19 (a PD-L1-targeting small molecule inhibitor reported by our group before) demonstrated enhanced anti-cancer efficacy in vivo. These results suggest that DPP-21 is a promising lead compound deserving further investigation as a potential anti-cancer agent., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Jianjun chen reports a relationship with Southern Medical University that includes: non-financial support. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Inflammation and reactive oxygen species (ROS) production often accompany the repair of severe skin wounds, and the management of wounds has always been a clinical challenge, so the design of a hydrogel wound dressing with antioxidant and anti-inflammatory properties is of significant importance. This work incorporated strontium ranelate (SrR) into the keratin/hyaluronic acid (K/HA) hydrogel, which could scavenge ROS and reduce inflammation. The optimized hydrogel exhibits large pore size (217.2 μm), high porosity (57 %), high swelling rate (1759.52 %), and an elastic modulus (3.41 kPa). In the in vitro study, incorporating SrR into hydrogel effectively inhibited oxidative damage in mouse fibroblasts (L929) and improved anti-inflammatory effect in RAW264.7 cells stimulated by lipopolysaccharide. The in vivo study showed that, compared with the control group, the expression of ROS, IL-6 and TNF - α in the K/HA/0.5 mM SrR group were significantly reduced to 31.6 %, 39.7 % and 61.1 %, respectively. The in vivo evaluation in a full-thickness wound defect model demonstrated that K/HA/0.5 mM SrR hydrogel promotes wound healing by attenuating ROS levels, reducing inflammation, and promoting microangiogenesis. In summary, the excellent ROS scavenging and anti-inflammatory properties of SrR make the K/HA/SrR hydrogel a promising and effective strategy for wound healing., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Sodium-glucose cotransporter 2 (SGLT2) inhibitors increase urine volume with glucosuria and natriuresis. We recently reported that osmotic diuresis by the SGLT2 inhibitor ipragliflozin induces fluid homeostatic action via the stimulation of fluid intake and vasopressin-induced water reabsorption in euvolemic rats. However, the effects of SGLT2 inhibitors on these parameters in hypervolemic animals remain unclear. In this study, Dahl salt-sensitive hypertensive rats, a hypervolemic rat model, were fed a low-salt (0.3%) or high-salt (8%) diet for 14 days, then divided into vehicle or ipragliflozin (0.01%) groups. During 7 days of treatment, the high-salt diet groups significantly increased fluid intake and urine volume. In the ipragliflozin groups, fluid intake and urine volume increased by 63% and 235%, respectively, in rats fed a normal-salt diet and by 46% and 72%, respectively, in rats fed a high-salt diet. Ipragliflozin increased urinary vasopressin by 200% and solute-free water reabsorption by 196% in the normal-salt group but by only 44% and 38%, respectively, in the high-salt group. A high-salt diet significantly increased fluid balance (fluid intake - urine volume) and Na + balance (Na + intake - urinary Na + ), but ipragliflozin did not change fluid and Na + balance in normal- or high-salt groups. A high-salt diet significantly increased systolic blood pressure, but ipragliflozin did not significantly change systolic blood pressure in normal- or high-salt groups. In conclusion, SGLT2 inhibitor ipragliflozin did not change fluid and Na + balance regardless of basal fluid retention, suggesting the potential of SGLT2 inhibitors to maintain body water and Na + ., (© 2024. The Author(s), under exclusive licence to The Japanese Society of Hypertension.)

One new bithiophene derivative, 5-(but-3-en-1-yn-1-yl)-5'-(methoxymethyl)-2,2'-bithiophene (1), along with twelve known compounds, senecioester (2), tiglinsaureester (3), 5-acetoxymethyl-2'-(but-3-en-1-yn-1-yl)-2,5'-bithiophene ( 4), 5-(4-isovaleroyloxybut-1-ynyl)-2,2'-bithiophene (5), 5-hydroxymethyl-(2,5':2',5'')-terthienyl tiglate (6), 5-hydroxymethyl-(2,5':2',5'')-terthienyl agelate (7), 5- hydroxymethyl-2,5':2',5''-terthiophene dimethylacrylate (8), 5-methoxymethyl-2,2':5',2''-terthiophene (9), α-terthiophene (10), 1,3,8,9-tetrahydroxycoumestan 3-sulfate (11), demethylwedelolactone (12), and wedelolactone (13) were isolated from the methanol extract of aerial parts of Eclipta prostrata (L.) L. All isolated compounds were evaluated for the protective ability on the HepG2 cells. At the concentration of 100 μM, compounds 11 - 13 showed the highest hepatoprotective effects, with HepG2 cell viability ranging from 38.68% to 48.54%. Bithiophenes showed higher hepatoprotective cell viability than terthiophenes.

The nucleotide excision repair (NER) system removes UV photoproducts from genomic DNA and is controlled by the circadian clock. Given that small-molecule compounds have been developed to target various clock proteins, we examined whether the cryptochrome inhibitor KS15 and REV-ERB antagonist SR8278 could modulate keratinocyte responses to UV radiation in vitro. We observed that though SR8278 promoted cell viability in UVB-irradiated cells, it had little effect on NER or on the expression of the clock-regulated NER factor XPA. Rather, we found that both KS15 and SR8278 absorb light within the UV spectrum to limit initial UV photoproduct formation in DNA. Moreover, SR8278 promoted UVB viability even in cells in which the core circadian clock protein BMAL1 was disrupted, which indicates that SR8278 is likely acting via other REV-ERB transcriptional targets. We further observed that SR8278 sensitized keratinocytes to light sources containing primarily UVA wavelengths of light likely due to the generation of toxic reactive oxygen species. Though other studies have demonstrated beneficial effects of SR8278 in other model systems, our results here suggest that SR8278 has limited utility for UV photoprotection in the skin and will likely cause phototoxicity in humans or mammals exposed to solar radiation., (© 2024 The Authors. Photochemistry and Photobiology published by Wiley Periodicals LLC on behalf of American Society for Photobiology.)

Aging leads to a reduced anabolic response to mechanical stimuli and a loss of bone mass and structural integrity. Chemotherapy agents such as doxorubicin exacerbate the degeneration of aging skeleton and further subject older cancer patients to a higher fracture risk. To alleviate this clinical problem, we proposed and tested a novel mechanobiology-based therapy. Building upon prior findings that i) Yoda1, the Piezo1 agonist, promoted bone growth in young adult mice and suppressed bone resorption markers in aged mice, and ii) moderate tibial loading protected bone from breast cancer-induced osteolysis, we hypothesized that combined Yoda1 and moderate loading would improve the structural integrity of adult and aged skeletons in vivo and protect bones from deterioration after chemotherapy. We first examined the effects of 4-week Yoda1 (dose 5 mg/kg, 5 times/week) and moderate tibial loading (4.5 N peak load, 4 Hz, 300 cycles for 5 days/week), individually and combined, on mature mice (∼50 weeks of age). Combined Yoda1 and loading was found to mitigate age-associated cortical and trabecular bone loss better than individual interventions. As expected, the non-treated controls experienced an average drop of cortical polar moment of inertia (Ct.pMOI) by -4.3 % over four weeks and the bone deterioration occurred in the majority (64 %) of the samples. Relative to no treatment, loading alone, Yoda1 alone, and combined Yoda1 and loading increased Ct.pMOI by +7.3 %, +9.5 %, +12.0 % and increased the % of samples with positive Ct.pMOI changes by +32 %, +26 %, and +43 %, respectively, suggesting an additive protection of aging-related bone loss for the combined therapy. We further tested if the treatment efficacy was preserved in mature mice following two weeks (six injections) of doxorubicin at the dose of 2.5 or 5 mg/kg. As expected, doxorubicin increased osteocyte apoptosis, altered bone remodeling, and impaired bone structure. However, the effects induced by DOX were too severe to be rescued by Yoda1 and loading, alone or combined, although loading and Yoda1 individually, or combined, increased the number of mice showing positive responsiveness by 0 %, +15 %, and +29 % relative to no intervention after doxorubicin exposure. Overall, this study supported the potentials and challenges of the Yoda1-based strategy in mitigating the detrimental skeletal effects caused by aging and doxorubicin., Competing Interests: Declaration of competing interest The authors have no conflict of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The rise of drug-resistant Mycobacterium tuberculosis (Mtb) has extended the duration of tuberculosis (TB) treatment and reduced the likelihood of cure. One strategy to combat this issue is the development of inhibitors targeting the virulence factors of bacterial pathogens. Mtb' catalase (KatG) is crucial for its detoxification mechanisms and also serves as a significant virulence factor for the bacterium. In this study, twelve derivatives synthesized from 5-fluoropyridine and benzo[b]thiophene demonstrated antimycobacterial efficacy with minimum inhibitory concentrations (MICs) varying between 0.5 and 32 μg/mL. Compound 2, 1-(benzo[b]thiophen-2-ylmethylene) thiosemicarbazide, emerged as the most potent candidate. It effectively inhibited Mtb KatG, enhanced the production of reactive oxygen species (ROS) in Mtb, and achieved Mtb killing within 96 hours at a concentration of 2 μg/mL (4×MIC). Molecular docking simulations revealed that compound 2 binds tightly to the active site of Mtb-KatG with a docking score of 114, indicating that it may serve as a potent inhibitor of Mtb-KatG. The rabbit skin tuberculosis model was employed to assess the virulence of Mtb. Animal study results indicated that the granulomas induced by Mtb after treatment with compound 2 were reduced in size, exhibited a lower bacterial load, and the bacteria were no longer aggregated, in contrast to those caused by untreated Mtb. Hence, compound 2 can be regarded as a molecule capable of neutralizing the virulence factors of Mtb. This research offers insights into the design of anti-Mtb molecules with novel mechanisms of action., (© 2024 Wiley-VHCA AG, Zurich, Switzerland.)

Lung cancer is one of the most common malignant tumors in the world, with high incidence rate and mortality. Monocarboxylate transporter (MCT) 1 has been found to be widely expressed in various tumors and plays a crucial role in regulating energy metabolism. Emodin, as an important traditional Chinese medicine in China, has been reported to inhibit the progression of lung cancer. However, its potential mechanism has not been fully elucidated. The effects of emodin and MCT1 inhibitor AZD3965 on the proliferation, migration, and invasion of lung cancer cells were detected using cell counting kit-8 (CCK-8) assay, wound-healing assay, and transwell small chamber assay. The content of glucose, lactate, and pyruvate in the cell culture medium was detected using a glucose, lactate, and pyruvate detection kit, and also detected protein expression using western blotting. In addition, to investigate the effects of emodin and AZD3965 on lung cancer in vivo, we constructed nude mice subcutaneous transplant tumor model by subcutaneous injection of lung cancer cells. The results showed that emodin and AZD3965 could inhibit the proliferation, migration, and invasion of lung cancer cells. At the same time, they could inhibit the expression of MCT1 in lung cancer cells and promote the release of lactate, but did not affect the content of glucose and pyruvate. In vivo experiments had shown that emodin and AZD3965 could effectively inhibit the growth of lung cancer and inhibit the expression of MCT1. All in all, our data suggested that emodin inhibited the proliferation, migration, and invasion of lung cancer cells, possibly by inhibiting MCT1, providing important theoretical basis for elucidating the mechanism of emodin in treating lung cancer., (© 2024. The Author(s) under exclusive licence to Japan Human Cell Society.)

Oltipraz (OPZ) is a synthetic dithiolethione and is considered a novel activator of nuclear factor E2-related factor 2 (Nrf2). Increasing evidence indicates that Nrf2 protects against cerebral ischemia/reperfusion (I/R) injury by antagonizing ferroptosis and lipid peroxidation. However, the protective effects of OPZ on cerebral I/R injury remain to be elucidated. We investigated the in vitro and in vivo neuroprotective effects of OPZ. Mice were subjected to middle cerebral artery occlusion/reperfusion (MCAO/R) to construct an in vivo model and PC12 cells were exposed to oxygen and glucose deprivation/reoxygenation (OGD/R) to establish an in vitro model. OPZ administration reduced the infarct volume and brain water content, and alleviated the neurological deficit of MCAO/R mice. Moreover, OPZ ameliorated MCAO/R-induced oxidative stress by decreasing the levels of 4-HNE and MDA and increasing the activities of SOD and GSH. We also found that OPZ ameliorated MCAO/R-induced ferroptosis by increasing SLC7A11 and GPX4 protein expression and downregulating ACSL4 protein expression. Similarly, the in vitro results revealed that OGD/R-induced oxidative stress and ferroptosis. Finally, mechanistic analysis revealed that OPZ significantly upregulated the Nrf2 expression and Nrf2 knockout (Nrf2 KO) abolished the OPZ-mediated protective effects. Taken together, these findings demonstrate that OPZ ameliorates cerebral I/R injury by suppressing the oxidative stress and ferroptosis., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)