Premature ovarian failure (POF) is a complex condition marked by early ovarian decline, reduced follicular reserve, and compromised oocyte quality. Oxidative stress (OS) and ferroptosis are critical drivers of POF progression. This study investigates the therapeutic potential of Phoenixin-14 (PNX-14) in alleviating POF in rats by modulating granulosa cell (GC) ferroptosis through the ATF4/SLC7A11/GPX4 signaling pathway. Cisplatin-induced POF rat models were used to evaluate PNX-14's effects on ovarian function, oxidative stress (MDA/SOD), and ferroptosis. Serum PNX-14 levels, GPR173 expression, body/ovarian weights, follicle development, and oxidative markers were analyzed. In cisplatin-induced POF rat models, serum PNX-14 levels and GPR173 expression were significantly downregulated, suggesting potential impairment of the PNX-14/GPR173 axis. PNX-14 administration improved body and ovarian weights, restored ovarian tissue structure, and reduced oxidative damage, as evidenced by reduced MDA levels and enhanced SOD activity. At the molecular level, PNX-14 suppressed ferroptosis in GCs by enhancing ATF4 expression, which in turn upregulated SLC7A11 and GPX4, critical components of cellular antioxidant defense. Caspase-3 assays suggested minimal apoptosis in cisplatin-treated cells. PNX-14 showed similar effectiveness to Fer-1 in reducing cisplatin-induced ferroptosis, evidenced by restored viability, lower Fe²⁺, and reduced MDA, without added benefit when combined. Silencing ATF4 reversed the beneficial effects of PNX-14 on GC viability and ferroptosis, confirming the pivotal role of ATF4 in mediating the protective effects of PNX-14. These results suggest that PNX-14 alleviates POF by inhibiting GC ferroptosis through the ATF4/SLC7A11/GPX4 axis, providing a potential therapeutic strategy for POF management.

Tyrosinase (EC 1.14.18.1) is a pivotal enzyme that catalyzes the conversion of L-tyrosine to dopaquinone through a dual oxidation process, initiating melanin biosynthesis. Melanin plays a critical role in various biological processes, and its overproduction is associated with multiple conditions. Tyrosinase plays a crucial role in immune regulation by regulating the activity of immune cells and enhancing the immune response of the body. It is essential for maintaining skin health and preventing autoimmune diseases. In addition, tyrosinase has shown potential in immunotherapy, especially in the treatment of malignant melanoma and autoimmune diseases such as vitiligo. Inhibiting tyrosinase to reduce melanin synthesis has emerged as a promising therapeutic strategy with applications in skin whitening, melasma treatment, acne management, Parkinson's disease (PD) intervention, melanoma prevention, and overcoming immunotherapy resistance. By leveraging the tyrosinase-related comprehensive data documented in the BRENDA database, we have systematically summarized the effective information, including its classification, structural characteristics, catalytic functions, biosynthesis pathways, substrate specificity profiles, reaction products, and associated disease mechanisms, and so forth. This review comprehensively examines the therapeutic mechanisms, development history, and current clinical status of tyrosinase inhibitors at preclinical and advanced stages. We highlight recent research progress, focusing on evidence from animal models, preclinical studies, and human clinical trials across different indications. Additionally, we critically analyze the challenges and limitations in the field and provide insights into future directions for optimizing tyrosinase inhibitors. By synthesizing current knowledge and advancements, this review aims to underscore the therapeutic potential of tyrosinase inhibition and its role in addressing diverse medical needs.

A new series of biologically active benzo[4,5]imidazo[1,2-a]pyrimidine derivatives containing different substitutions such as thiophene, pyridine, pyrrole, and 3,4-dimethoxyphenyl at carbon 2 and, phenyl-pyrrolidinyl, -morpholinyl, -piperidinyl at carbon 4 were synthesized. The treatment of chalcone derivatives 5-16 with 2-aminobenzimidazole in DMF and drops of TEA afforded the targeted benzo[4,5]imidazo[1,2-a]pyrimidine derivatives (18-29) in good to excellent yields. These compounds were tested to evaluate their antimicrobial activity against different microbial pathogens such as Aspergillus niger, Candida albicans, Staphylococcus aureus and Salmonella typhimurium. Potently compounds 19 and 23 were contributed in a broad-spectrum inhibition process against all tested pathogens with lower MIC values ranging between 10 and 60 µg/mL. Furthermore, the efficiency of the potent compounds to inhibit the biofilm formation was moderately detected by compounds 18, 19 and 23. This study investigated the antimicrobial potential of synthesized compounds through experimental and computational approaches. Compounds 18, 19, 23, 25, and 28 demonstrated strong binding affinities to antimicrobial target proteins (1AD4, 2SIL, 4ZA5, and 5TZ1), suggesting their ability to inhibit key enzymes via diverse molecular interactions. Computational ADMET profiling confirmed their compliance with Lipinski's rules, indicating favorable drug-like properties. Molecular dynamics simulations further validated the stability of complexes formed by compounds 19 and 28, with stable RMSD values (0.17-0.45 nm), low RMSF fluctuations (0.10-0.7 nm), and consistent structural compactness (Rg: 1.45-1.75 nm). Solvent exposure (SASA: 120-220 nm²) varied across complexes. These results highlight the compounds' potential as promising candidates for antimicrobial drug development, warranting further preclinical exploration.

ABSTRACTMotivated by the anti‐leukemic synergy between histone deacetylase (HDAC) inhibitors and the FDA‐approved BCL‐2 inhibitor venetoclax, coupled with our interests in polypharmacology, we sought to bolster the anti‐leukemic efficacy of the clinical drug by grafting HDAC1‐selective or HDAC6‐selective inhibitor motifs onto a solvent‐accessible domain of venetoclax. We discovered multiple polypharmacological agents that both retained the potent BCL‐2 inhibitory activity of venetoclax and effectively inhibited either HDAC1 or HDAC6 with excellent (up to 80‐fold) selectivities for the desired HDAC isoform. In addition, relative to parental venetoclax, two of our lead compounds, BD‐4‐213 and AMC‐4‐154, exhibited superior activities against the acute myeloid leukemia cell line MV4;11 and an MV4;11 cell line engineered to overexpress BCL‐2. Annexin‐V assay results confirmed an on‐target mechanism of apoptosis for these novel chimeric molecules. Efforts to further boost the HDAC1 or HDAC6 binding affinities and/or selectivities proved unsuccessful due to synthetic chemistry challenges and solubility problems, which may underscore the difficulties of polypharmacology approaches involving a large inhibitor, such as venetoclax.

Tannic acid (TA) is a polyphenol present in many plant foods and beverages such as green tea and wines. As a food additive, it has been recognized by Food and Drug Administration as generally safe. As a candidate drug, its pharmacological effects cover a wide spectrum, ranging from antibacterial, anticancer, cardioprotection to neuroprotection. TA has been shown to modulate a number of ion channels such as Ca2+-activated Cl- channels (CaCC), voltage-gated K+ (Kv) channels and transient receptor potential (TRP) channels, producing effects such as analgesia, antihypertensive effects and reduction of airway hypersensitivity. In this review we focus on how ion channel modulation by TA may account for the pharmacological effects of TA in various cells and organ systems. Further emphasis should be paid to factors, such as dosage and routes of administration, before the pharmacological actions of TA could be translated into therapeutic applications.

Dihydroartemisinin (DHA) is a derivative of artemisinin, which affects inflammation, oxidative stress, and immune regulation. However, the mechanism underlying its effects remains largely unknown. This study aims to explore the mechanism by which DHA affects radiation-induced lung injury (RILI), providing new insights for lung radiotherapy. To elucidate its mechanism of action, C57BL/6 J mice were irradiated with 15 Gy whole chest. RILI was evaluated by qRT-PCR, ELISA, histology, Western blot analysis, immunohistochemistry, and RILI signaling cascade studies. In addition, small interfering RNAs were employed to knockdown cGAS proteins in the cGAS-STING signaling pathway in the human bronchial epithelium cell line (BEAS-2B). Both In Vivo and Vitro experiments were conducted to investigate the specific mechanism by which DHA alleviated RILI. We observed the activation of the cGAS-STING pathway, along with the phosphorylation of the downstream target NF-κB and an increase in inflammatory factor levels in the mouse model following radiation exposure. In the cell model, irradiation also triggered the activation of the cGAS-STING signaling pathway and its downstream targets, leading to elevated levels of inflammatory factors. Notably, knocking down the cGAS using small interfering RNA in the BEAS-2B cells significantly alleviated RILI in the cell model. Our study elucidated the mechanism of DHA reducing RILI through the cGAS/STING/NF-κB signaling pathway, and revealed that the GAS/STING/NF-κB axis may be a potential therapeutic target for RILI.

Hemagglutinin (HA) is a viral glycoprotein that mediates influenza virus entry into the host cell and is considered a relevant viral target. We here report the identification of a class of 4-tert-butylphenyl-substituted spirothiazolidinones as HA-mediated fusion inhibitors with specific activity against influenza A/H3N2 virus. The novel spirocyclic compounds were achieved by using one-pot cyclocondensation method and the chemical structures were characterized by IR, 1H NMR, 13C NMR, and elemental analysis. Compound 2c, bearing methyl substitutions at positions 2- and 8- of the spiro ring displayed an EC50 value against influenza A/H3N2 virus of 1.3 μM and an antiviral selectivity index of 30. The fusion-inhibiting effect of compound 2c was revealed in the polykaryon assay which is based on cell-cell fusion when influenza virus H3 HA-transfected cells are exposed to low pH. Computer-aided docking was performed to predict the possible binding pocket in the H3 HA trimer. Resistance data and in silico studies indicated that compound 2c has an overlapping binding pocket in the stem region of H3 HA with the known fusion inhibitors TBHQ and arbidol.

Studies suggest that vegetarians and Asians have lower mortality rates from prostate cancer compared to men who follow a Western diet. β-sitosterol, a key compound of plant-based diets, has been found to induce significant changes in the ultrasonic structure of the prostatic adenomas, making it a promising candidate for further prostate cancer research. Consequently, we investigated the potential of β-sitosterol and the synthetic derivative 2 as potent inhibitors of androgen synthesis, a critical process for the growth and survival of prostate tumor LNCaP cells. Solubilized LNCaP microsomes were used as a source of SRD5A1 and AKR1C3 to monitor androgen synthesis from labeled androstenedione, both in the presence and absence of β-sitosterol or 2. Furthermore, the effect of these steroids on LNCaP viability was determined using the MTT method. Our findings revealed significant insights into the androgen synthesis pathways in LNCaP cells. The most efficient metabolic route for dihydrotestosterone formation was the conversion of androstenedione to 5α-androstanedione rather than from testosterone in LNCaP. This conclusion is supported by the Vmax values for 5α-androstanedione formation (271.05 ± 5.0 ng/mg protein/min) and the Vmax of testosterone formation (80.1 ± 8.0 ng/mg protein/min). Both β-sitosterol and 2 demonstrated substantial inhibitory effects of these enzymes for dihydrotestosterone formation and significantly reduced cell viability, highlighting their therapeutic potential. These findings enhance our understanding of the inhibitory effects of β-sitosterol and 2 on LNCaP cells and suggest their promising application in the treatment of prostate cancer.

Herein, novel benzosuberone/indanone-linked thiazoles were designed and synthesized as small-molecule SARS-CoV-2 Main protease (Mpro) inhibitors with potential anti-COVID activity. All thiazole derivatives were synthesized from the reaction of thiosemicarbazone derivatives with α-halocarbonyl derivatives. The structures of novel benzosuberone/indanone-linked thiazoles were confirmed based on their spectral data. Thiazolyl-benzosuberone 9d and thiazolyl-indanone 14 were the most potent against Mpro displaying one-digit IC50 values of 5.94 and 8.47 µM, respectively, compared to ritonavir (IC50 = 2.4 µM). Moreover, antiviral assay revealed the ability of compounds 9d and 14 to inhibit the replication of SARS-CoV-2 in Vero cells at EC50 values of 9.33 and 28.75 µM, respectively, relative to ritonavir (EC50 = 1.72 µM). Cytotoxicity assay in Vero cells was also conducted. 9d and 14 showed CC50 values of 289.63 and 229.42 µM and SI of 31.0 and 7.9, respectively. In addition, a docking study revealed proper orientation and well-fitting of title compounds into the binding pocket of SARS-CoV-2 Mpro.

Triple-negative breast cancer (TNBC) is difficult to treat due to the lack of clear therapeutic targets. Paclitaxel (PTX) is commonly used to treat TNBC, but drug resistance limits its effectiveness. Myeloid differentiation protein 2 (MD2) and serum amyloid A1 (SAA1) are involved in various diseases, including infections, inflammatory diseases, and cancer. We investigated their role in PTX resistance to identify potential anti-TNBC drugs. In this study, we investigated the changes of SAA1 in TNBC tissues and its role in PTX-induced TNBC cells. Our study revealed SAA1 expressed in the human TNBC subtype and TNBC cells. PTX and CIS induce SAA1 in TNBC cells, and PTX induces inflammatory response via SAA1 in TNBC cells. MD2 blockade increased the sensitivity of TNBC cells to PTX, which was related to the expression of SAA1 during PTX-caused damage of TNBC cells. In further research, SAA1 binds to MD2, promotes the combination of TLR4/MD2 and TLR4/MyD88, activates the NF-κB signaling pathway, and creates the inflammatory microenvironment for cancer cells. Our study reports for the first time that the PTX/SAA1/MD2 axis exists in the PTX-resistance process, which could be a potential treatment target of PTX-resistance.