Non-small cell lung cancer (NSCLC) is a malignant tumor with high morbidity and mortality. Ginsenosides have been shown to have strong antitumor activity, inhibiting tumor cell growth and promoting apoptosis. In this paper, the effects of ginsenoside CK on the proliferation and apoptosis of NSCLC 95D and NCI-H460 cells were investigated by CCK8, colony formation assay, flow cytometry, fluorescence staining assay, and Western Blot, and it was found that ginsenoside CK could significantly inhibit the growth and proliferation of non-small cell lung cancer, and it was also clarified that the mechanism of its action was realized by the mitochondrial apoptosis pathway. It provides new therapeutic ideas for lung cancer and other major tumor diseases.

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.

MAPKAPK2/MK2 is well implicated in the progression of Head and Neck Squamous Cell Carcinoma (HNSCC), and potent MK2-inhibitors are required to suppress its activity. Several MK2-inhibitors have been developed in recent years to combat its effects on cancer. However, inadequate solubility, insufficient cellular permeability, systemic toxicity-mediated side effects, and low bioavailability have severely impeded the advancement of MK2-inhibitors to clinical trials. This void necessitates research to develop less toxic and more bioavailable potent MK2-inhibitors in HNSCC. In the present article, we have evaluated the in-vitro efficacy, in-vivo single-dose acute toxicity, and in-vivo pharmacokinetic profiling of recently developed PfBS (pyrrolone-fused benzosuberene) MK2-inhibitor analogues against HNSCC. The PfBS MK2 inhibitor analogues impeded HPV+ and HPV- HNSCC cell proliferation and two-dimensional migration. Moreover, MK2-inhibitors lowered HNSCC cell clonogenic survival in a dose-dependent manner, significantly enhancing radiation-induced cell death via exerting radio-sensitization effects. Furthermore, γ-H2AX immunostaining revealed that PfBS analogues impaired DNA damage repair in HNSCC cells exposed to gamma radiation. In mice, PfBS MK2 inhibitors at 300 mg/kg were well-tolerated without any lethal effects. Pharmacokinetic studies showed that PfBS analogues exhibited rapid absorption (Tmax), adequate plasma concentration above the micromolar level (C0 or Cmax), limited tissue distribution (Vd), and faster elimination from the body (Cl). Overall, this study summarizes in-vitro efficacy, safety, and pharmacokinetics of developed MK2-inhibitors and opens doors for pharmacodynamics and mechanism of action study of most effective leads in HNSCC.

The headway for the management of emerging resistant microbial strains has become a demanding task. Over the years, antimicrobial peptides (AMP), have been recognized and explored for their highly systematized SAR and antibacterial properties. With this background, we have reported a new class of AMPs. These peptides incorporate an unnatural amino acid, with a motivation from cruciferous bioactive phytochemical bisindoles methane derivatives with highly selective antimicrobial action. These peptides may also be considered as linear derivatives of hirsutide isolated from entomopathogenic fungus. The synthesized peptides were tested for their antimicrobial activity against an ESKAPE pathogen panel, where peptide 3 exhibited equipotent MIC and potent synergistic action along with gentamicin against Staphylococcus aureus and Enterococcus clinical isolates. This combination was also able to repotentiate gentamicin against NRS119, a gentamicin-resistant MRSA. Molecular dynamics study and free energy calculations provided insights to membrane disruptive properties of AMP action, which assisted gentamicin pass through the lipid-water interface.

Owing to the presence of the blood-brain barrier and the lack of significant specificity towards tumor cells after entry into the brain, the unsuccessful delivery of anticancer drugs to the treatment of brain tumors. The hypothesis that cholesterol-PEG co-modified poly (N-butyl) cyanoacrylate nanoparticles (CLS-PEG NPs) are an effective carrier for the treatment of brain tumors was verified, and the mechanism of its treatment for brain tumors was preliminarily explored. In this study, we used multifunctional poly (N-butyl) cyanoacrylate nanoparticles modified with cholesterol and polyethylene glycol (PEG) as a drug delivery system to encapsulate the anticancer drug docetaxel (DTX). Cell anti-proliferation tests showed that CLS-PEG NPs increased the inhibitory effect of DTX. A pharmacokinetic study indicated that CLS-PEG NPs achieved sustained release for 8 h. These experimental results demonstrated that CLS-PEG NPs amplified the concentration of the drug transported to the brain and sustained drug release in the brain. In addition, CLS-PEG NPs led to better pharmacological efficacy in an orthotopic brain glioma rat model. The survival rate of rats in the CLS-PEG NPs group was significantly prolonged to 28 d. We also found that CLS-PEG NPs inhibited M2 microglial polarization. These results indicate that CLS-PEG NPs are a prospective drug delivery system for targeting brain tumors.

Palmatine (PAL), as an active ingredient in traditional Chinese medicine, had been demonstrated efficacy in ameliorating the manifestations of AD. Our research group has previously designed and synthesized the novel oxo-PAL derivative 2q and found that it has exhibited notable neuroprotective properties. However, compound 2q therapeutic impact on AD remains uncertain. In the current investigation, our findings demonstrated that compound 2q displayed significant anti-AβOs activity in vitro by using xCELLigence analysis, and showed a high likelihood of crossing the blood-brain barrier. Furthermore, administration of compound 2q yielded a notable amelioration in Aβ accumulation and hyperphosphorylation of Tau in 3×Tg mice. Additionally, it was observed that compound 2q potentially enhanced the pathological characteristics of AD by targeting Potassium/Sodium Hyperpolarization-Activated Cyclic Nucleotide-Gated Channel 2 (HCN2). In conclusion, compound 2q emerged as a promising candidate for AD treatment, as it effectively restored AD-associated pathological impairments. Furthermore, it has been identified as a potential target of HCN2, thereby offering novel avenues for the development of treatments for AD.

Recently, there has been an increasing interest in the use of protein kinase inhibitors as a therapeutic strategy for the treatment of cancer. In this study, a new series of 2H-chromene derivatives (2-5 and 6-8) and 3H-benzo[f]chromene carbohydrazide derivative (9) were synthesized. The structure of the designed derivatives was characterized by IR, H/C NMR, and elemental analysis. Moreover, the cytotoxic activity of the newly synthesized chromenes was evaluated against breast cancer cell lines (MDA-MB-231 and MCF-7) and a cervical cancer cell line (HeLa). The results of these evaluations demonstrated promising activity, ranging from good to moderate. Additionally, the lung fibroblast cell line (WI-38), as a normal cell line, was also utilized to assess the active derivatives' selectivity. Among the compounds tested, chromene derivative 3 demonstrated the highest potency, exhibiting IC values of 5.36 ± 0.50, 7.82 ± 0.60, and 9.28 ± 0.70 µM against the MDA-MB 231, MCF-7, and HeLa cell lines, respectively. The potential of chromone 3 as a multi-targeted anticancer agent was assessed by evaluating its activity against BRAF and VEGFR-2. Notably, the most promising chromene derivative 3 demonstrated significant VEGFR2 activity with an IC value of 0.224 µM compared to sorafenib's 0.045 µM, while exhibiting inhibitory activity against BRAF with an IC value of 1.695 µM relative to Vemurafenib's IC value of 0.468 µM. In addition, compound 3 inhibits the DHFR enzyme with an IC value of 2.217 ± 0.014 µM, compared to methotrexate (IC = 0.4315 ± 0.019 µM). These results revealed that the compound has multifaceted mechanisms of action that may augment its therapeutic effectiveness. In addition, compound 3 causes overexpression of caspase-3 and Bax by 6.13 and 8.85-fold, respectively. It also downregulates the antiapoptotic Bcl-2 level by 0.4775-fold compared to the untreated MDA-MB 231 cells. Flow cytometry analysis of MDA-MB-231 cells indicates that compound 3 induces cell cycle arrest in the G0-G1 phase, with an observed percentage of 73.15%. The in-silico toxicity prediction was evaluated and demonstrated a good toxicity profile. Finally, molecular docking studies supported these findings by confirming strong binding affinities of the derivatives to VEGFR-2, BRAF, and DHFR.

Herein, we report the design, synthesis, and characterization of novel organoselenium (OSe) hybrids (5-19) via modifications of the lead, N-(4-selaneylphenyl)-2-selaneylacetamide. The OSe-based thiazol 9 showed the highest growth inhibition % (GI%) of 64.72% relative to the positive reference doxorubicin (DOX), with a GI% of 79.5%. Furthermore, the novel OSe derivatives showed low GI% values compared to the normal cell lines employed, demonstrating their selectivity. The OSe tethered N-chloroacetamide 5 and Schiff base 19 showed a cytotoxic effect with an IC of (25.07 and 11.61 µM), respectively, against the A549 tumor cell line and IC of (34.22 and 20.12 µM), respectively, against the HELA cancer cell line. Enzyme-linked immunosorbent assay to study the JAK1 and the STAT3 inhibitory potentials of OSe compounds 5 and 19 in the A549 cancer cells both showed promising inhibitory activities with IC values of 25.07 and 11.61 µM, respectively. Protein expression analysis on the A549 cancer cell line on OSe compounds 5 and 19 showed upregulation of P53, BAX, and Caspases 3, 6, 8, and 9 as apoptotic proteins. However, both candidates expressed downregulation of the antiapoptotic proteins (BCL2, MMP2, and MMP9). Moreover, OSe compounds 5 and 19 described the downregulation of the examined inflammatory proteins: COX2, IL-6, and IL-1β. In addition, OSe compound 19 showed potential cell cycle arrest at the G0, S, and G2-M layers, with an increase in cellular levels. Finally, molecular docking studies of OSe compound 19 showed the most promising inhibitory potential toward the JAK1 and STAT3 target receptors, with binding scores and interactions exceeding that of the cocrystallized inhibitor of JAK1.

Although topical minoxidil is the most common drug for alopecia areata (AA), it has limited therapeutic effect in the treatment of patients with moderate and severe AA because it can only promote hair follicle growth and improve the characteristics of hair follicle degeneration in AA and cannot alleviate local inflammatory response. Therefore, we designed a novel topical compound gel loading minoxidil and Janus kinases (JAK) inhibitors tofacitinib. The compound gel not only had good semi-solid properties and the effect of permeation but also maintained stability for up to 3 months under accelerated conditions, ensuring the long-term quality of the formulation. This compound gel can effectively improve hair follicle growth and significantly alleviate local inflammatory response by downregulation of the ratio of inflammatory factor interferon-γ to anti-inflammatory factor interleukin-4 in C3H/HeN mice bearing AA, achieving the purpose of synergistic treatment of AA. The first combination of minoxidil and tofacitinib in a topical formulation gives a new idea for the clinical treatment of AA.

Intracerebral hemorrhage (ICH) is the most common subtype of hemorrhage stroke, with a high disability, morbidity and mortality rate globally. Panaxadiol (PD), a triterpenoid sapogenin monomer, is isolated from the roots of ginseng, which has shown a variety of biological properties, such as anti-inflammation, anti-cancer, and neuroprotection. However, its effect and mechanism on ICH were still unknown. Thirty-six rats were randomly divided into six group (n = 6), namely, sham, ICH, ICH + 5 mg/kg PD, ICH + 10 mg/kg PD, ICH + 20 mg/kg PD, and ICH + 10 mg/kg PD + 50 mg/kg vismodegib. Rats were treated with type IV collagenase to induce an in vivo model of ICH, and then intraperitoneally injected with PD (5, 10 and 20 mg/kg) and 50 mg/kg vismodegib (an inhibitor of hedgehog signal). The effect and potential mechanism of PD on ICH were explored by behavioral test, brain water content measurement, Evans blue detection, hematoxylin-eosin (HE) staining, iron level examination, Prussian blue staining, western blot and immunohistochemistry, respectively. An increase in the mNSS (13.17 ± 1.17), and a decrease in the rotarod latency (40.67 ± 9.31), modified Garcia score (9.83 ± 1.47), forelimb use times (3.33 ± 0.82), left forepaw placements (29.90 ± 4.38) and left turns (17.34 ± 3.55) in ICH rats were reversed with the PD treatment (6.83 ± 0.75, 113.5 ± 11.95, 17.50 ± 1.87, 8.17 ± 0.98, 63.56 ± 9.84, and 42.13 ± 4.52 respectively). PD treatment reduced the brain water content (73.13 ± 3.16 vs. 86.82 ± 4.74), the level of Evans blue (2.14 ± 0.25 vs. 4.03 ± 0.20) and cerebral hemorrhage in ICH rats. Also, PD injection decreased the iron level (0.06 ± 0.005 vs. 0.17 ± 0.02) and the expression of ACSL4 (0.56 ± 0.07 vs. 1.23 ± 0.16), with the increased expression of GPX4 (1.14 ± 0.08 vs. 0.21 ± 0.03) in ICH rats. Mechanically, PD treatment restored the decreased expression of SHH (0.96 ± 0.13 vs. 0.20 ± 0.03), GLI1 (0.89 ± 0.13 vs. 0.06 ± 0.007) and PTCH (0.75 ± 0.05 vs. 0.10 ± 0.01) in ICH rats. Inhibition of SHH signaling by vismodegib reversed the ameliorative effect of PD on ICH rats. PD improved brain damage by suppressing ferroptosis via the activation of the SHH/GLI signaling pathway, which could lay a theoretical foundation for the treatment of ICH.

Herein, novel benzosuberone/indanone-linked thiazoles were designed and synthesized as small-molecule SARS-CoV-2 Main protease (M) 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 M displaying one-digit IC values of 5.94 and 8.47 µM, respectively, compared to ritonavir (IC = 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 EC values of 9.33 and 28.75 µM, respectively, relative to ritonavir (EC = 1.72 µM). Cytotoxicity assay in Vero cells was also conducted. 9d and 14 showed CC 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 M.

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, H NMR, C NMR, and elemental analysis. Compound 2c, bearing methyl substitutions at positions 2- and 8- of the spiro ring displayed an EC 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.

Carboxymethyl starch (CMS) represents a significant advancement in addressing the multifaceted challenges of anticancer drug delivery, including poor aqueous solubility, nonspecific biodistribution, and premature drug release. The strategic incorporation of carboxymethyl moiety (-CHCOOH) onto the starch backbone confers a suite of physicochemical properties that markedly enhance its efficacy as a drug carrier. The carboxymethyl groups, with a pKa of approximately 4.5, exhibit pronounced pH-responsiveness, undergoing a transition from a predominantly deprotonated, hydrophilic state at physiological pH (7.4) to a more protonated form in the acidic tumor microenvironment (pH 6.5-6.8) facilitating targeted drug release at neoplastic site. The mucoadhesive attributes ascribable to carboxyl-mucin interactions, prolong gastrointestinal residence time for oral formulations, optimizing drug absorption. Furthermore, these functional groups serve as reactive sites for subsequent modifications, facilitating the development of multifunctional, targeted drug delivery systems with enhanced biocompatibility and minimized off-target effects. The versatility and biocompatibility of CMS position it as a promising platform for next-generation anticancer therapeutics, offering potential for significant advancements in oncological treatment modalities.

Biofilm is a "growing" problem and needs effective remedial agents. Here we report novel methyl 4-((4-(4-chlorophenyl)-2,5-dioxoimidazolidin-1-yl) methyl) benzoate derivatives (5a-l) as antibiofilm and antimicrobial agents evaluated with both in silico and in vitro techniques. When it comes to Gram-positive bacterial strains like Staphylococcus aureus (MTCC 737), MRSA and Streptococcus pneumoniae (MTCC 1936), and Gram-negative bacterial strains like Pseudomonas aeruginosa (MTCC 424) and Escherichia coli (MTCC 443), the minimum inhibitory concentration (MIC), minimum biofilm inhibition concentration (MBIC), and anti-biofilm activity were measured. Out of all the compounds (5a-l), 5b and 5d showed no toxicity to mammalian cells and were equally active against various Gram-positive and Gram-negative bacteria at low concentrations (MIC: 0.1-9.5 µg/mL). Compounds 5b and 5d were also validated for the DNA gyrase inhibition potential as an antimicrobial mechanism of action in vitro. These compounds showed high level DNA gyrase inhibition potentials (IC 0.025 µM, ≥ 98 relative % activity and 0.24 µM, ≥ 94 relative % activity respectively. In the end, we have identified 5b and 5d as most effective among 5a-l and are considered for further preclinical studies.

Tissue plasminogen activators (tPAs) are critical in fibrinolysis and have become central to treating thrombotic disorders, including heart attacks, strokes, and pulmonary embolisms. Despite their efficacy, challenges such as bleeding complications, limited fibrin specificity, and rapid clearance necessitate the discovery of novel tPAs and the engineering of improved variants. This review highlights strategies for the discovery of tPAs from natural sources, including human, bacterial, venom-derived, and bat saliva-derived agents, as well as enzyme engineering approaches that enhance functional characteristics such as half-life, fibrin specificity, resistance to inhibitors, and clot penetration. Furthermore, this review explores alternative therapeutic approaches independent of tPAs, focusing on nonplasminogen activator agents and strategies that target platelets. By addressing current challenges and identifying future opportunities, this review provides a comprehensive perspective on advancing thrombolytic therapies through innovative discovery and design strategies.

The fungal infection gradually poses a life threat to mankind, candidiasis caused by Candida sp. is one among them. We describe the aspartate protease inhibition potentials of 12 sulfonyl-containing imidazolidines (5a-l) anti-candidal agents. Candida Albicans secretes aspartic proteases (Saps), one of its most important virulent agents. These hydrolytic enzymes are critical for both fungal physiological processes and host-fungus interactions. Compounds 5a-l were examined for their fungal aspartate protease inhibition apart from their anti-candida activity. These findings were equipped and validated in silico using molecular docking and in vitro enzyme inhibition assays. The study found that imidazolidine derivatives inhibited aspartic protease and exhibited anti-candida action. Conclusively, imidazolidines 5g, 5h, and 5j were perceived as the most potent anti-candida compounds and are presently being evaluated for their preclinical studies.

The emergence of drug-resistant bacteria, often referred to as "superbugs," poses a profound and escalating challenge to global health systems, surpassing the capabilities of traditional antibiotic discovery methods. As resistance mechanisms evolve rapidly, the need for innovative solutions has never been more critical. This review delves into the transformative role of AI-driven methodologies in antibiotic development, particularly in targeting drug-resistant bacterial strains (DRSBs), with an emphasis on understanding their mechanisms of action. AI algorithms have revolutionized the antibiotic discovery process by efficiently collecting, analyzing, and modeling complex datasets to predict both the effectiveness of potential antibiotics and the mechanisms of bacterial resistance. These computational advancements enable researchers to identify promising antibiotic candidates with unique mechanisms that effectively bypass conventional resistance pathways. By specifically targeting critical bacterial processes or disrupting essential cellular components, these AI-designed antibiotics offer robust solutions for combating even the most resilient bacterial strains. The application of AI in antibiotic design represents a paradigm shift, enabling the rapid and precise identification of novel compounds with tailored mechanisms of action. This approach not only accelerates the drug development timeline but also enhances the precision of targeting superbugs, significantly improving therapeutic outcomes. Furthermore, understanding the underlying mechanisms of these AI-designed antibiotics is crucial for optimizing their clinical efficacy and devising proactive strategies to prevent the emergence of further resistance. AI-driven antibiotic discovery is poised to play a pivotal role in the global fight against antimicrobial resistance. By leveraging the power of artificial intelligence, researchers are opening new frontiers in the development of effective treatments, ensuring a proactive and sustainable response to the growing threat of drug-resistant bacteria.

Leishmaniasis, caused by protozoan parasites of the genus Leishmania, affects nearly 12 million people annually worldwide, and has limited, highly toxic therapeutic options. This study reports the synthesis, in vitro and in silico evaluations of four novel antimony complexes (3a-3d) as potent and safe antileishmanial agents. The complexes were synthesized using Sb-salts with different phenolic ligands and characterized by elemental analysis, FT-IR and NMR spectroscopic techniques. Structural parameters were further evaluated via DFT studies. The antileishmanial activity of these complexes (3a-3d) was assessed in vitro against promastigote and axenic amastigote forms of Leishmania tropica, showing promising potential as antileishmanial agents. Complex 3a and 3c were particularly active, with IC values of 10.8 ± 2.1 and 11.0 ± 2.0 μmol/L against promastigotes, and 20.14 ± 6.11 and 27.72 ± 0.13 μmol/L against amastigotes, respectively. Molecular docking analysis against receptor protein (PDB ID: 8FI6) from genus Leishmania revealed high binding conformations of synthesized molecules within the active cavity of the target protein. With the lowest Ki value of 1.25 and a pattern of hydrophobic π-interactions and strong conventional hydrogen bonds, complex 3d demonstrated excellent binding affinities within the active pocket. Notably, these complexes exhibited low cytotoxicity, compared to the standard antileishmanial drugs, TA (potassium antimonyl tartrate) and AmB (Amphotericin B), with hemolysis rates of < 12% for all complexes. Our findings suggest that these complexes (3a-3d) are promising candidates for the development of new, safer antileishmanial therapies, combining potent activity against L. tropica with significantly lower cytotoxicity compared to existing treatments.

Curcumin, a polyphenol compound derived from turmeric, has garnered attention for its anti-inflammatory and antioxidant properties, making it a promising candidate for treating skin inflammation. Despite its potential, the underlying pharmacological effects to skin inflammation remain unclear. Therefore, this study aimed to reveal the curcumin's molecular targets and its potential in suppressing skin inflammation using network pharmacology and in vitro experiments. A total of 7,393 and 239 targets related to curcumin and skin inflammation, respectively, were obtained from public databases. By drawing a Venn diagram, 216 common targets were identified as candidate targets. These targets were subjected to gene function and pathway enrichment analyses, and a protein-protein interaction network was established to investigate curcumin's impact on inflammation. The gene functions were mainly associated with inflammatory response, membrane raft, and serine-type endopeptidase activity. The NF-κB and MAPK pathways could be the major pathways through which curcumin acts on skin inflammation. Ten major targets of curcumin in the treatment of skin inflammation were identified: AKT1, TNF, EGFR, APP, MMP9, STAT3, HIF1A, PTGS2, EP300, and GSK3B. Molecular docking analysis results showed high binding affinity of curcumin to PTGS2, GSK3B, HIF1A, and STAT3, which may contribute to its inhibitory effect on skin inflammation. In vitro experiments confirmed curcumin's anti-inflammatory effect on inflammation by reducing the expression levels of NO, IL-1β, and IL-6 in LPS-induced HaCaT cells. Taken together, this study reveals major targets and pathways of curcumin in the treatment of skin inflammation, paving the way for invivo and clinical investigations.

This study aimed to explore the function and regulatory mechanism of ALKBH5 in the progression of coronary artery calcification. Human aortic vascular smooth muscle cells (HA-VSMCs) were treated with inorganic phosphate (Pi) and exosomes derived from bone marrow mesenchymal stem cell (BMSC) carrying ALKBH5, a GSDME overexpression vector or si-GSDME. The morphology and size of the exosomes were assessed using nanoparticle tracking analysis (NTA) and transmission electron microscopy (TEM). Calcium deposition was measured using Alizarin red staining and cell pyroptosis was evaluated using Hoechst 33342/PI staining. The association between ALKBH5 and m6A modifications was confirmed by methylated-RNA immunoprecipitation assay (MeRIP) and dot blot assays. The expression levels of ALKBH5 and GSDME were quantified by quantitative real-time polymerase chain reaction (qRT-PCR), and protein levels were quantified by western blot. BMSCs-derived exosomes reduced calcium deposition and cell pyroptosis in Pi-treated HA-VSMCs. Exosomes containing ALKBH5 overexpression inhibited high mobility group box 1 (HMGB1) and cell apoptosis, thereby promoting vascular calcification, whereas ALKBH5 knockdown in exosomes exerted the opposite effect on calcification development. Additionally, ALKBH5 was found to regulate the m6A modification of GSDME. Overexpression of GSDME reversed the effects of ALKBH5 in exosomes on HMGB1 expression and cell apoptosis. Exosomal ALKBH5 mitigated HMGB1 expression and cell pyroptosis by modulating the m6A modification of GSDME, thus influencing the progression of coronary artery calcification.