Anti-Inflammatory, Analgesic and Anti-Oxidant Effects of Shirakiopsis Indica (Willd). Fruit Extract: A Mangrove Species in the Field of Inflammation Research.

Background: Shirakiopsis indica (Willd)., commonly known as Sa-Mor-Ta-Lay in Thailand, is a mangrove plant belonging to the Euphorbiaceae family. As mangrove plants' medicinal potentials are less explored, this study sought to qualitatively and quantitatively verify the bioactive components of Shirakiopsis indica fruits methanolic extract (SIF-ME) at the side of its analgesic, anti-inflammatory and anti-oxidant effects followed by in-silico studies. Methods: The in-vivo assessments of analgesic activity involved the hot plate test, acetic acid-induced writhing test, and formalin-induced licking test. The anti-inflammatory efficacy was assessed through the human RBC membrane stabilization assay (HRBC), protein denaturation assay, and xylene-induced ear edema methods. Antioxidant potential was implemented by the DPPH scavenging method. Results: The SIF-ME consistently displayed significant anti-nociceptive activity in a dose-dependent pattern (p < 0.05). The maximum analgesic activity was found in the highest dose (200 mg/kg; p < 0.001) in a hot plate, acetic acid-induced writhing test 43.47%, and in formalin-induced licking test in both early phase (43.3%; p < 0.01) and late phase (61.84%; p < 0.001%). The extract provided optimal protection against hemolysis (83.41% decrease) at 1000 µg/mL and significantly inhibited protein denaturation (67.34-26.05%) at doses of 1000-62.5 µg/mL. At 200 mg/kg, the extract showed dose-dependent and substantial inhibition (54.07%; p < 0.01) of xylene-induced ear edema. The in-vitro DPPH (IC50 = 469.5 µg/mL) results showed remarkable scavenging activity and concentration-dependent reducing power. The extract demonstrates no acute oral toxicity, as indicated by an LD50 value exceeding 1000 mg/kg body weight. Gas Chromatography-Mass Spectrometry/Mass Spectrometry (GC-MS/MS) analysis was performed which yielded sixty bioactive compounds. In-silico and molecular docking studies revealed favorable pharmacological properties, including good binding affinities and ADME/T profiles. Conclusion: These results support the medicinal use of the plant, which makes it a potential source of analgesic, anti-inflammatory, and antioxidant candidates.

Chemico-pharmacological evaluations of the dwarf elephant ear (Colocasia affinis Schott) plant metabolites and extracts: health benefits from vegetable source.

Introduction: Colocasia affinis Schott (Family: Araceae), found in the Asian region, is a traditional root vegetable consumed by the locals and well-known as Dwarf Elephant Ear. Methods: For the pharmacological exploration of this root vegetable, four kupchan fractions (i.e. HSF, DCMSF, EASF, and AQSF) from ethanolic extract of C. affinis were employed to in vitro i.e. antioxidant, cytotoxicity, and antimicrobial and in vivo i.e. antidiarrheal and analgesic assays, followed by phytochemical screening and GC-MS protocol. Result and Discussion: In the antioxidant assay, the AQSF showed promising potential with an IC50 value of 29.4 µg/mL and additionally, it exhibited the greatest overall phenolic content, measuring 57.23 mg GAE/gm. of extract among other fractions. The AQSF also revealed promising cytotoxic activity in brine shrimp lethality assay with an LC50 value of 1.36 µg/mL. Both AQSF and EASF exhibited substantial antimicrobial efficacy against both gram-positive and gram-negative bacteria as well as various fungus species with a remarkable zone of inhibitions compared to standards. Whereas, during both the castor oil-induced antidiarrheal and acetic acid-induced writhing assay, the DCMSF at 400 mg/kg dose exhibited the highest 51.16% reduction of diarrhea and 52.33% reduction of writhing. Phytochemical screening revealed several chemical groups while GC-MS study of different fractions of dwarf elephant ear ethanolic extract revealed 48 different bioactive phytochemicals in total. Several targets such as KAS, DHFR for anti-microbial activities, GLR, URO for antioxidant activities, EGFR, BCL-2 for cytotoxicity, KOR, DOR for antidiarrheal activities and COX-2, TNF-α for analgesic activities are considered for molecular docking against identified phytocompounds and standards along with ADME/T studies to ascertain their safety, efficacy and drug likeliness profiles. Conclusion: To recapitulate, our study revealed that vegetables such as dwarf elephant ear can be considered as a prospective source of therapeutics and drug development besides their nutritive food values.

Unveiling the Therapeutic Potentials of Water Hyacinth (Eichhornia crassipes (Mart.) Solms) Flower against Oxidative Stress, Inflammation and Depressive Disorders: GC-MS/MS, In Vitro, In Vivo and In Silico Approaches.

Water hyacinth (Eichhornia crassipes (Mart.) Solms) is a highly invasive aquatic weed native to the Amazonia basin, known for its rapid propagation, adaptability and utilization in traditional medicine. The study aims to unveil the therapeutic potential of water hyacinth flowers methanolic extract (EC-CME) and its four kupchan fractions (EC-PESF, EC-DCMSF, EC-EASF, EC-ASF) through diversified chemical-pharmacological approaches. GC-MS/MS of EC-CME uncovered a rich tapestry of 72 phytochemical components. In vitro DPPH scavenging assay and total phenolic content determination assay deciphered promising antioxidant assays with remarkably low IC50 values of 0.353 and 0.485 µg/mL, respectively for EC-ESF and EC-ASF. Besides, different in vivo tests, including tail emersion, acetic acid-induced writhing, and thiopental-induced sleeping test of EC-CME, yielded a remarkable 8.61 ± 0.29 minutes of tail immersion time compared to the control's 2.05 ± 0.11 minutes at the highest dose (600 mg/kg). The best % inhibition of writhing was recorded as 47.96% accrued in 400 mg/kg dose, indicating robust pain-relieving properties. The onset and duration of sleep are significantly ameliorated for EC-CME, unveiling its antidepressant potential. Besides, molecular docking studies along with ADME/T analysis also validated the wet lab findings as well as their safety, efficacy and drug-likeliness profile.

Asymmetric Intramolecular Amination Catalyzed with Cp*Ir-SPDO via Nitrene Transfer for Synthesis of Spiro-Quaternary Indolinone.

An asymmetric intramolecular spiro-amination to high steric hindering α-C-H bond of 1,3-dicarbonyl via nitrene transfer using inactive aryl azides has been carried out by developing a novel Cp*Ir(III)-SPDO (spiro-pyrrolidine oxazoline) catalyst, thereby enabling the first successful construction of structurally rigid spiro-quaternary indolinone cores with moderate to high yields and excellent enantioselectivities. DFT computations support the presence of double bridging H-F bonds between [SbF6]- and both the ligand and substrate, which favors the plane-differentiation of the enol π-bond for nitrenoid attacking. These findings open up numerous opportunities for the development of new asymmetric nitrene transfer systems.

Macrophage biomimetic nanoparticle-targeted functional extracellular vesicle micro-RNAs revealed via multiomics analysis alleviate sepsis-induced acute lung injury.

Patients who suffer from sepsis typically experience acute lung injury (ALI). Extracellular vesicles (EVs) contain miRNAs, which are potentially involved in ALI. However, strategies to screen more effective EV-miRNAs as therapeutic targets are yet to be elucidated. In this study, functional EV-miRNAs were identified based on multiomics analysis of single-cell RNA sequencing of targeted organs and serum EV (sEV) miRNA profiles in patients with sepsis. The proportions of neutrophils and macrophages were increased significantly in the lungs of mice receiving sEVs from patients with sepsis compared with healthy controls. Macrophages released more EVs than neutrophils. MiR-125a-5p delivery by sEVs to lung macrophages inhibited Tnfaip3, while miR-221-3p delivery to lung neutrophils inhibited Fos. Macrophage membrane nanoparticles (MM NPs) loaded with an miR-125a-5p inhibitor or miR-221-3p mimic attenuated the response to lipopolysaccharide (LPS)-induced ALI. Transcriptome profiling revealed that EVs derived from LPS-stimulated bone marrow-derived macrophages (BMDMs) induced oxidative stress in neutrophils. Blocking toll-like receptor, CXCR2, or TNFα signaling in neutrophils attenuated the oxidative stress induced by LPS-stimulated BMDM-EVs. This study presents a novel method to screen functional EV-miRNAs and highlights the pivotal role of macrophage-derived EVs in ALI. MM NPs, as delivery systems of key sEV-miRNA mimics or inhibitors, alleviated cellular responses observed in sepsis-induced ALI. This strategy can be used to reduce septic organ damage, particularly lung damage, by targeting EVs.

Enhanced Pharmacokinetics of Celastrol via Long-Circulating Liposomal Delivery for Intravenous Administration.

Background: Rheumatoid Arthritis (RA) involves prolonged inflammation of the synovium, damaging joints and causing stiffness and deformity. Celastrol (Cel), derived from the Chinese herbal medicine Tripterygium wilfordii Hook F, offers immunosuppressive effects for RA treatment but is limited by poor solubility and bioavailability. Purpose: In this study, long-circulating Cel-loaded liposomes (Cel-LPs) were used to increase the pharmacokinetics of Cel, thereby improving drug delivery and efficacy for the treatment of RA. Methods: Cel-LPs were prepared and administered orally and intravenously to compare the elimination half-life of drugs and bioavailability of Cel. Cel-LPs were prepared using the lipid thin-layer-hydration-extrusion method. Human rheumatoid arthritis synovial (MH7A) cells were used to investigate the compatibility of Cel-LPs. The pharmacokinetic studies were performed on male Sprague-Dawley (SD) rats. Results: The Cel-LPs had an average size of 72.20 ± 27.99 nm, a PDI of 0.267, a zeta potential of -31.60 ± 6.81 mV, 78.77 ± 5.69% drug entrapment efficiency and sustained release (5.83 ± 0.42% drug loading). The cytotoxicity test showed that liposomes had excellent biocompatibility and the fluorescence microscope diagram indicated that liposome entrapment increased intracellular accumulation of Rhodamine B by MH7A cells. Furthermore, the results exhibited that Cel-LPs improved the pharmacokinetics of Cel by increasing the elimination half-life (t1/2) to 11.71 hr, mean residence time (MRT(0-∞)) to 7.98 hr and apparent volume of distribution (Vz/F) to 44.63 L/kg in rats, compared to the Cel solution. Conclusion: In this study, liposomes were demonstrated to be effective in optimizing the delivery of Cel, enabling the formulation of Cel-LPs with prolonged blood circulation and sustained release characteristics. This formulation enhanced the intravenous solubility and bioavailability of Cel, developing a foundation for its clinical application in RA and providing insights on poorly soluble drug management.

Pyroptosis in Diabetic Peripheral Neuropathy and its Therapeutic Regulation.

Pyroptosis is a pro-inflammatory form of cell death resulting from the activation of gasdermins (GSDMs) pore-forming proteins and the release of several pro-inflammatory factors. However, inflammasomes are the intracellular protein complexes that cleave gasdermin D (GSDMD), leading to the formation of robust cell membrane pores and the initiation of pyroptosis. Inflammasome activation and gasdermin-mediated membrane pore formation are the important intrinsic processes in the classical pyroptotic signaling pathway. Overactivation of the NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome triggers pyroptosis and amplifies inflammation. Current evidence suggests that the overactivation of inflammasomes and pyroptosis may further induce the progression of cancers, nerve injury, inflammatory disorders and metabolic dysfunctions. Current evidence also indicates that pyroptosis-dependent cell death accelerates the progression of diabetes and its frequent consequences including diabetic peripheral neuropathy (DPN). Pyroptosis-mediated inflammatory reaction further exacerbates DPN-mediated CNS injury. Accumulating evidence shows that several molecular signaling mechanisms trigger pyroptosis in insulin-producing cells, further leading to the development of DPN. Numerous studies have suggested that certain natural compounds or drugs may possess promising pharmacological properties by modulating inflammasomes and pyroptosis, thereby offering potential preventive and practical therapeutic approaches for the treatment and management of DPN. This review elaborates on the underlying molecular mechanisms of pyroptosis and explores possible therapeutic strategies for regulating pyroptosis-regulated cell death in the pharmacological treatment of DPN.

Recent advances in molecular mechanisms of skin wound healing and its treatments.

The skin, being a multifaceted organ, performs a pivotal function in the complicated wound-healing procedure, which encompasses the triggering of several cellular entities and signaling cascades. Aberrations in the typical healing process of wounds may result in atypical scar development and the establishment of a persistent condition, rendering patients more vulnerable to infections. Chronic burns and wounds have a detrimental effect on the overall quality of life of patients, resulting in higher levels of physical discomfort and socio-economic complexities. The occurrence and frequency of prolonged wounds are on the rise as a result of aging people, hence contributing to escalated expenditures within the healthcare system. The clinical evaluation and treatment of chronic wounds continue to pose challenges despite the advancement of different therapeutic approaches. This is mainly owing to the prolonged treatment duration and intricate processes involved in wound healing. Many conventional methods, such as the administration of growth factors, the use of wound dressings, and the application of skin grafts, are used to ease the process of wound healing across diverse wound types. Nevertheless, these therapeutic approaches may only be practical for some wounds, highlighting the need to advance alternative treatment modalities. Novel wound care technologies, such as nanotherapeutics, stem cell treatment, and 3D bioprinting, aim to improve therapeutic efficacy, prioritize skin regeneration, and minimize adverse effects. This review provides an updated overview of recent advancements in chronic wound healing and therapeutic management using innovative approaches.

Atroposelective synthesis of biaxial bridged eight-membered terphenyls via a Co/SPDO-catalyzed aerobic oxidative coupling/desymmetrization of phenols.

Bridged chiral biaryls are axially chiral compounds with a medium-sized ring connecting the two arenes. Compared with plentiful methods for the enantioselective synthesis of biaryl compounds, synthetic approaches for this subclass of bridged atropisomers are limited. Here we show an atroposelective synthesis of 1,3-diaxial bridged eight-membered terphenyl atropisomers through an Co/SPDO (spirocyclic pyrrolidine oxazoline)-catalyzed aerobic oxidative coupling/desymmetrization reaction of prochiral phenols. This catalytic desymmetric process is enabled by combination of an earth-abundant Co(OAc)2 and a unique SPDO ligand in the presence of DABCO (1,4-diaza[2.2.2]bicyclooctane). An array of diaxial bridged terphenyls embedded in an azocane can be accessed in high yields (up to 99%) with excellent enantio- (>99% ee) and diastereoselectivities (>20:1 dr).

Discovery of Small and Bifunctional Molecules Targeting PD-L1/CD73 for Cancer Dual Immunotherapy.

In this work, a series of bifunctional PD-L1/CD73 (cluster of differentiation 73) small-molecule inhibitors were designed and synthesized. Among them, CC-5 showed the strongest PD-L1 inhibitory effects with an IC50 of 6 nM and potent anti-CD73 activity with an IC50 of 0.773 µM. The high PD-L1/CD73 inhibitory activity of CC-5 was further confirmed by SPR assays with KD of 182 nM for human PD-L1 and 101 nM for CD73, respectively. Importantly, CC-5 significantly suppressed tumor growth in a CT26 and B16-F10 tumor model with TGI of 64.3% and 39.6%, respectively. Immunohistochemical (IHC) and flow cytometry analysis of tumor-infiltrating lymphocytes (TILs) indicated that CC-5 exerted anticancer effects via activating the tumor immune microenvironment. Collectively, CC-5 represents the first dual PD-L1/CD73 inhibitor worthy of further research as a bifunctional immunotherapeutic agent.

The Impact of Baohuoside I on the Metabolism of Tofacitinib in Rats.

Purpose: To study the potential drug-drug interactions between tofacitinib and baohuoside I and to provide the scientific basis for rational use of them in clinical practice. Methods: A total of eighteen Sprague-Dawley rats were randomly divided into three groups: control group, single-dose group (receiving a single dose of 20 mg/kg of baohuoside I), and multi-dose group (receiving multiple doses of baohuoside I for 7 days). On the seventh day, each rat was orally administered with 10 mg/kg of tofacitinib 30 minutes after giving baohuoside I or vehicle. Blood samples were collected and determined using UPLC-MS/MS. In vitro effects of baohuoside I on tofacitinib was investigated in rat liver microsomes (RLMs), as well as the underlying mechanism of inhibition. The semi-inhibitory concentration value (IC50) of baohuoside I was subsequently determined and its inhibitory mechanism against tofacitinib was analyzed. Furthermore, the interactions between baohuoside I, tofacitinib and CYP3A4 were explored using Pymol molecular docking simulation. Results: The administration of baohuoside I orally has been observed to enhance the area under the concentration-time curve (AUC) of tofacitinib and decrease the clearance (CL). The observed disparity between the single-dose and multi-dose groups was statistically significant. Furthermore, our findings suggest that the impact of baohuoside I on tofacitinib metabolism may be a mixture of non-competitive and competitive inhibition. Baohuoside I exhibit an interaction with arginine (ARG) at position 106 of the CYP3A4 enzyme through hydrogen bonding, positioning itself closer to the site of action compared to tofacitinib. Conclusion: Our study has demonstrated the presence of drug-drug interactions between baohuoside I and tofacitinib, which may arise upon pre-administration of tofacitinib. Altogether, our data indicated that an interaction existed between tofacitinib and baohuoside I and additional cares might be taken when they were co-administrated in clinic.

Effect of P. corylifolia on the pharmacokinetic profile of tofacitinib and the underlying mechanism.

This work aimed to explore the mechanisms underlying the interaction of the active furanocoumarins in P. corylifolia on tofacitinib both in vivo and in vitro. The concentration of tofacitinib and its metabolite M8 was determined using UPLC-MS/MS. The peak area ratio of M8 to tofacitinib was calculated to compare the inhibitory ability of furanocoumarin contained in the traditional Chinese medicine P. corylifolia in rat liver microsomes (RLMs), human liver microsomes (HLMs) and recombinant human CYP3A4 (rCYP3A4). We found that bergapten and isopsoralen exhibited more significant inhibitory activity in RLMs than other furanocoumarins. Bergapten and isopsoralen were selected to investigate tofacitinib drug interactions in vitro and in vivo. Thirty rats were randomly allocated into 5 groups (n = 6): control (0.5% CMC-Na), low-dose bergapten (20 mg/kg), high-dose bergapten (50 mg/kg), low-dose isopsoralen (20 mg/kg) and ketoconazole. 10 mg/kg of tofacitinib was orally intervented to each rat and the concentration level of tofacitinib in the rats were determined by UPLC-MS/MS. More imporrantly, the results showed that bergapten and isopsoralen significantly inhibited the metabolism of tofacitinib metabolism. The AUC(0-t), AUC(0-∞), MRT(0-t), MRT(0-∞) and Cmax of tofacitinib increased in varying degrees compared with the control group (all p < 0.05), but CLz/F decreased in varying degrees (p < 0.05) in the different dose bergapten group and isopsoralen group. Bergapten, isopsoralen and tofacitinib exhibit similar binding capacities with CYP3A4 by AutoDock 4.2 software, confirming that they compete for tofacitinib metabolism. P. corylifolia may considerably impact the metabolism of tofacitinib, which can provide essential information for the accurate therapeutic application of tofacitinib.

Discovery of Novel Heterotricyclic Compounds as DNA-Dependent Protein Kinase (DNA-PK) Inhibitors with Enhanced Chemosensitivity, Oral Bioavailability, and the Ability to Potentiate Cancer Immunotherapy.

In this work, a novel series of heterotricyclic DNA-PK inhibitors were rationally designed, synthesized, and assessed for their biological activity. In the DNA-PK biochemical assay, most compounds displayed potent enzymatic activity, with IC50 values between 0.11 and 71.5 nM. Among them, SK10 exhibited the most potent DNA-PK-inhibitory activity (IC50 = 0.11 nM). Studies of the mechanism of action indicated that SK10 could lower γH2A.X expression levels and demonstrate optimal synergistic antiproliferative activity against Jurkat cells (IC50 = 25 nM) when combined with doxorubicin. Importantly, in CT26 and B16-F10 tumor-bearing mouse models, the combination therapies of SK10 with chemotherapeutic drug doxorubicin, a PD-L1 antibody, and SWS1 (a potent PD-L1 small-molecule inhibitor) demonstrated superior synergistic anticancer and potential immunomodulatory effects. Furthermore, SK10 possessed favorable in vivo pharmacokinetic properties [e.g., oral bioavailability (F) = 31.8%]. Taken together, SK10 represents a novel heterotricyclic DNA-PK inhibitor with antitumor immune effects and favorable pharmacokinetics.

The Mechanism of Pyroptosis and Its Application Prospect in Diabetic Wound Healing.

Pyroptosis defines a form of pro-inflammatory-dependent programmed cell death triggered by gasdermin proteins, which creates cytoplasmic pores and promotes the activation and accumulation of immune cells by releasing several pro-inflammatory mediators and immunogenic substances upon cell rupture. Pyroptosis comprises canonical (mediated by Caspase-1) and non-canonical (mediated by Caspase-4/5/11) molecular signaling pathways. Numerous studies have explored the contributory roles of inflammasome and pyroptosis in the progression of multiple pathological conditions such as tumors, nerve injury, inflammatory diseases and metabolic disorders. Accumulating evidence indicates that the activation of the NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome results in the activation of pyroptosis and inflammation. Current evidence suggests that pyroptosis-dependent cell death plays a progressive role in the development of diabetic complications including diabetic wound healing (DWH) and diabetic foot ulcers (DFUs). This review presents a brief overview of the molecular mechanisms underlying pyroptosis and addresses the current research on pyroptosis-dependent signaling pathways in the context of DWH. In this review, we also present some prospective therapeutic compounds/agents that can target pyroptotic signaling pathways, which may serve as new strategies for the effective treatment and management of diabetic wounds.

Phyto-pharmacological evaluation and characterization of the methanolic extract of the Baccaurea motleyana Müll. Arg. seed: promising insights into its therapeutic uses.

Introduction: Plants and their extracts have been integral to the development of medicinal treatments throughout history, offering a vast array of compounds for innovative therapies. Baccaurea motleyana Müll. Arg., commonly known as Rambai, is an evergreen tree with economic importance in the Old-World Tropics. Method: The study investigates its phytochemical composition through Gas Chromatography-Mass Spectrometry (GC-MS) and evaluates its pharmacological properties, including antidiabetic, antidiarrheal, antimicrobial, and antidepressant effects. Result and Discussion: The GC-MS analysis revealed 15 bioactive compounds in the methanol extract, with Phenol, 3,5-bis(1,1-dimethylethyl)-, Methyl stearate, and Hexadecanoic acid, methyl ester being the predominant ones. The cytotoxicity assay demonstrated significant activity in the ethyl acetate fraction. Antimicrobial assays indicated mild to moderate antibacterial activity. In vivo studies on mice revealed significant hypoglycemic, antidiarrheal, and antidepressant properties. Molecular docking studies against EGFR, DHFR, GLUT-3, KOR, and MOA identified promising compounds with potential therapeutic effects. The identified compounds exhibited favorable ADME/T properties, emphasizing their potential for drug development. The study underscores the promising therapeutic potential of Baccaurea motleyana, showcasing its diverse bioactive compounds with significant medicinal properties. Conclusion: These findings lay the groundwork for future research, emphasizing the exploration of B. motleyana as a source of natural remedies for addressing prevalent health conditions.

XRCC1 rs1799782 Promotes DNA Damage Repair in Lung Cancer Cells by Enhancing Its Binding to FOXA1 to Facilitate FOXA1-Mediated Transcription of XRCC1.

BACKGROUND: X-ray repair cross complementing 1 (XRCC1) rs1799782 polymorphism is associated with an increased risk of lung cancer (LC). The aim of this study is to analyze the underlying biological mechanisms. METHODS: Dual luciferase reporter assay was utilized to verify the impact of XRCC1 polymorphism upon promoter activity of XRCC1. Cell counting kit-8 (CCK-8) assay, colony formation assay, senescence-associated beta-galactosidase (SA-ß-gal) staining, and immunofluorescent staining were used to assess the viability, proliferation, senescence, and DNA damage of LC cells. Senescence-related proteins (cyclin dependent kinase inhibitor 1A (P21) and eukaryotic translation elongation factor 1-alpha (EF1A)) were quantified by Western blot. Chromatin immunoprecipitation was applied to validate the binding affinity of forkhead box A1 (FOXA1) and XRCC1. FOXA1-specific short hairpin RNA (shFOXA1) was used to perform the rescue assay. RESULTS: In LC cells, XRCC1 rs1799782 promoted viability and proliferation, inhibited senescence, and resulted in upregulation of EF1A as well as downregulation of P21 and phosphorylated H2A.X variant histone (γH2AX). XRCC1 rs1799782 promoted FOXA1-mediated transcription of XRCC1 through enhancing its binding to FOXA1. shFOXA1 counteracted the effects of XRCC1 rs1799782 upon the viability, proliferation, and senescence of LC cells. CONCLUSIONS: XRCC1 rs1799782 promotes DNA damage repair in LC cells through enhancing its binding to FOXA1, which facilitates FOXA1-mediated transcription of XRCC1.

Identification and Functional Assessment of Eight CYP3A4 Allelic Variants *39-*46 Detected in the Chinese Han Population.

Cytochrome P450 3A4 (CYP3A4), a key enzyme, is pivotal in metabolizing approximately half of the drugs used clinically. The genetic polymorphism of the CYP3A4 gene significantly influences individual variations in drug metabolism, potentially leading to severe adverse drug reactions (ADRs). In this study, we conducted a genetic analysis on CYP3A4 gene in 1163 Chinese Han individuals to identify the genetic variations that might affect their drug metabolism capabilities. For this purpose, a multiplex polymerase chain reaction (PCR) amplicon sequencing technique was developed, enabling us to perform the genotyping of CYP3A4 gene efficiently and economically on a large scale. As a result, a total of 14 CYP3A4 allelic variants were identified, comprising six previously reported alleles and eight new nonsynonymous variants that were nominated as new allelic variants *39-*46 by the PharmVar Association. Further, functional assessments of these novel CYP3A4 variants were undertaken by coexpressing them with cytochromes P450 oxidoreductase (CYPOR) in Saccharomyces cerevisiae microsomes. Immunoblot analysis indicated that with the exception of CYP3A4.40 and CYP3A4.45, the protein expression levels of most new variants were similar to that of the wild-type CYP3A4.1 in yeast cells. To evaluate their catalytic activities, midazolam was used as a probe drug. The results showed that variant CYP3A4.45 had almost no catalytic activity, whereas the other variants exhibited significantly reduced drug metabolism abilities. This suggests that the majority of the CYP3A4 variants identified in the Chinese population possess markedly altered capacities for drug metabolism. SIGNIFICANCE STATEMENT: In this study, we established a multiplex polymerase chain reaction (PCR) amplicon sequencing method and detected the maximum number of new CYP3A4 variants in a single ethnic population. Additionally, we performed the functional characterizations of these eight novel CYP3A4 allele variants in vitro. This study not only contributes to the understanding of CYP3A4 genetic polymorphism in the Chinese Han population but also holds substantial reference value for their potential clinical applications in personalized medicine.

Near-infrared-responsive GE11-CuS@Gal nanoparticles as an intelligent drug release system for targeting therapy against oral squamous cell carcinoma.

Galangin (Gal) is a natural plant flavonoid. More and more evidence shows that Gal can achieve anti-tumor effects by regulating various mechanisms. However, its poor water solubility, low bioavailability, and insufficient lesion targeting limit its clinical application. To overcome these shortcomings, we designed and developed a mesoporous nanosystem (GE11-CuS) that actively located the target area and photo-controlled drug release, which promoted the rapid accumulation of drugs in tumor tissues under NIR irradiation, thus achieving positive effects against cancer. In this study, we explored the application of the Gal-loaded nanometer system (GE11-CuS@Gal) in the treatment of oral squamous cell carcinoma (OSCC) both in vitro and in vivo. The results exhibited that GE11-CuS@Gal had excellent targeting ability and could accumulate efficiently in tumor cells (HSC-3). Meanwhile, the temperature of GE11-CuS@Gal increasing rapidly under NIR illumination damaged the integrity of the carrier and allowed Gal molecules to escape from the pores of the nanoparticles. When the accumulation of Gal in the nidus reached a certain level, the intracellular ROS level could be significantly increased and the antioxidative stress pathway mediated by Nrf2/OH-1 was effectively blocked, to inhibit the growth and migration of tumors. In conclusion, the GE11-CuS improved the antitumor activity of Gal in the body, which laid a foundation for the treatment of OSCC with traditional Chinese medicine ingredients.