Therapeutic Effect Research Articles

Drug delivery potential of γ-graphyne, 6,6,12-graphyne and γ-graphdiyne for 5-Fluorouracil: insights from DFT calculations

ABSTRACT The present work aims to investigate the potential of γ-Graphyne, 6,6,12-Graphyne and γ-Graphdiyne as nanocarriers for the anti-cancer drug 5-Fluorouracil (5FU) using density functional theory (DFT). The 5FU drug is effective in treating various cancers. However, 5FU results in severe toxicological damage to the gastrointestinal (GI) system and blood factors, which necessitates the development of promising drug delivery systems to achieve a better therapeutic effect with fewer side effects. To proceed with the aim, the drug and selected carriers were optimized using the DFT/B3LYP/6–31 G(d,p) method. The optimized drug was adsorbed on the surface of carriers and the existence of non-bonding interactions validated the adsorption process. The adsorption energies incorporating the basis set superposition error (BSSE) were calculated and analyzed. The solvent effect on the complexes was studied, and corresponding solvation energies were calculated. The interaction behavior of the drug-nanocarrier complexes has been analyzed at different pH values representative of the physiological range, including acidic, neutral and slightly basic conditions. The results suggest the capability of γ-Graphyne, 6,6,12-Graphyne and γ-Graphdiyne as carriers for 5-Fluorouracil drug in drug delivery system.

Neurotropin® alleviates nerve damage in a mouse chronic nerve compression model.

Chronic nerve compression disorders, such as carpal tunnel syndrome, are common and can significantly impair daily activities due to motor and sensory dysfunctions. Currently, no systemic pharmacotherapy exists for preventing or treating disease progression. This study aims to investigate whether Neurotropin®, an established analgesic, has therapeutic effects. A chronic nerve compression model was created by wrapping a silicone tube around the sciatic nerve in C57BL/6 mice. Nerves were evaluated electrophysiologically and histologically 2 weeks post-surgery. To confirm the preventive effect on disease onset, we administered Neurotropin® subcutaneously. Additionally, continuous subcutaneous administration of Neurotropin® was started 2 weeks post-surgery, and the therapeutic effects were evaluated at 4 and 8 weeks. Furthermore, the therapeutic effects of daily oral administration of Neurotropin®, starting 2 weeks post-surgery, were evaluated at 8 weeks. Significant decreases in nerve conduction velocity and axonal myelination were observed at 2 weeks post-injury. Neurotropin® administration initiated concurrently with model creation did not prevent disease onset at 2 weeks post-surgery. However, starting administration of Neurotropin® 2 weeks post-injury significantly improved outcomes at 8 weeks post-surgery compared to the control group, with continuous subcutaneous and daily oral administration. Neurotropin® may exhibit therapeutic effects for chronic nerve compression disorders.

Effects of irisin on ovariectomy-induced depression, anxiety, and bodyweight growth in female mice.

Hormone replacement therapy (HRT) for postmenopausal syndrome (PMS) carries high risks of undesirable side effects. This study explores irisin as a potential alternative to HRT and investigates the underlying mechanisms. Ovariectomized (OVX) female mice was used as an animal model. The experimental mice were divided into sham, OVX, OVX + irisin (1, 3 μg/kg), OVX+ estradiol (0.5 mg/kg), and OVX + irisin + compound C (AMPK inhibitor) groups. Results showed that OVX induced depression, anxiety, and bodyweight growth in female mice. These OVX-induced abnormalities were reversed by irisin treatment, while AMPK inhibitor abolished irisin's function, indicating that irisin's therapeutic effects on OVX mice were achieved by activating AMPK. Moreover, irisin could increase pAMPK levels and ameliorate the overexpression of NF-κB and its downstream factors including inflammatory factors (IL-1β, IL-6, and TNF-α) and neurotoxic mediators (COX-2 and iNOS) in the hippocampus, frontal cortex, and serum of the OVX mice. However, irisin did not affect hypothalamus pAMPK level or food intake. These findings indicate that irisin's therapeutic effects on depression and anxiety may be linked to its inhibition of inflammatory factors and neurotoxic mediators in the serum and brain, occurring through the AMPK/NF-κB pathway. Additionally, irisin's effect of reducing bodyweight may be associated with an increase in serum pAMPK level, rather than a direct impact on food intake. Further mechanistic exploration revealed that the beneficial effects of irisin, including both the attenuation of bodyweight gain and the improvement of neurological deficits, are attributed to the activation of αVβ5 receptors.

Therapeutic effect of low-dose BMSCs-Loaded 3D microscaffold on early osteonecrosis of the femoral head.

The early treatment of Osteonecrosis of Femoral Head (ONFH) remains a clinical challenge. Conventional Bone Marrow Mesenchymal Stem Cell (BMSC) injection methods often result in unsatisfactory outcomes due to mechanical cell damage, low cell survival and retention rates, inadequate cell matrix accumulation, and poor intercellular interaction. In this study, we employed a novel cell carrier material termed "3D Microscaffold" to deliver BMSCs, addressing these issues and enhancing the therapeutic effects of cell therapy for ONFH. We injected 3D microscaffold loaded with low-dose BMSCs or free high-dose BMSCs into the femoral heads of ONFH rats and assessed therapeutic effects using imaging, serology, histology, and immunohistochemistry. To understand the mechanism of efficacy, we established a co-culture model of human osteoblasts and BMSCs, followed by cell proliferation and activity detection, flow cytometry analysis, Quantitative RT-PCR, and Western blotting. Additionally, RNA sequencing was performed on femoral head tissues. Results showed that the 3D microscaffold with low-dose BMSCs had a therapeutic effect comparable to high-dose free BMSCs. Osteoblasts in the 3D microscaffold group exhibited superior phenotypes compared to the non-3D microscaffold group. Furthermore, we have, for the first time, preliminarily validated that the low-dose BMSCs-loaded 3D microscaffolds may promote the repair of femoral head necrosis through the synergistic action of the MAPK and Hippo signaling pathways.

Innovative role of the antidepressant imipramine in esophageal squamous cell carcinoma treatment: Promoting apoptosis and protective autophagy.

Esophageal squamous cell carcinoma (ESCC) is among the most prevalent malignant tumors; it is associated with dismal prognosis, and effective therapeutic agents are lacking. Depression is prevalent concern among cancer patients and is linked to diminished quality of life, poor adherence to treatment, heightened risk of suicide, and poorer prognosis. Imipramine (IM) is a tricyclic antidepressant with anti-inflammatory activity. Recent reports have indicated antitumor effects of IM in various cancers, although its role in ESCC remains unclear. The depression status of patients with ESCC was graded with the Patient Health Questionnaire-9, and the effects of antidepressants (moclobemide, milnacipran, venlafaxine, escitalopram, amitriptyline, trazodone, fluvoxamine, and IM) on cell viability were evaluated through CCK-8 assays. The effects of IM on cell proliferation were evaluated through clone formation assays, whereas Transwell assays were used to assess effects on ESCC cell migration and invasion. IM-induced apoptosis was confirmed with annexin V-FITC/Caspase-3 assays, and immunofluorescence staining was used to investigate the formation of IM-induced autophagosomes. Furthermore, western blotting analysis was conducted to determine the expression levels of apoptosis- and autophagy-related proteins. RNA sequencing (RNA-seq) was used to examine signaling pathway changes. Finally, we investigated the influence of IM on tumor progression in vivo in a xenograft model. The PHQ-9 scores of patients with ESCC were higher than those of healthy controls and positively correlated with the TNM stage of ESCC. Among the antidepressants examined in our study, IM demonstrated the most potent inhibitory effect on ESCC cell viability, and effectively suppressed the proliferation, migration, and invasion of ESCC cells. Additionally, IM treatment induced apoptosis and autophagy in ESCC cells. Furthermore, blocking autophagy with chloroquine (CQ) intensified IM-induced apoptosis, thereby suggesting a protective role of cellular autophagy against apoptosis. RNA-seq results indicated that the Hippo pathway was associated with IM treatment. Upregulation of YAP reversed the apoptosis and autophagy triggered by IM, and targeting YAP intensified this effect. Finally, in animal experiments, IM hindered the growth of ESCC cells and promoted apoptosis and autophagy in tumors while causing minimal toxicity. Our findings provide the first reported evidence that IM triggers apoptosis and protective autophagy in ESCC cells via the Hippo signaling pathway, thus suggesting that IM may offer a promising therapeutic approach for patients with ESCC and depression.

Therapeutic effects and mechanisms of Juanbilijieqing fang in ameliorating gouty arthritis in a murine model.

This study aims to assess the safety, efficacy, and mechanisms of Juanbilijieqing Fang in a mouse model of gouty arthritis. C57BL/6 mice were allocated into six groups: control, gouty arthritis model, and treatment groups receiving varying doses of Juanbilijieqing Fang (low, medium, high), along with a positive control group treated with febuxostat. Gouty arthritis was induced via MSU crystal injection following a high-fat diet. Mice were treated with Juanbilijieqing Fang or febuxostat, and safety was evaluated by measuring spleen, kidney, and liver indices. Efficacy was assessed by monitoring foot thickness, pain threshold, and biochemical markers, including serum uric acid (UA), myeloperoxidase (MPO), xanthine oxidase (XOD), and adenosine deaminase (ADA). Serum pro-inflammatory cytokines were analyzed, and intestinal inflammation and barrier integrity were examined through histological and molecular assays. Juanbilijieqing Fang did not significantly affect spleen, kidney, or liver indices, indicating its safety. Therapeutically, it significantly reduced foot swelling, improved pain threshold, and decreased serum uric acid levels. It also lowered MPO activity in foot tissue and reduced XOD and ADA activity in the liver. Additionally, the formula downregulated pro-inflammatory cytokines, such as IL-1α, IL-1β, IL-6, TNF-α, and IFN-γ, demonstrating a strong anti-inflammatory effect. It ameliorated gut inflammation by decreasing NLRP3 inflammasome components (NLRP3, ASC, and Caspase-1) and enhanced gut mucosal integrity by upregulating ZO-1 and Occludin expression. Juanbilijieqing Fang is a safe and effective treatment for gouty arthritis, primarily through reducing systemic and intestinal inflammation and restoring gut barrier function.

Transcriptomics and metabolomics reveal the alleviation effect of pectic polysaccharide on dextran sodium sulfate-induced colitis mice.

Ulcerative colitis (UC) is a relapsing disease with an increasing morbidity and prevalence. Dietary polysaccharides have recently become a research hotspot because of their therapeutic effects and safety on UC. Our previous research elucidated that pectic polysaccharide from Phyllanthus emblica L. (PEP-1) could alleviate dextran sodium sulfate-induced UC mice. Herein, metabolomics and transcriptomics were further applied to disclose the underlying mechanisms behind PEP-1's anti-inflammatory effects. PEP-1 intervention altered the serum metabolite contents and pathways represented by decreasing xanthine and sphinganine levels. Changes in gene expressions correlated with metabolite variations led by the suppression of the expression of the inflammatory factors, colorectal cancer promoter, and NF-κB pathway as well as the enhancement of tight junctions. This study demonstrated that the ameliorating effect of chronic UC was partially ascribed to the alteration of the serum metabolites and changes in gene expression.

Promoting macrophage phagocytosis of cancer cells for effective cancer immunotherapy.

Cancer therapy has been revolutionized by immunotherapeutic agents exploiting adaptive antitumor immunity in the past two decades. However, the overall response rate of these immunotherapies is limited, and patients also develop resistance upon treatment, promoting a rapidly growing exploration of anti-tumor innate immunity for effective cancer therapy. Among these, macrophage immunotherapy through harnessing macrophage phagocytosis has been thrust into the spotlight due to its potential for simultaneously inducing cancer cell killing effect and mobilizing adaptive antitumor responses. Here in this review, we summarize the current macrophage immunotherapy such as therapeutic antibodies, phagocytosis checkpoint blockades, and CAR-macrophages with a particular emphasis on the resistant mechanisms limiting their therapeutic effects. Moreover, we further survey the efforts being placed to seek synergistic mechanisms and combination strategies for promoting macrophage phagocytosis which might stand as next-generation cancer immunotherapy.

Cranioplasty infection in porous hydroxyapatite: Potential antibacterial properties.

Intensive research is dedicated to the development of novel biomaterials and medical devices to be used as grafts in reconstructive surgery, with the purpose of enhancing their therapeutic effectiveness, safety, and durability. A variety of biomaterials, from autologous bone to polymethylmetacrylate, polyether ether ketone, titanium, and calcium-based ceramics are used in cranioplasty. Porous hydroxyapatite (PHA) is reported as a possible material for bone reconstruction, with good signs of biocompatibility, osteoconductive and osteointegrative properties. In the present paper we studied the possible antibacterial properties of PHA in a laboratory test in order to provide a possible overview of the occurrence of post-operative infections in PHA cranioplasty. The test method has been designed to evaluate the potential antimicrobial activity of specimens under dynamic contact conditions to overcome difficulties in ensuring contact of inoculum to the specimen surface. The test was conducted using Staphylococcus aureus ATCC6538 as a bacterial strain. Two experimental sets were performed to evaluate the antimicrobial properties of the specimens against two different Staphylococcus aureus concentrations. The first preliminary test (a) verified the antibacterial property at 0, 1, 2, and 4 h of contact time; the second confirmatory test (b) was repeated to verify the antibacterial property at 0, 4, 8 h. In the first experiment, after the first hour of contact, the bacterial inoculum was reduced by 7.96% compared to "inoculum only," which increased to 26.11% at the second hour, and up to 52.33% after 4 h. In the second experiment, the confirmation test showed that bacterial growth reaches maximum inhibition after 4 h of contact. At 4 h, there was a higher bacterial reduction of 72.93%, which decreased at 8 h (36.45%). Analyzing the growth trend of viable microorganisms under Dynamic Contact Conditions it can be seen that PHA cranioplasty appears to inhibit exponential growth by inducing bacterial stasis in the early hours of contact, reaching a maximum reduction within 4 h, in this adopted experimental condition.

Xanthone Derivatives: A Pharmacological Panorama of Versatility

Xanthones are a class of naturally occurring compounds found in various plant sources. Over the years, studies have revealed therapeutic impending xanthones in treating and managing several ailments, including cancer, inflammation, and microbial infections. Xanthones exert their therapeutic effects through various mechanisms, such as anti-inflammatory, antioxidant, and anti-proliferative activities. It has also been found that xanthones induce apoptosis, inhibit cell proliferation, and arrest cell cycles by modulating several signaling pathways. This review objective is to deliver an inclusive overview of the therapeutic essence of xanthones and their potential use as a natural remedy for managing and treating various diseases.

The bitter flavor of Banxia Xiexin decoction activates TAS2R38 to ameliorate low-grade inflammation in the duodenum of mice with functional dyspepsia.

Banxia Xiexin Decoction (BXD) is a traditional herbal formulation with a bitter flavor that has a long-standing history of use in Asia for treating functional dyspepsia (FD). In traditional Chinese medicine, the bitter flavor is believed to play a critical role in the therapeutic activity of BXD. The ethnopharmacological properties of bitter plant extracts are closely associated with their anti-inflammatory effects, which may contribute to their efficacy in FD. However, the specific mechanisms remain unknown. The objective of this study is to uncover the bitter active compounds of BXD and their effects in the treatment of FD. The chemical compounds of BXD were identified using HPLC-Q-Exactive-MS. Active compounds in BXD were obtained from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) database, and bitter active compounds were further identified using BitterDB and PlantMolecularTasteDB. Molecular docking was employed to identify potential targets of these bitter active compounds, and their activation was validated through flow cytometry analysis of Ca2+. Subsequently, a mouse model of FD was established, and our hypothesis was further validated using enzyme linked immunosorbent assay, immunohistochemistry, immunofluorescence, and western blotting. Through HPLC-Q-Exactive-MS analysis, TCMSP, BitterDB, and PlantMolecularTasteDB database, a total of 11 bitter active compounds in BXD were identified: Baicalein, Baicalin, Berberine, Coptisine, Formononetin, Isorhamnetin, Kaempferol, Naringenin, Palmatine, Quercetin, and Wogonin. Molecular docking results indicated that these active compounds exhibited strong affinity for TAS2R38, with Berberine showing the highest scoring. Flow cytometry analysis of Ca2+ revealed that both Berberine and BXD elevated intracellular calcium concentrations, although this effect was partially antagonized by the TAS2R38 inhibitor probenecid. In vivo experiments demonstrated that BXD effectively improved eosinophil infiltration in the duodenum of FD mice, downregulated the expression of inflammatory factors IL-1β, IL-5, and TNF-α, inhibition of NF-κB signaling pathway activation, alleviated damage to the duodenal mucosal barrier, and reversed gastrointestinal motility disorders, with the therapeutic effect enhancing with increasing doses of BXD. However, this therapeutic effect was partially inhibited following probenecid intervention. BXD contains numerous bitter active compounds that play a significant role in regulating inflammatory activity in the duodenum of FD through the activation of TAS2R38. This finding unveils, for the first time, the ethnopharmacological activity of bitter plant taste agents in anti-inflammatory effects, providing new insights for the treatment and drug development of FD.

Silibinin alleviates house dust mite induced allergic airway inflammation by inhibiting NLRC4 inflammasome and MMP-9 expression.

Silibinin, a major compound of silymarin, has been reported to alleviate respiratory diseases including acute lung injury, asthma, chronic obstructive pulmonary disease, and pulmonary fibrosis through its antifibrotic, anti-inflammatory, and antioxidant properties. However, the specific mechanisms underlying its therapeutic effects, particularly in allergic asthma, are not fully understood. With the increasing prevalence and impact of allergic asthma, there is a need to elucidate the exact underlying mechanisms of its potential treatment effects. Herein, we investigated the therapeutic effects of silibinin on allergic asthma using house dust mite (HDM)-exposed mice and an HDM-stimulated human bronchial epithelium cell line, focusing on the roles of the NLR family CARD domain containing 4 (NLRC4) inflammasome and matrix metalloproteinase-9 (MMP-9). To induce airway inflammation, HDM extracts were instilled intranasally on days 0, 4, 8, and 12 to mice. Silibinin (20 and 40 mg/kg) was orally administered daily from days 0-12. The results showed that silibinin treatment attenuated allergic immune responses induced by HDM exposure, as evidenced by decreased airway hyperresponsiveness, reduced inflammatory cells and cytokines, lower immunoglobulin E levls, and decreased mucus production. Furthermore, silibinin treatment suppressed NLRC4 inflammasome activation and downregulated MMP-9 expression in the lungs. In HDM-stimulated cells, silibinin treatment decreased inflammatory cytokine levels and the expression of NLRC4 and interleukin-1β, indicating inhibition of NLRC4 inflammasome activation. Overall, our data demonstrated that silibinin alleviated allergic responses in HDM-induced asthmatic mice by inhibiting NLRC4 inflammasome activation and MMP-9 expression, underscoring its therapeutic potential in the treatment of asthma.

Corydalis decumbens and tetrahydropalmatrubin inhibit macrophages inflammation to relieve rheumatoid arthritis by targeting Fosl2.

Corydalis decumbens (Thunb.) (CD) is a traditional Chinese medicine and as a single herb or formula has been used to treat RA for decades. Rheumatoid arthritis (RA) is a persistent, systemic autoimmune inflammatory disease. However, the anti-inflammatory target, effective constituents and mechanism was unclear. The purpose of this study was to identify anti-RA and anti-inflammatory targets of CD, elucidate effective constituents and molecular pharmacological mechanism. Anti-RA and anti-inflammatory effect of CD were evaluated on CIA-rats and in LPS-induced RAW264.7 cells respectively. The anti-inflammatory target of CD was identified using thermal proteome profiling (TPP). The recombinant Fosl2 protein was expressed and purified and the target-based effective constituents was screened with bio-layer interferometry (BLI) analysis. Combining photoaffinity probe, LC-MS/MS analysis, docking and point mutation, the binding site was confirmed between Fosl2 and THP. Furtherly, immunofluorescence (IF), co-immunoprecipitation (co-IP) were used to research the pharmacological mechanism of THP and the THP-influenced downstream pathways were elucidated by transcriptomics analysis. CD had therapeutic effect on CIA-rats and a significant anti-inflammation on macrophages. Fosl2 was identified as a target of CD and we elucidated the target-based effective constituents was protoberberine-type alkaloids. THP can inhibit inflammation and transcription of AP-1 via targeting Fosl2 on LPS-induced RAW264.7 cells. For mechanism, THP promoted Fosl2 nuclear translocating and interacting with c-Jun. These findings firstly elucidated the target and effective constituents of CD treating RA, and found that "undruggable target" Fosl2 can be used as therapeutic targets for RA. Meanwhile, our research suggested that THP has a significant potential for the treatment of RA.

Integrated network pharmacology, bioinformatics, and experiment analysis to decipher the molecular mechanism of Salidroside on Gastric cancer via targeting NCOA4-mediated ferritinophagy.

Gastric cancer (GC) is a highly aggressive and heterogeneous malignancy. The process of ferroptosis regulates tumor growth and represents a promising therapeutic target for GCs. Despite Salidroside (Sal) being able to regulate ferroptosis in a variety of diseases, there are still limited reports on its therapeutic effects and potential targets in treating GC. This study aimed to investigate the potential mechanism of Sal-induced ferroptosis in GC. Our analysis, integrating databases like PharmMapper, Swiss Target Prediction, TargetNet, GeneCards, TTD, OMIM, STRING, and DAVID. Human gastric cancer MGC803cells and tumor-bearing mice were used to evaluate the anti-tumor effect of Sal on GC in vitro and in vivo. CCK-8, LDH, and Calcein-AM/PI were used to assess cell viability and damage. FerroOrange, Lillie's Ferrous Iron Stain, MDA, ROS, BODIPY™ 581/591C11, GSH, and GPxs were used to detect intracellular Fe2+ concentration, lipid peroxidation level, and antioxidant defense system. qRT-PCR and Western blot were performed to explore relevant mechanism studies. Network pharmacology results showed that Sal shares 322 targets with GC, which have biological functions related to lipid metabolism, cell death, and lipid peroxidation. Experiments further confirmed that Sal inhibits MGC803cells by inducing ferroptosis, as evidenced by the induction of elevated Fe2+ and increased lipid peroxidation. Fer-1, an inhibitor of ferroptosis, reversed the anti-GC effect of Sal in MGC803cells and GC tumor-bearing mice. Further confirmation of the association between Sal and ferroptosis in GC. Subsequently, bioinformatics and machine learning algorithms identified nuclear receptor coactivator 4 (NCOA4) as a candidate signature gene associated with ferroptosis in GC, and molecular docking shows that NCOA4 binds Sal. We then performed in vivo and in vitro experiments to elucidate that Sal targeting NCOA4, a cargo receptor mediating ferritinophagy, mediates autophagic degradation of ferritin heavy chain 1 (FTH1, Fe2+ storage protein), which further increases Fe2+ and lipid peroxidation. In addition, Sal induces mitochondrial dysfunction and increases mitochondrial ROS levels, which activates autophagy and triggers autophagic degradation of FTH1. Taken together, we revealed that NCOA4 is a new target for Sal-anchored GC and that Sal may be a potential therapeutic drug for the treatment of GC.

Cumulative experience meets modern science: Remarkable effects of TongXieYaoFang formula on facilitating intestinal mucosal healing and secretory function.

TongXieYaoFang (TXYF), a classical formula used in Traditional Chinese Medicine, is renowned for its efficacy in treating chronic abdominal pain and diarrhoea. Modern research suggests that fundamental relief from these symptoms depends on complete intestinal mucosal healing, which normalises gut secretory functions. Consensus between traditional and modern medical theories indicates that TXYF is particularly suitable for treating the remission phase of ulcerative colitis (UC). Unfortunately, its potential in the remission phase has not received sufficient attention, and its use has been largely limited to a supportive role during the acute phase. This study aimed to elucidate the efficacy of TXYF in promoting intestinal mucosal healing and enhancing gut secretory function during the non-acute damage phase, as well as to identify the underlying mechanisms contributing to its effects. A mouse model of dextran sulphate sodium salt (DSS)-induced colitis was optimised to specifically evaluate the effects of TXYF on mucosal healing during the repair phase. The effects of TXYF on murine colon function were assessed by measuring faecal pellet count and water content, and further evaluated through immunohistochemical analyses. The underlying mechanisms of action of TXYF were elucidated using mouse intestinal organoid cultures, intestinal stem cell (ISCs) transplantation, immunofluorescence, and western blotting. Active components of TXYF were identified via LC-MS/MS analysis and integrated with network pharmacology for bioinformatics assessment. TXYF significantly promoted mucosal healing, as reflected by reduced disease activity scores, increased colon length, enhanced epithelial proliferation, and decreased histological damage. Furthermore, TXYF enhanced the recovery of critical intestinal functions, including barrier integrity, absorption, secretion, and motility. Notably, the improvement in the secretory function was particularly pronounced. Mechanistically, these therapeutic effects were mediated by the upregulation of the Atonal homolog 1/SAM pointed domain containing ETS transcription factor/Mucin 2 pathway, which facilitates the differentiation and maturation of ISCs into goblet cells, thereby contributing to both mucosal repair and enhanced secretory function. Our study demonstrated that TXYF significantly promotes intestinal mucosal healing and enhances secretory function. These findings offer a solid basis for exploring the potential applications of TXYF in UC management during the remission phase.

Investigation of synergistic effects in trials of combination therapies with immune-checkpoint inhibitors in advanced gastric or gastroesophageal junction cancer.

405 Background: Combinations of immune checkpoint inhibitors (ICI) and chemotherapy (CT) have been approved for gastric cancer. However, there is a hypothesis that this combination may blunt antitumor immune responses because most chemotherapeutic agents also target lymphocytes. The primary objective was to investigate that the ICI and CT does not interfere each other’s therapeutic effects in advanced gastric cancer (GC) or gastroesophageal junction cancer (GEJC) patients. Methods: The reconstructed individual patient data was electronically extracted from the Kaplan-Meier curve of phase III randomized controlled trials (RCTs). The observed PFS curve of each constituent monotherapies was used to estimate simulated PFS curves expected under a model of independent drug action. If the observed curve demonstrated significantly better PFS than simulated curve, the combination of ICI and CT may have a synergistic effect, implying a superior outcome compared to simply adding the component monotherapy. Results: The study included 2,538 unresectable advanced, recurrent, or metastatic GC or GEJC patients from three RCTs comparing pembrolizumab (KEYNOTE-061, KEYNOTE-062 and KEYNOTE-859). In patients with programmed cell death ligand 1 (PD-L1) combined positive score (CPS) of 1 or greater, the 1-year and median PFS of the observed and simulated curves were 28.0% vs. 27.9%, and 6.89 months vs. 6.88 months, respectively. One sample log-rank test showed no significant differences between the observed and simulated curves (p = 0.107). In the subgroups with PD-L1 CPS ≥10 or <1, the 1-year PFS of the observed and simulated curves was 34.7% vs 32.8%, and 28.5% vs 26.8%. Conclusions: The observed PFS of ICT involving pembrolizumab was comparable to the simulated PFS estimated from the data for each monotherapy regardless of the magnitude of PD-L1 CPS. Although it was not clear whether potential synergies existed for ICT, these findings at least suggest that the benefits of ICI and CT are not interfering each other, thereby providing theoretical support for the efficacy of ICT in patients with advanced GC or GEJC.

Spermidine alleviates diabetic periodontitis by reversing human periodontal ligament stem cell senescence via mitophagy.

Type 2 Diabetes Mellitus (T2DM) exacerbates periodontal disease lesions, and human periodontal ligament stem cells (PDLSCs) depletion may be the key to periodontal healing impair by T2DM. This study aims to explore the mechanism of PDLSCs depletion in diabetes periodontitis (DP). Firstly, we observed aggravated periodontal destruction in the DP animal model, accompanied by oxidative damage and accumulation of senescent cells. In the high-glucose inflammatory environment in vitro, we revealed that PDLSCs underwent senescence, oxidative stress, mitochondrial dysfunction, and activation of cGAS-STING signaling pathway triggered by mitochondrial DNA. Lineage tracing confirmed that SPD recruited Tdtomato-Gli1+ PDLSCs to the damaged area and alleviated periodontal destruction in DP models. Evidence in vitro further showed that SPD inhibited PDLSCs senescence and oxidative stress, enhanced mitochondrial function, reduced membrane permeability transition pore opening, and reduced DNA leakage, which blocked the STING activation. Mechanistically, SPD reduced STING-TBK1 phosphorylation by scavenging mitochondrial-derived dsDNA in a mitophagy-dependent manner, its therapeutic effect was abolished by incorporation of cGAMP, a STING activator. In summary, our study reveals the mechanism of PDLSCs depletion due to excessive oxidative damage in the DP environment. Local injection of SPD reactivates mitophagy, recruits Gli1+ stem cells by inhibiting STING activation for periodontal regeneration.

Revealing rutaecarpine's promise: A pathway to parkinson's disease relief through PPAR modulation.

The pathological mechanisms of Parkinson's disease (PD) is complex, and no definitive cure currently exists. This study identified Rutaecarpine (Rut), an alkaloid extracted from natural plants, as a potential therapeutic agent for PD. To elucidate its mechanisms of action and specific effects in PD, network pharmacology, molecular docking, and experimental validation methods were employed. Our findings demonstrated the efficacy of Rut in ameliorating PD symptoms. Network pharmacology analysis indicated that Rut exerts its therapeutic effects through the PPAR signaling pathway and the lipid pathway. Molecular docking results revealed that Rut forms stable protein-ligand complexes with PPARα and PPARγ. Animal experiments showed that Rut improved motor function in PD mice, protected dopaminergic neurons, ameliorated lipid metabolism disorders, and reduced neuroinflammation. This study identified the critical molecular mechanisms and therapeutic targets of Rut in the treatment of PD, providing a theoretical foundation for future investigations into the pharmacodynamics of Rut as a potential anti-PD agent.

Synergistic Effect of HAD-B1 and Osimertinib Against Gefitinib Resistant HCC827 Non-Small Cell Lung Cancer Cells.

In this study, we investigated the synergistic effect of co-administration of osimertinib and HAD-B1 using gefitinib-resistant non-small cell lung cancer cells, HCC827-GR. HAD-B1 is composed of 4 natural drugs, Panax Notoginseng Radix, Panax ginseng C. A. Meyer, Cordyceps militaris, and Boswellia carterii Birdwood, and has been reported to have therapeutic effects on patients with advanced non-small cell lung cancer in several studies. Resistance to gefitinib in HCC827 cells was acquired through MET activity. Co-treatment with osimertinib and HAD-B1 reduced the cell viability of HCC827-GR cells. In addition, phosphorylation of MET and ERK were effectively suppressed for HCC827-GR cells. And, compared to when osimertinib and HAD-B1 were administered alone, cell proliferation was significantly inhibited and apoptosis was effectively induced when osimertinib and HAD-B1 were co-administered to HCC827-GR cells. We found that the synergistic effect of osimertinib and HAD-B1 combination therapy resulted in cancer cell death and cell cycle arrest by targeting the ERK and mTOR signaling pathways. In conclusion, this study confirmed that the combination of osimertinib, a third-generation anticancer drug, and HAD-B1, a natural anticancer drug, had a potentially synergistic effect on non-small cell lung cancer resistant to EGFR-targeted anticancer drugs.

Efficacy of brain stimulation therapies across psychiatric, movement, and cognitive disorders: an umbrella review synthesizing meta-analyses of randomized controlled trials.

Brain stimulation therapy (BST) has significant potential in treating psychiatric, movement, and cognitive disorders. Given the high prevalence of comorbidities among these disorders, we conducted an umbrella review to comprehensively assess the efficacy of BSTs in treating the core symptoms across these three categories of disorders. We systematically searched for meta-analyses and network meta-analyses of randomized controlled trials with sham controls up to September 25, 2024, from databases including PubMed, PsycINFO, Embase, and the Cochrane Library. Our primary outcome was improvements in core symptoms. We evaluated quality using 11 criteria. We calculated pooled effect estimates for core symptoms based on the largest meta-analyses, then conducted sensitivity and subgroup analyses, and assessed heterogeneity, publication bias, and small-study effects. Finally, we synthesized effect sizes from all meta-analyses to provide a comprehensive overview of BSTs' efficacy. PROSPERO registration: CRD42023439090. We included 198 articles with 108,377 patients evaluating 14 BSTs across 21 disorders. The largest meta-analysis showed a moderate standardized mean difference (SMD) of 0.56 (95% CI: 0.49, 0.64; I2=70%). Subgroup analyses revealed significant SMDs for psychiatric disorders (0.60; 95% CI: 0.49, 0.71; I2=66%), movement disorders (0.56; 95% CI: 0.42, 0.69; I2=79%), and cognitive disorders (0.46; 95% CI: 0.32, 0.61; I2=48%). SMDs were 0.44 (95% CI: 0.23, 0.65; I2=70%) for follow-up≤1 month and 0.69 (95% CI: 0.43, 0.94; I2=84%) for follow-up>1 month. Compared to other conditions, BSTs show better therapeutic effects in treating depression, post-traumatic stress disorder, obsessive-compulsive disorder, pain, fibromyalgia, and post-stroke motor recovery. This review explored the potential of BSTs for comorbidities of the three disorders from a disorder-specific perspective, providing a roadmap for their clinical application and future research. This work was supported by the Anhui Natural Science Foundation (2023AH040086), Key Laboratory of Philosophy and Social Science of Anhui Province on Adolescent Mental Health and Crisis Intelligence Intervention (SYS2023B08), and the Joint Funds of the National Natural Science Foundation of China (U23A20424).