Molecular Medicine最新文献

Targeted therapy represents a form of cancer treatment that specifically focuses on molecular markers regulating the growth, division, and dissemination of cancer cells. It serves as the cornerstone of precision medicine and is associated with fewer adverse effects compared to conventional chemotherapy, thus enhancing the quality of patient survival. These make targeted therapy as a vital component of contemporary anti-cancer strategies. Although targeted therapy has achieved excellent anti-cancer results, there are still many factors affecting its efficacy. Among the numerous factors affecting anti-cancer treatment, the role of intestinal bacteria and its metabolites are becoming increasingly prominent, particularly in immunotherapy. However, their effects on anticancer targeted therapy have not been systematically reviewed. Herein, we discuss the crosstalk between gut bacteria and anticancer targeted therapies, while also highlighting potential therapeutic strategies and future research directions.

Inflammation plays a key role in the development of neurodegenerative disorders that are currently incurable. Licochalcone A (LCA) has been described as an emerging anti-inflammatory drug with multiple therapeutical properties that could potentially prevent neurodegeneration. However, its neuroprotective mechanism remains unclear. Here, we investigated if LCA prevents cognitive decline induced by Lipopolysaccharide (LPS) and elucidated its potential benefits. For that, 8-week-old C57BL6/J male mice were intraperitonially (i.p.) treated with saline solution or LCA (15 mg/kg/day, 3 times per week) for two weeks. The last day, a single i.p injection of LPS (1 mg/kg) or saline solution was administered 24 h before sacrifice. The results revealed a significant reduction in mRNA expression in genes involved in oxidative stress (Sod1, Cat, Pkm, Pdha1, Ndyfv1, Uqcrb1, Cycs and Cox4i1), metabolism (Slc2a1, Slc2a2, Prkaa1 and Gsk3b) and synapsis (Bdnf, Nrxn3 and Nlgn2) in LPS group compared to saline. These findings were linked to memory impairment and depressive-like behavior observed in this group. Interestingly, LCA protected against LPS alterations through its anti-inflammatory effect, reducing gliosis and regulating M1/M2 markers. Moreover, LCA-treated animals showed a significant improvement of antioxidant mechanisms, such as citrate synthase activity and SOD2. Additionally, LCA demonstrated protection against metabolic disturbances, downregulating GLUT4 and P-AKT, and enhanced the expression of synaptic-related proteins (P-CREB, BDNF, PSD95, DBN1 and NLG3), leading all together to dendritic spine preservation. In conclusion, our results demonstrate that LCA treatment prevents LPS-induced cognitive decline by reducing inflammation, enhancing the antioxidant response, protecting against metabolic disruptions and improving synapsis related mechanisms.

Background: Extracellular vesicles (EVs) derived from specific bacteria exert therapeutic potential on inflammatory diseases. Previous reports suggest the protective role of Odoribacter splanchnicus (O.splanchnicus) in inflammatory bowel disease (IBD). The effect of EVs derived from O.splanchnicus (Os-EVs) and the underlying mechanism on IBD were surveyed here.

Methods: Os-EVs were derived with ultracentrifugation before characterization by transmission electron microscopy and nanoparticle tracking analysis. Based on IBD model mice induced by dextran sulfate sodium (DSS), the effects of Os-EVs on IBD symptoms, intestinal barrier dysfunction, and colonic apoptosis, inflammation as well as NLRP3 inflammasome activation were analyzed. NLRP3 knockout mice were exploited to judge the role of NLRP3 in Os-EVs against IBD.

Results: Os-EVs were typically shaped as a double concave disc (average diameter = 95 nm). The administration of Os-EVs attenuated DSS-induced body weight loss, colon shortening, disease activity index score, and histological injury in mice. Os-EVs could also relieve intestinal barrier dysfunction and colonic apoptosis, as evidenced by the up-regulation of zona occludens-1 and Occludin and the decrease of TUNEL-positive staining in colonic tissues of IBD mice. Os-EVs downregulated the expression of the interleukin-1β (IL-1β), tumor necrosis factor-α, and IL-6, and elevated IL-10, accompanied by blockage of the NLRP3 inflammasome activation in DSS-induced mice. Furthermore, NLRP3 knockout mice experiments revealed that the protective role of Os-EVs in IBD relies on regulating NLRP3.

Conclusion: Our finding indicated that Os-EVs effectively ameliorated IBD through repressing NLRP3, strongly supporting the potential of probiotic-derived EVs for alleviating IBD.

Background: Cardiac fibrosis is significant global health problem, which is associated with numerous cardiovascular diseases, and ultimately leads to the progression to heart failure. β-adrenergic receptor (β-AR) overactivation play a role in the development of cardiac fibrosis. Miglustat (Mig) has shown anti-fibrosis effects in multiple fibrotic diseases. However, it is unclear whether and how Mig can ameliorate cardiac fibrosis induced by β-AR overactivation.

Methods: In vivo, mice were injected with isoproterenol (ISO) to induce cardiac fibrosis and treated with Mig. In vitro, primary cardiac fibroblasts were stimulated by ISO and treated with Mig. Levels of cardiac fibrosis, cardiac dysfunction, activation of cardiac fibroblasts were evaluated by real-time polymerase chain reaction, western blots, sirius red staining, immunohistochemistry staining and echocardiography. Through GEO data and knockdown UDP-glucose ceramide glycosyltransferase (UGCG) in primary cardiac fibroblasts, whether Mig alleviates cardiac fibrosis by targeting UGCG was explored.

Results: The results indicated that Mig alleviated ISO-induced cardiac dysfunction. Consistently, Mig also suppressed ISO-induced cardiac fibrosis. Moreover, Mig attenuated ISO-induced cardiac fibroblasts (CFs) activation. To identify the protective mechanism of Mig on cardiac fibrosis, several classical β-AR downstream signaling pathways, including ERK, STAT3, Akt and GSK3β, were further analyzed. As expected, ISO activated the ERK, STAT3, Akt and GSK3β in both CFs and mouse hearts, but this effect was reversed pretreated with Mig. Besides, Mig ameliorates ISO-induced cardiac fibrosis by targeting UDP-glucose ceramide glycosyltransferase (UGCG) in CFs.

Conclusions: Mig ameliorates β-AR overactivation-induced cardiac fibrosis by inhibiting ERK, STAT3, Akt and GSK3β signaling and UGCG may be a potential target for the treatment of cardiac fibrosis.

Immune checkpoint therapy targeting PD-1/PD-L1 has shown promise in treating tumors, however, its clinical benefits are limited to a subset of gastric cancer (GC) patients. Recent research has highlighted a the correlation between PD-L1 expression and the clinical efficacy of anti-PD-1/PD-L1 therapies. Human cytomegalovirus (HCMV) has been implicated in GC, but its specific role in modulating this disease remains elusive. In this study, we analyzed clinical tissue samples using bioinformatics and real-time quantitative polymerase chain reaction (RT-qPCR). We found that GC tissues infected with HCMV presented higher PD-L1 expression compared to those without virus. Furthermore, we demonstrated that HCMV infection enhances PD-L1 expression in GC cells. Cytotoxicity assays revealed that HCMV modulates cancer immune responses via the PD-1/PD-L1 pathway. Mechanistically, we showed that HCMV activates the PI3K-Akt signaling cascade and modulates PD-L1 expression through its tegument protein UL23. Functionally, increased UL23 expression leads to elevated PD-L1 levels, which diminishes tumor cell sensitivity to T-cell-mediated cytotoxicity and triggers T-cell apoptosis. Additionally, in vivo experiments revealed that UL23-induced PD-L1 upregulation inhibits CD8⁺ T-cell infiltration and reduces the expression of inflammatory factors in tumor microenvironment, ultimately weakening antitumor immunity. Our findings reveal a novel mechanism whereby HCMV and its tegument protein UL23 contribute to cancer immunosuppression through the regulation of PD-L1 expression. This discovery may serve as a potential therapeutic target for enhancing the efficacy of cancer immunotherapy.

Background: Inflammation and proinflammatory programmed cell death, referred to as pyroptosis, are important causes of poor functional recovery after traumatic spinal cord injury (TSCI). Heat shock protein family A member 1A (HSPA1A) is a molecular chaperone protein that is highly expressed after TSCI and is thought to be neuroprotective. However, the mechanisms underlying the protective effects of HSPA1A after TSCI are unclear.

Methods: The levels of pyroptosis and inflammation after TSCI were determined by enzyme-linked immunosorbent assay (ELISA) and western blotting analysis. The role of HSPA1A in regulating pyroptosis and inflammation in TSCI was verified by in vivo and in vitro experiments. The molecular mechanism of the effects of HSPA1A in TSCI was elucidated by bioinformatics and coimmunoprecipitation analyses.

Results: Pyroptosis and inflammation are significantly increased after TSCI. HSPA1A overexpression in microglia attenuated nigericin- and lipopolysaccharide (LPS)-induced pyroptosis and inflammation in vitro, whereas knockdown of HSPA1A aggravated pyroptosis and inflammation. In vivo, overexpression of HSPA1A reduced tissue damage, nerve cell death, pyroptosis, and inflammation in TSCI rats and promoted functional recovery. Mechanistically, we identified that HSPA1A interacts with dual specificity phosphatase 1 (DUSP1) and inhibits activation of the mitogen-activated protein kinase (MAPK) pathway, thereby attenuating pyroptosis and inflammation.

Conclusion: HSPA1A reduces pyroptosis and inflammation after TSCI by upregulating DUSP1 and inhibiting MAPK pathway activation. HSPA1A activation has potential as a therapeutic approach to promote functional recovery after TSCI.

Gastric cancer (GC) is one of the most common malignant tumors worldwide, and its treatment has been a focus of medical research. Herein we systematically review the current status of and advancements in targeted therapy and immunotherapy for GC, which have emerged as important treatment strategies in recent years with great potential, and summarize the efficacy and safety of such treatments. Targeted therapies against key targets in GC, including epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2), and vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR), have shown remarkable therapeutic efficacies by inhibiting tumor progression and/or blood supply. In particular, markable breakthroughs have been made in HER2-targeting drugs for HER2-positive GC patients. To address intrinsic and acquired resistances to HER2-targeting drugs, novel therapeutic agents including bispecific antibodies and antibody-drug conjugates (ADC) targeting HER2 have been developed. Immunotherapy enhances the recognition and elimination of cancer cells by activating body anticancer immune system. Programmed cell death protein 1 (PD-1) and programmed cell death-ligand 1 (PD-L1) antibodies are the most commonly used immunotherapeutic agents and have been used with some success in GC treatment. Innovative immunotherapy modalities, including adoptive immune cell therapy, tumor vaccines, and non-specific immunomodulators therapy, and oncolytic viruses have shown promise in early-stage clinical trials for GC. Clinical trials have supported that targeted therapy and immunotherapy can significantly improve the survival and quality of life of GC patients. However, the effects of such therapies need to be further improved and more personalized, with advancement in researches on tumor immune microenvironment. Further studies remain needed to address the issues of drug resistance and adverse events pertaining to such therapies for GC. The combined application of such therapies and individualized treatment strategies should be further explored with novel drugs developed, to provide more effective treatments for GC patients.

Lactation is a crucial phase of brain development, and the events and nutrients during this period have long-term consequences for the occurrence of depression. This study investigated the effect and mechanism of lactoferrin (LF) deficiency during lactation on depression in adulthood. Lactation LF-deficient mice were established by nursing wild-type mice using LF systemic knockout mother mice. Additionally, 14-day-old mice were injected with lipopolysaccharide (LPS) and subjected to chronic unpredictable mild stress when they reached 6 weeks of age. The results show that lactation lactoferrin deficiency increases depression-like behavior in adult mice, and the mechanism is associated with heightened neuronal damage, abnormal microglial activation, and decreased BDNF in the hippocampus. In contrast, recombinant human lactoferrin promotes neuronal proliferation by upregulating ERK 1 and 2 phosphorylation and attenuates LPS-induced neuronal injury and microglial activation by inhibiting the activation of Toll-like receptor 4-nuclear factor-kappa B pathway in vitro. Our findings suggest that lactoferrin intake during lactation protects neurons by regulating microglial activation, thereby effectively reducing depressive symptoms in adults.

Engaging in activity has proven to have beneficial effects on different facets of well-being, such as conditions related to the deterioration of the nervous system. Non-coding RNAs (ncRNAs) and exosomal ncRNAs associated with vesicles have been recognized as influencers of gene expression and cell signaling, potentially contributing to the positive impact of physical activity on neurodegenerative conditions. It is hypothesized that exercise-induced changes in ncRNA expression may regulate key processes involved in neuroprotection, including neuroinflammation, oxidative stress, protein aggregation, and synaptic function. Exercise has shown promise in preventing neurodegenerative diseases (NDs), and ncRNAs and exosomal ncRNAs are emerging as potential mediators of these benefits. In review, we explored how ncRNAs and exosomal ncRNAs play a role in enhancing the impacts of activity on neurodegenerative disorders for future treatments. Research studies, both preclinical and clinical, that have documented the use of various exercises and their effects on ncRNAs and exosomal ncRNAs for the treatment of NDs have been compiled and enlisted from the PubMed database, spanning the time period from the year 2000 up to the current time. Studies show that manipulating specific ncRNAs or harnessing exercise-induced changes in ncRNA expression and exosomal cargo could potentially be utilized as therapeutic strategies for preventing or treating NDs. In conclusion, studies suggest that various exercise modalities, including aerobic, resistance, and high-intensity interval training, can modulate the expression of ncRNAs and exosomal ncRNAs in the context of NDs. The altered ncRNA profiles may contribute to the neuroprotective and therapeutic effects observed with exercise interventions. However, more research is needed to fully understand the underlying mechanisms and to further explore the potential of exercise-induced ncRNA signatures as biomarkers and therapeutic targets for neurodegenerative disorders.

Background: Exosomes are communication carriers and suitable biomarker candidates due to their cargoes with specific dynamic profiles. Integrins, as valuable prognostic markers in cancer, have importance in exosome-cell interaction. However, the role of exosome integrins in chemoresistant colorectal cancer remained unclear.

Methods: Oxaliplatin- and 5-FU-resistant cells (OXR and FUR) were established from human HCT-116 cells of colorectal cancer. Exosomes were collected from untreated and treated cells with oxaliplatin or 5-FU. Exosomes were isolated via ultracentrifugation and characterized using DLS and electron microscopy to evaluate size and morphology. Western blot analysis was employed to identify exosomal markers. The effects of exosomes on parental cells were examined using various methods, including MTT assay for proliferation, wound healing assay for migration, flow cytometry for cell cycle and apoptosis analysis, Matrigel-coated transwell inserts for invasion, and western blot for integrin expression evaluation.

Results: Exosome integrins determine resistance behaviors in cells. We observed that exosomes from OXR cells or OXR cells treated with oxaliplatin increased ITGβ3 expression and decreased ITGβ4 expression in parental cells, resulting in distinct resistance behaviors. Exosomes from FUR cells or FUR cells treated with 5-FU reduced ITGβ4 levels and elevated ITGαv levels in parental cells, leading to varying degrees of invasive resistance behaviors. These findings suggest that exosome integrins may affect these behaviors. High ITGβ3 exosomes induced oxaliplatin resistance behaviors in parental cells. Lowering ITGβ3 levels in these exosomes inhibited the resistance behaviors observed in these cells. FUR exosomes that overexpressed ITGαv or ITGβ4 resulted in invasive 5-FU resistance behaviors in parental cells. A reduction in these exosome integrin levels led to moderate invasive behaviors. The decrease of ITGβ4 in FUR cell exosomes inhibited resistant migration and proliferation in parental cells. A twofold reduction of ITGαv in FUR cell exosomes resulted in a threefold decrease in invasion and inhibited migration in parental cells compared to those treated with high ITGαv exosomes.

Conclusion: Our findings reveal that, despite discrepancies between cellular integrin patterns and cellular behaviors, the levels of exosomal ITGβ3, ITGαv, or ITGβ4 could serve as potential diagnostic and therapeutic markers for resistance to oxaliplatin and 5-FU in future cancer treatments.