搜索结果：Target

The long-term use of opioids for analgesia is associated with serious adverse effects such as addiction and respiratory depression, as well as a potential increased risk of all-cause mortality, necessitating the development of safer alternative therapies. This review systematically elaborates on the latest advances in non-opioid analgesic research, covering diverse target strategies ranging from peripheral ion channels and GPCRs to central neuro-immune inflammation and specific neural circuits. It also discusses the advantages of multi-target ligands in overcoming signal redundancy. Concurrently, the review highlights how cutting-edge technologies-such as multi-omics analysis, artificial intelligence (AI) and computational pharmacology, and human induced pluripotent stem cell (iPSC) and organoid models-are revolutionizing target discovery, drug screening, and preclinical assessment. Despite significant ongoing challenges in target clinical translation, safety balance, and personalized treatment, the integration of these systematic interventional strategies with precise technological approaches holds promise for advancing the development of next-generation non-opioid analgesics. This progress aims to ultimately provide safer and more effective therapeutic options for patients with chronic pain, thereby addressing the opioid crisis.

The lack of tumor-specific targeting remains a major bottleneck in photothermal therapy. Here, we exploit the natural affinity of nicotinamide (NAM) for Ki67, a tumor proliferation marker, to design a targeted photothermal nanomaterial. NAM-derived carbon dots (NAM-CDs) were synthesized via a one-step solvothermal method, in which the carbon core serves as a scaffold for the multivalent presentation of NAM moieties. Dynamic molecular docking simulations revealed that NAM-CDs exhibited a markedly enhanced binding affinity toward Ki67, with binding energy of -7.7 kcal/molcompared with -3.8 kcal/mol for free NAM. These results indicate that the multivalent display of NAM not only preserves but also amplifies its intrinsic Ki67-targeting capability. To further optimize the photophysical properties of NAM-CDs, the synthesis temperature was systematically tuned. At 180 °C, the resulting NAM-CDs developed a pyridine-rich surface characterized by maximized pyrrolic-N content and enhanced amide bond formation, facilitating efficient energy transfer from the carbon core to surface states. This optimized electronic structure synergistically enhanced both red fluorescence emission and photothermal conversion efficiency. The pyridine-rich NAM-CDs exhibited excellent biocompatibility, specific nuclear retention through Ki67-mediated interactions in cancer cells, and potent photothermal tumor ablation upon 660 nm laser irradiation in vivo, achieving complete tumor regression without recurrence over a 30-day observation period. By harnessing the inherent Ki67 affinity of NAM, this work provides a facile strategy for imparting tumor-targeting capability to photothermal agents, opening a new avenue for proliferation-marker-directed cancer therapy.

Dry eye disease, as an ocular surface disorder, affects millions of people globally and has consequently become one of the most prevalent conditions encountered in ophthalmic clinics. The pathogenesis of dry eye involves several key factors, including tear film instability, hyperosmolarity, chronic ocular surface inflammation, and neurosensory abnormalities. The ocular surface expresses a diverse array of ion channels, which play essential physiological roles in maintaining tear film stability, regulating osmotic pressure, balancing ion transport, and modulating inflammatory responses. This review systematically elucidates the relationship between ion channels and dry eye disease through three key aspects: the distribution and physiological functions of ion channels in ocular surface tissues, the therapeutic efficacy and mechanistic basis of ion channel targeted modulators in dry eye treatment, and a comprehensive classification of molecular mechanisms underlying ion channel targeted therapies for dry eye. Research on these targeted mechanisms establishes a theoretical foundation for clinical dry eye management and provides innovative strategies for developing novel ion channel based therapeutics.

The TMPRSS2:ERG gene fusion, present in approximately 50% of prostate cancers in patients of European ancestry, drives oncogenesis through aberrant overexpression of the ERG transcription factor. Despite its role as a truncal oncogenic driver, ERG has been considered undruggable due to the absence of enzymatic activity and apparent lack of ligandable pockets. Here, we demonstrate continued dependency on ERG in metastatic prostate cancer and identify a druggable pocket within its N-terminal Pointed (PNT) domain. Using an inducible shRNA system in TMPRSS2:ERG-positive VCaP cells, we show that ERG depletion causes profound growth inhibition. To therapeutically exploit this vulnerability, we conducted a domain-focused differential scanning fluorimetry screen targeting the ERG PNT domain, followed by structure-activity relationship optimization. This approach yielded PBITE-1 (PNT-Binding Inhibitor of the Transcription factor ERG), a small molecule that selectively binds the ERG PNT domain. NMR chemical-shift perturbation mapping and molecular docking revealed that PBITE-1 engages a discrete, solvent-exposed surface comprising two α-helices and an adjacent flexible loop, defining a ligand-binding pocket within the PNT domain. In cellular models, PBITE-1 directly engaged ERG, selectively inhibited proliferation and invasion, and induced apoptosis in ERG-driven prostate and hematologic malignancies. PBITE-1 potently suppressed growth of ERG-positive mouse and human-derived prostate cancer organoids. Furthermore, PBITE-1 treatment significantly induced tumor cell apoptosis in VCaP xenograft models. These findings establish the ERG PNT domain as ligandable and provide preclinical evidence that ERG is directly targetable by small molecules, enabling future development of ERG-directed inhibitors and targeted protein degraders.

Non-Small-Cell Lung Cancer (NSCLC) often responds poorly to immune checkpoint blockade due to its immunosuppressive, "cold" tumor microenvironment. Activating alternative immune effectors may overcome this limitation. Here we identified lung-enriched γδ T cells as a key compartment in NSCLC and developed a lung-targeted lipid nanovaccine to activate them in situ. Analysis of patient transcriptomic data sets reveals that γδ T cell and CD1d signatures are associated with improved patient survival in NSCLC. Using this insight, we engineered α-galactosylceramide (α-GalCer) and poly(I:C)-loaded lipid nanoparticles that preferentially accumulated in the lung after intravenous administration. In orthotopic NSCLC models, the nanovaccine activated γδ T cells, enhanced functional CD8+ T cell infiltration, remodeled the immunosuppressive tumor microenvironment, and significantly prolonged survival. Depletion of γδ T cells abolished therapeutic benefit, demonstrating that γδ T cells represented the important effector population for this strategy. Furthermore, splenectomy attenuated vaccine efficacy, suggesting a contribution of systemic immune crosstalk to vaccine efficacy. Together, these findings establish a γδ T cell-centered lung-targeted immunotherapy strategy for treating immune-resistant NSCLC.

LIKE-HETEROCHROMATIN PROTEIN 1 (LHP1) is a polycomb group protein that exists in shared multiprotein complexes that harbor core PRC1 and PRC2 proteins. We previously characterized LHP1 in the moss Physcomitrium patens and showed that its function is closely linked with regulation of RNA metabolic processes and the protein is distributed in the nucleoplasm, subnuclear foci, and the nucleolus. To gain mechanistic insight into PpLHP1-mediated gene regulation, in the present study genome-wide changes in transcript profiles of genes affected by loss-of-PpLHP1 function were studied using pplhp1 mutants. RNA-seq analysis reveals a key role for PpLHP1 in regulating energy metabolic processes, ribosome-related pathways, stress signaling/responsive pathways, DNA transcription, etc. ChIP using H3K27me3 coupled with qRT-PCR shows that PpLHP1 suppresses transcription at 5S rRNA promoters and the untimely activation of genes regulating developmental transition by PRC2-dependent and independent mechanisms. To study how PpLHP1 finds its targets in different nuclear compartments and the roles of the multiple NLSs and the conserved domains in guiding the protein, FRAP and deletion studies were performed. These show that PpLHP1 is a mobile protein that diffuses freely in the nucleoplasmic space showing different retention times in the nucleolus, nucleoplasm, and the subnuclear foci indicating its differential affinity for targets at these sites. Expression of PpLHP1 fragments in protonema cells and its subsequent visualization under confocal microscope shows that localization of PpLHP1 to different subnuclear compartments is guided by the monopartite NLS2, CD, and CSD that also play a key role in promoting subnuclear foci formation in the nucleoplasm.

Huntington's disease (HD) is a progressive, autosomal dominant neurodegenerative disorder caused by cytosine-adenine-guanine (CAG) trinucleotide repeat expansion in the huntingtin gene (HTT), resulting in mutant huntingtin (mHTT) with toxic gain-of-function and partial loss of normal huntingtin function. This narrative review summarizes recent advances in genetics, pathophysiology, clinical features, diagnostic assessment, biomarkers, and therapeutic development. Genetic testing demonstrating an expanded HTT CAG repeat is the definitive diagnostic test and should be interpreted with genetic counseling and attention to allele categories. Pathophysiologically, HD involves CAG instability, age-dependent somatic expansion in vulnerable neurons, transcriptional dysregulation, proteostasis failure, mitochondrial dysfunction, excitotoxicity, and neuroinflammation, leading primarily to degeneration of striatal medium spiny neurons and later cortical involvement. Clinically, HD can begin from juvenile to late-adult life and manifests with motor, cognitive, psychiatric, and behavioral symptoms that evolve from premanifest biological change to functional decline. Current clinical care relies on symptom-directed treatment, whereas quantitative neuroimaging, cerebrospinal fluid biomarkers are mainly used for research and trial enrichment. Symptomatic management includes vesicular monoamine transporter type 2 inhibitors, antipsychotics, rehabilitation, nutritional support, and multidisciplinary care. Emerging disease-modifying approaches include HTT-lowering, somatic expansion inhibition, and gene-based therapies, but efficacy depends on target selectivity, timing, delivery route, dose, and patient selection.

Gestational diabetes mellitus (GDM) is a common metabolic complication during pregnancy, which can readily lead to adverse pregnancy outcomes. Studies have shown that icariin (ICA) possesses anti-inflammatory and anti-oxidative stress properties and can mitigate high glucose-induced cellular damage. This study aims to investigate the effects and underlying mechanisms of ICA on a GDM cell model. An in vitro GDM model was established by exposing HTR-8/Svneo cells to high glucose (HG) medium. Cell viability was measured using the CCK-8 assay. Cytotoxicity was assessed with the lactate dehydrogenase (LDH) assay kit. Flow cytometry was employed to evaluate apoptosis, mitophagy flux, and intracellular mitochondrial reactive oxygen species (ROS) levels. Western blotting and JC-1 staining were used to assess mitophagy and mitochondrial membrane potential, respectively. ICA alleviated the inhibitory effect of HG on the proliferation of HTR-8/SVneo cells and reduced high glucose-induced intracellular LDH level and apoptosis. Furthermore, ICA promoted mitophagy flux, decreased mitochondrial ROS levels, and attenuated mitochondrial damage in HG-treated HTR-8/SVneo cells. Mechanistically, ICA protected HTR-8/SVneo cells from HG-induced injury by targeting the S100A9/RAGE pathway. ICA ameliorates high glucose-induced trophoblast injury by modulating the S100A9/RAGE pathway, offering a potential therapeutic strategy for the treatment of GDM.

Cytotoxic T cells produce the cytokine interferon-γ (IFN-γ). We sought to determine whether IFN-γ directly kills target cells and found that T cells used IFN-γ to kill murine melanoma cells lacking the kinases TBK1 and IKKε. In the absence of both kinases, IFN-γ induced the production of TNF receptor 1 (TNFR1) and the sensor Z-DNA binding protein 1 (ZBP1) in the tumor cells to stimulate receptor-interacting protein kinase 1 (RIPK1)-dependent apoptosis in a cell-autonomous manner. IFN-γ also enhanced the activation of nuclear factor κB (NF-κB) signaling in a TNFR1-dependent manner in cells deficient in both TBK1 and IKKε. Because IFN-γ-induced apoptosis occurred in a transcription-dependent manner with slow kinetics, STAT1 and NF-κB cooperated to activate the expression of inflammatory genes in the dying cells. Thus, IFN-γ-induced cell death was accompanied by an inflammatory signature in the absence of TBK1 and IKKε. TBK1 and IKKε not only mediated the induction of type I IFN but also inhibited RIPK1-dependent death and NF-κB-dependent inflammation. Therefore, we propose that these kinases may have gained these intertwined functions so that cells infected by pathogens that produce antagonists of TBK1 and IKKε are eliminated by IFN-γ-secreting T cells in an inflammatory manner to compensate for the inhibition of type I IFN production.

Endolysosomal compartments act as critical sorting hubs for viral entry, trafficking, and uncoating, yet the contribution of lipid-modifying enzymes to these processes remains incompletely understood. Acid sphingomyelinase (ASM), a key regulator of endolysosomal membrane composition, has been implicated in host-pathogen interactions, and is actively engaged in human adenovirus (HAdV) infection. Here, we confirm ASM activity as an essential host determinant of efficient HAdV infection and demonstrate that its pharmacological inhibition synergizes with direct-acting antiviral therapy. Analysis of publicly available human datasets revealed age-associated changes in expression of host cell determinants for HAdV entry like ASM expression in respiratory epithelial tissues and colonic tissue, suggesting that ASM-dependent endolysosomal functions are modulated across the human lifespan. Using epithelial cell models of HAdV infection, we show that viral entry and replication critically depend on ASM activity. Pharmacological inhibition of ASM by functional inhibitors such as fluoxetine resulted in a dose-dependent suppression of viral replication and significantly reduced infection rates in single-cycle infection assays, indicating disruption of early stages of the viral life cycle. Mechanistically, ASM inhibition impaired HAdV uptake and trafficking by reducing viral internalization and co-localization with early endosomes. Importantly, combined treatment with fluoxetine and the viral DNA polymerase inhibitor brincidofovir acts synergistically in reducing HAdV titer. These findings demonstrate that targeting host-controlled endosomal entry pathways can potentiate the antiviral efficacy of direct-acting agents. Together, our study validates ASM as a central regulator of HAdV entry and identifies combined host- and virus-directed therapy as a promising strategy to suppress HAdV infection.

As the primary receptor of oxidized low-density lipoprotein (ox-LDL), LOX-1 is a putative therapeutic target for atherosclerotic disorders including ischemic stroke (IS), whereas the regulatory mechanism of LOX-1 remains largely unknown in IS. We employed computational algorithms to screen candidate miRNAs, followed by integrative analysis of differentially expressed miRNA profiles derived from blood cells of 25 acute IS cases and 25 controls matched with age and gender. MiR-187-3p-mediated regulation of LOX-1 was confirmed by a dual-luciferase reporter assay and Western Blot in THP-1 derived macrophages. Elevated blood levels of miR-187-3p were observed both in IS patients and the atherosclerotic mice. In a case-control study enrolling 279 IS cases and 279 controls, we found that miR-187-3p level was significantly associated with the occurrence of IS (adjusted OR&#x2009;=&#x2009;1.204; 95% CI: 1.086-1.335; p&#x2009;<&#x2009;0.001). Similar results were replicated in another coronary heart disease case-control population. In&#xa0;vivo, systemic delivery of agomiR-187-3p significantly reduced atherosclerotic plaque burden alongside decreased plasma lipids and suppressed inflammation. In&#xa0;vitro, miR-187-3p over-expression attenuated foam cell formation induced by ox-LDL and down-regulated pro-inflammatory mediators in macrophages. Conversely, miR-187-3p inhibition exacerbated these effects, which were partially rescued by LOX-1 inhibitor BI-0115. This study establishes miR-187-3p as a novel epigenetic regulator of LOX-1 and provides critical evidence supporting its therapeutic potential for modulating IS progression.

Decreased dietary K+-intake stimulates the expression of Regulatory-Associated-Protein-of-mTOR (RAPTOR) in kidneys and increases mRNA of Raptor in aldosterone sensitive distal nephrons. The aim of the study is to explore the role of mTORc1 in stimulating Kir4.1/Kir5.1 and Na-Cl-cotransporter (NCC), and inhibiting renal-outer-medullary K+ channel (ROMK or Kir1.1) and epithelial-Na+-channel (ENaC) during overnight low-K+-intake (LK). Deletion of RAPTOR in kidneys inhibited basolateral Kir4.1/Kir5.1 of distal convoluted tubule (DCT) and decreased the expression of phosphor-NCC and total-NCC. Furthermore, ENaC and ROMK baseline activity in late-DCT/early connecting tubule (CNT) and cortical collecting duct (CCD) of kidney-tubule-specific-RAPTOR knockout mice (Ks-RAPTOR-KO) were higher than Raptorflox/flox mice. Consequently, Ks-RAPTOR-KO mice had higher baseline kidney K+ excretion and lower plasma K+ concentrations than Raptorflox/flox mice. Overnight-LK-intake stimulated Kir4.1/Kir5.1 activity of DCT and the expression of phosphor-NCC and total-NCC in Raptorflox/flox mice. In contrast, overnight-LK failed to stimulate Kir4.1/Kir5.1 of the DCT and did not increase the expression of phosphor-NCC and total-NCC in Ks-RAPTOR-KO mice. Moreover, overnight-LK inhibits ROMK and ENaC in late-DCT/early-CNT and CCD only in Raptorflox/flox mice but not in Ks-RAPTOR-KO mice. Thus, male/female Ks-RAPTOR-KO mice on overnight-LK had lower plasma K+ levels and higher kidney K+ excretion than Raptorflox/flox mice. We conclude that mTORc1 plays a key role in suppressing kidney K+ excretion during decreased dietary K+ intake.