Background Arsenic exposure has been implicated as an important environmental contributor to pulmonary fibrosis, the pathogenesis of which is closely associated with abnormal activation of pulmonary fibroblasts. However, the specific mechanism remain incompletely understood. Objective To examine sirtuin 3 (SIRT3) expression during arsenite-induced fibrotic responses in lung fibroblasts, and to investigate its effects on aerobic glycolysis and profibrotic progression, as well as its underlying mechanisms. Methods Human embryonic lung fibroblasts (HELF) were treated with sodium arsenite (NaAsO₂) at different concentrations (0, 2.5, 5, 10, 20, 40, and 80 μmol·L⁻¹) for 48 h. Cell viability was assessed, and lactate and hydroxyproline (HYP) levels were measured as indicator of glycolytic activity and fibrotic response. Western blot and quantitative polymerase chain reaction (q-PCR) were used to determine the protein and mRNA expression levels of SIRT3, hypoxia-inducible factor 1-alpha (HIF-1α), fibrosis-related genes [Collagen type Ⅰ (Collagen-Ⅰ), and α-smooth muscle actin (α-SMA)], and glycolysis-related genes [pyruvate kinase M2 (PKM2), hexokinase 2 (HK2), and lactate dehydrogenase A (LDHA)]. Results Based on the cell viability results, the NaAsO₂ concentrations of 2.5, 5, and 10 μmol·L⁻¹ for 48 h were selected for subsequent experiments. Compared with the control group, HYP levels were significantly increased in the 2.5, 5, and 10 μmol·L⁻¹ NaAsO₂ exposure groups (P <0.05). The protein and mRNA expression levels of HIF-1α, glycolysis-related genes (PKM2, HK2, and LDHA) and fibrosis-related genes (Collagen-Ⅰ, and α-SMA) were significantly upregulated, whereas SIRT3 protein and mRNA expression levels were significantly down-regulated, in the NaAsO₂ treated groups compared with the control group (P<0.05). SIRT3 overexpression significantly reduced HYP levels and downregulated the protein and mRNA expression levels of HIF-1α, glycolysis-related genes (PKM2, HK2, and LDHA), fibrosis-related genes (Collagen-Ⅰ, and α-SMA) compared with the NaAsO₂ + negative control group (P<0.05). Similarly, HIF-1α knockdown significantly decreased HYP levels and downregulated the protein and mRNA expression levels of glycolysis-related genes (PKM2, HK2, and LDHA) and fibrosis-related genes (Collagen-Ⅰ, and α-SMA) compared with the NaAsO₂ + negative control group (P<0.05). In contrast, simultaneous overexpression of SIRT3 and HIF-1α abolished the inhibitory effects of SIRT3 overexporession, as HYP levels and the expression of glycolysis- and fibrosis-related markers showed no statistically significant differences compared with the NaAsO₂ + negative control group (P>0.05). Conclusion NaAsO₂ exposure could induce profibrotic and glycolysis-related responses in HELF cells, accompanied by SIRT3 downregulation and HIF-1α activation. These findings suggest that the SIRT3/HIF-1α regulatory axis may be a potential target for preventing or attenuating arsenic exposure-related pulmonary fibrotic responses.

This consensus will introduce the characteristics of fillers used in the surgical cavities of domestic nasal surgery patients based on relevant literature and expert opinions. It will also provide recommendations for the selection of cavity fillers for different nasal diseases, with chronic sinusitis as a representative example.
Humans ; Nasal Cavity/surgery* ; Nasal Surgical Procedures ; China ; Consensus ; Sinusitis/surgery* ; Dermal Fillers

Among tumor microenvironment (TME), the entire metabolic characteristics of tumor-resident cells are reprogrammed to benefit the expansion of tumor cells, which count on glutamine in large part to fuel the tricarboxylic acid cycle for energy generation and anabolic metabolism support. Endothelial cells that are abducted by tumor cells to form a pathological tumor vascular network for constructing the hypoxic immunosuppressive TME, also rely on glutaminolysis as the "engine" of angiogenesis. Additionally, the glutamine metabolic preference benefits the polarization of TAMs towards pro-tumoral M2 phenotype as well. Herein, we developed a type of siRNA micelleplexes (MH@siGLS1) to reverse immunosuppressive TME by targeting glutaminolysis within tumor-resident cells for tumor vasculature normalization- and TAMs repolarization-enhanced photo-immunotherapy. Tumor cell starvation and antioxidant system destruction achieved by MH@siGLS1-mediated glutaminolysis inhibition could promote photodynamic therapy efficacy, which was available to trigger immunogenic cell death for adaptive antitumor immune responses. Meanwhile, glutaminolysis inhibition of tumor endothelial cells and TAMs could realize tumor vascular normalization and TAMs repolarization for antitumor immunity amplification. This study provides a unique perspective on cancer treatments by focusing on the interrelations of metabolic characteristics and the biofunctions of various cell types within TME.

Hypertrophic scar is a fibrous hyperplastic disorder that arises from skin injuries. The current therapeutic modalities are constrained by the dense and rigid scar tissue which impedes effective drug delivery. Additionally, insufficient autophagic activity in fibroblasts hinders their apoptosis, leading to excessive matrix deposition. Here, we developed an active microneedle (MN) system to overcome these challenges by integrating micromotor-driven drug delivery with autophagy regulation to remodel the scar microenvironment. Specifically, sodium bicarbonate and citric acid were introduced into the MNs as a built-in engine to generate CO₂ bubbles, thereby enabling enhanced lateral and vertical drug diffusion into dense scar tissue. The system concurrently encapsulated curcumin (Cur), an autophagy activator, and triamcinolone acetonide (TA), synergistically inducing fibroblast apoptosis by upregulating autophagic activity. In vitro studies demonstrated that active MNs achieved efficient drug penetration within isolated scar tissue. The rabbit hypertrophic scar model revealed that TA-Cur MNs significantly reduced the scar elevation index, suppressed collagen I and transforming growth factor-β1 (TGF-β1) expression, and elevated LC3 protein levels. These findings highlight the potential of the active MN system as an efficacious platform for autonomous augmented drug delivery and autophagy-targeted therapy in fibrotic disorder treatments.

Patients suffering from nerve injury often experience exacerbated pain responses and complain of memory deficits. The dorsal hippocampus (dHPC), a well-defined region responsible for learning and memory, displays maladaptive plasticity upon injury, which is assumed to underlie pain hypersensitivity and cognitive deficits. However, much attention has thus far been paid to intracellular mechanisms of plasticity rather than extracellular alterations that might trigger and facilitate intracellular changes. Emerging evidence has shown that nerve injury alters the microarchitecture of the extracellular matrix (ECM) and decreases ECM rigidity in the dHPC. Despite this, it remains elusive which element of the ECM in the dHPC is affected and how it contributes to neuropathic pain and comorbid cognitive deficits. Laminin, a key element of the ECM, consists of α-, β-, and γ-chains and has been implicated in several pathophysiological processes. Here, we showed that peripheral nerve injury downregulates laminin β1 (LAMB1) in the dHPC. Silencing of hippocampal LAMB1 exacerbates pain sensitivity and induces cognitive dysfunction. Further mechanistic analysis revealed that loss of hippocampal LAMB1 causes dysregulated Src/NR2A signaling cascades via interaction with integrin β1, leading to decreased Ca²⁺ levels in pyramidal neurons, which in turn orchestrates structural and functional plasticity and eventually results in exaggerated pain responses and cognitive deficits. In this study, we shed new light on the functional capability of hippocampal ECM LAMB1 in the modulation of neuropathic pain and comorbid cognitive deficits, and reveal a mechanism that conveys extracellular alterations to intracellular plasticity. Moreover, we identified hippocampal LAMB1/integrin β1 signaling as a potential therapeutic target for the treatment of neuropathic pain and related memory loss.
Animals ; Laminin/genetics* ; Hippocampus/metabolism* ; Neuralgia/metabolism* ; Cognitive Dysfunction/etiology* ; Male ; Peripheral Nerve Injuries/metabolism* ; Extracellular Matrix/metabolism* ; Integrin beta1/metabolism* ; Pyramidal Cells/metabolism* ; Signal Transduction

OBJECTIVE: Hepatocellular carcinoma (HCC) is sensitive to ferroptosis, a new form of programmed cell death that occurs in most tumor types. However, the mechanism through which ferroptosis modulates HCC remains unclear. This study aimed to investigate the oncogenic role and prognostic value of FANCD2 and provide novel insights into the prognostic assessment and prediction of immunotherapy. METHODS: Using clinicopathological parameters and bioinformatic techniques, we comprehensively examined the expression of FANCD2 macroscopically and microcosmically. We conducted univariate and multivariate Cox regression analyses to identify the prognostic value of FANCD2 in HCC and elucidated the detailed molecular mechanisms underlying the involvement of FANCD2 in oncogenesis by promoting iron-related death. RESULTS: FANCD2 was significantly upregulated in digestive system cancers with abundant immune infiltration. As an independent risk factor for HCC, a high FANCD2 expression level was associated with poor clinical outcomes and response to immune checkpoint blockade. Gene set enrichment analysis revealed that FANCD2 was mainly involved in the cell cycle and CYP450 metabolism. CONCLUSION To the best of our knowledge, this is the first study to comprehensively elucidate the oncogenic role of FANCD2. FANCD2 has a tumor-promoting aspect in the digestive system and acts as an independent risk factor in HCC; hence, it has recognized value for predicting tumor aggressiveness and prognosis and may be a potential biomarker for poor responsiveness to immunotherapy.
Humans ; Carcinoma, Hepatocellular/diagnosis* ; Liver Neoplasms/diagnosis* ; Immunotherapy ; Fanconi Anemia Complementation Group D2 Protein/metabolism* ; Prognosis ; Male ; Female ; Middle Aged ; Biomarkers, Tumor/metabolism*

BACKGROUND: Blood glucose and serum albumin have been associated with cardiovascular disease prognosis, but the impact of admission-blood-glucose-to-albumin ratio (AAR) on adverse outcomes in critical ill coronary artery disease (CAD) patients was not investigated. METHODS: Patients diagnosed with CAD were non-consecutively selected from the MIMIC-IV database and categorized into quartiles based on their AAR. The primary outcome was 1-year mortality, and secondary endpoints were in-hospital mortality, acute kidney injury (AKI), and renal replacement therapy (RRT). A restricted cubic splines model and Cox proportional hazard models assessed the association between AAR and adverse outcomes in CAD patients. Kaplan-Meier survival analysis determined differences in endpoints across subgroups. RESULTS: A total of 8360 patients were included. There were 726 patients (8.7%) died in the hospital and 1944 patients (23%) died at 1 year. The incidence of AKI and RRT was 63% and 4.3%, respectively. High AAR was markedly associated with in-hospital mortality (HR = 1.587, P = 0.003), 1-year mortality (HR = 1.502, P < 0.001), AKI incidence (HR = 1.579, P < 0.001), and RRT (HR = 1.640, P < 0.016) in CAD patients in the completely adjusted Cox proportional hazard model. Kaplan-Meier survival analysis noted substantial differences in all endpoints based on AAR quartiles. Stratified analysis and interaction test demonstrated stable correlations between AAR and outcomes. CONCLUSIONS The results highlight that AAR may be a potential indicator for assessing in-hospital mortality, 1-year mortality, and adverse renal prognosis in critical CAD patients.