Zhongbo Liu

Improper orthodontic treatment can disrupt alveolar bone remodeling, leading to excessive alveolar bone resorption and complications such as bone fenestration and dehiscence. Although ferroptosis has emerged as an important regulator of bone metabolism, its role in mechanical force-induced periodontal tissue remodeling during orthodontic tooth movement (OTM) remains incompletely understood. This study investigated whether ferroptosis regulates the osteogenic response of human periodontal ligament stem cells (hPDLSCs) under compressive force (CF), focusing on stearoyl-CoA desaturase 1 (SCD1). hPDLSCs were subjected to static CF, and RNA sequencing, RT–qPCR, Western blotting, and immunofluorescence were performed to analyze SREBP1 and SCD1 expression. Ferroptosis-related alterations were evaluated using biochemical and mitochondrial analyses. Ferrostatin-1 (Fer-1) rescue, SCD1 knockdown/overexpression, and a rat OTM model were used for functional validation. Prolonged CF downregulated SREBP1 and SCD1 expression, accompanied by ferroptosis-associated alterations and reduced RUNX2 and OPN expression. Fer-1 alleviated these changes, whereas SCD1 overexpression partially restored osteogenic markers and SCD1 knockdown further impaired osteogenic responses. In vivo, SREBP1 and SCD1 expression were reduced on the compression side. Collectively, these findings identify SCD1 as an important regulator linking CF-induced ferroptosis-associated alterations with impaired osteogenic differentiation of hPDLSCs, suggesting SCD1 as a potential target for orthodontic bone remodeling.

Communication between hepatocytes and hepatic stellate cells (HSCs) is essential for liver homeostasis, yet its potential role in mitigating fibrosis remains largely unexplored. Here, we define a protective signaling axis from hepatocytes to HSCs, mediated by hepatocyte‐expressed eNOS, that restrains HSC activation and fibrotic progression. In human fibrotic liver samples and mouse models, eNOS expression is markedly suppressed, and its hepatocyte‐specific deletion aggravates injury and fibrosis. We further establish that the anti‐fibrotic benefits of alternate‐day fasting (ADF) critically depend on this intercellular pathway. ADF enhanced hepatocyte eNOS expression, and hepatocyte‐specific eNOS knockout abolished the protective metabolic and anti‐fibrotic effects of ADF. Mechanistically, ADF downregulates the mitochondrial chaperone SDHAF4, thereby suspending complex II assembly and promoting eNOS‐derived nitric oxide (NO) production. The resulting NO acts in a paracrine manner on HSCs to induce S‐nitrosylation of ATG7 at cysteine 184, which in turn constraining autophagic flux and preventing HSC transdifferentiation. Our study reveals a fasting‐responsive hepatocyte–stellate cell circuit that protects against liver fibrosis, highlighting the eNOS/NO/ATG7 S‐nitrosylation axis as a tractable therapeutic target.

Background: Postmenopausal osteoporosis (PMOP) leads to systemic bone metabolism disorders, significantly affecting oral bone health and complicating treatment. Osteocytes, the most abundant cells in bone tissue, play a crucial role in bone remodeling through cellular communication. However, the mineralized bone matrix surrounding osteocytes presents significant challenges for studying their dendritic networks. Methods: Eight week old C57BL/6J female mice were randomly assigned to either a Sham group or an ovariectomized (OVX) group. The PMOP animal model was established via bilateral ovariectomy and analyzed after 12 weeks. Osteocyte dendrites and the lacuno‐canalicular network (LCN) were examined via SEM and immunohistochemical staining. Quantification of nodes and connectomic measurements were performed for LCN and phalloidin network analyses. Furthermore, the expression levels of MMP13 and CTSK were assessed via immunohistochemical staining and real‐time PCR. Results: Our findings revealed that both Sham and OVX mice exhibited two distinct morphological types of osteocyte lacunar structures in the mandible. In Sham mice, direct communication was observed between osteocytes, adjacent cells, and blood vessels via canaliculi. In contrast, connectivity analysis of the osteocyte dendritic network in OVX mice revealed a reduced material transport capacity between cells compared with Sham controls. OVX‐induced systemic osteoporosis altered the osteocyte dendritic network and lacunar canaliculi in the mandible, potentially due to periluminal canalicular remodeling. Conclusions: This study offers new insights into the changes and mechanisms affecting the dendritic network and lacunar canaliculi of mandibular osteocytes in postmenopausal osteoporosis, contributing to a deeper understanding of oral bone lesions in this condition. Plain Language Summary: After menopause, many women develop osteoporosis—a condition where bones become weak and break easily. This not only affects bones such as the spine or hips but also damages the jawbone, making dental treatments harder. We wanted to understand how osteoporosis weakens the jawbone by studying tiny bone cells called osteocytes, which act like “messengers” controlling bone health. Using advanced microscopy and special staining techniques, we mapped communication networks between osteocytes in the jawbone (like tracing telephone wires between cells). We then compared bone structures between healthy mice and mice with osteoporosis after ovary removal. Osteoporosis damaged the “wires” (dendrites) connecting osteocytes, reducing their ability to share nutrients and signals. It also widened tunnels (canaliculi) around osteocytes—like potholes in roads—disrupting their links to blood vessels and neighboring cells. These changes likely occur because osteoporosis impairs the bone's self‐repair system around these tunnels. Our discovery that osteoporosis breaks bone cell networks reveals a new mechanism for jawbone weakening, paving the way for better dental treatments, protective drugs, and patient education.

Matrix stiffness is a key feature of the mechanical microenvironment. Periodontal tissue is a multicomponent structure composed of cementum, periodontal li

Metabolic alterations in chondrocytes play a crucial role in the progression of temporomandibular joint osteoarthritis (TMJOA). However, the precise molecular mechanisms underlying these changes remain poorly understood. In this study, we identify ubiquitin-specific protease 32 (USP32) as a key regulator of TMJOA progression through its interaction with pyruvate kinase M2 (PKM2), a vital enzyme in glycolysis. Our results demonstrate that USP32 is significantly upregulated in TMJOA cartilage and inflammatory chondrocytes. USP32 stabilizes PKM2 by removing K48- and K11-linked ubiquitin chains, thereby preventing its proteasomal degradation. This stabilization promotes the accumulation of PKM2, leading to enhanced glycolysis, increased lactate production, and mitochondrial dysfunction, all of which exacerbate chondrocyte apoptosis and the degradation of extracellular matrix. Knocking down USP32 or PKM2 mitigates these detrimental effects, restoring mitochondrial function and reducing inflammation. Furthermore, cartilage-specific knockdown of USP32 alleviates TMJOA pathology in a rat model, highlighting the therapeutic potential of targeting the USP32-PKM2 axis. Our findings reveal a novel mechanism through which USP32 regulates chondrocyte metabolism and inflammation via PKM2 deubiquitination, providing new insights into the pathogenesis of TMJOA and potential therapeutic strategies for its treatment.

This study investigates the mechanisms underlying osteocyte injury in a high glucose (HG) environment and explores potential therapeutic targets and diagnostic markers for diabetic osteoporosis, a common complication of type 2 diabetes mellitus (T2DM). Hyperglycemia induces oxidative stress through the reactive oxygen species (ROS) production, which impair osteocytes and accelerate bone loss. To examine these effects, MLO-Y4 cells and primary mouse osteocytes were cultured under normal glucose and HG conditions, with additional treatments using N-acetylcysteine (NAC, ROS scavenger) and rapamycin (autophagy promoter and mTOR inhibitor). Cell viability, ROS levels, and the autophagy and apoptosis markers expression (Beclin1, LC3, p62, Bax, Bcl2, cytochrome C, and caspase3) were assessed using CCK8/ATP level assay, flow cytometry, Western blot, qRT-PCR, immunofluorescence, and TUNEL staining. The results showed that HG inhibits cell proliferation, induces insulin resistance, generates ROS, alters antioxidant enzymes, and promotes oxidative stress, leading to mTOR activation, subsequent autophagy inhibition, and osteocyte apoptosis. NAC mitigated these effects, while rapamycin prevented HG-induced apoptosis by inhibiting mTOR activation and promoting autophagy. This suggests that ROS-induced mTOR activation impairs autophagy and hinders the clearance of damaged osteocytes, triggering apoptosis. This research provides foundational evidence and novel insights into diabetic osteoporosis pathogenesis and potential therapies.

Background: SHR-5 has been used as an “adaptogen” for enhancing physical and mental performance and for fighting stress in the healthy population. The purpose of this study is to determine the chemopreventive efficacy of SHR-5 for superficial bladder cancer and to investigate the underlying mechanisms of action. Methods: UPII-mutant Ha-ras bladder-cancer-transgenic mice, that developed low-grade and noninvasive papillary transitional urothelial cell carcinoma, were fed with 1.25 and 6.25 mg/mL SHR-5 in drinking water for 6 months. The survival of the mice, obstructive uropathy, tumor burden and morphology, and proliferation were evaluated by pathological, molecular, metabolic, and statistical analyses. Results: Approximately 95% or more of the male UPII-mutant Ha-ras mice that drank SHR-5 daily survived over 6 months of age, while only 33.3% of those mice that drank normal water survived over 6 months of age (p < 0.0001); SHR-5 drinking exposure also reduced tumor-bearing bladder weight and urinary tract obstruction and inhibited mTOR signaling in neoplastic tissues. Global metabolic analysis revealed that SHR-5 resulted in increased phenolic metabolites and decreased CoA, a critical metabolic cofactor for lipid metabolism. Conclusions: Our findings highlight the potential of SHR-5 as an anti-aging agent for bladder cancer prevention through reshaping tumor metabolism via the inhibition of the mTOR signaling. Global metabolomics profiling provides a unique and efficient tool for studying the mechanisms of complex herb extracts’ action.