Insights and implications of sexual dimorphism in osteoporosis.

Osteoporosis, a metabolic bone disease characterized by low bone mineral density and deterioration of bone microarchitecture, has led to a high risk of fatal osteoporotic fractures worldwide. Accumulating evidence has revealed that sexual dimorphism is a notable feature of osteoporosis, with sex-specific differences in epidemiology and pathogenesis. Specifically, females are more susceptible than males to osteoporosis, while males are more prone to disability or death from the disease. To date, sex chromosome abnormalities and steroid hormones have been proven to contribute greatly to sexual dimorphism in osteoporosis by regulating the functions of bone cells. Understanding the sex-specific differences in osteoporosis and its related complications is essential for improving treatment strategies tailored to women and men. This literature review focuses on the mechanisms underlying sexual dimorphism in osteoporosis, mainly in a population of aging patients, chronic glucocorticoid administration, and diabetes. Moreover, we highlight the implications of sexual dimorphism for developing therapeutics and preventive strategies and screening approaches tailored to women and men. Additionally, the challenges in translating bench research to bedside treatments and future directions to overcome these obstacles will be discussed.

HSPA8 Activates Wnt/ß-Catenin Signaling to Facilitate BRAF V600E Colorectal Cancer Progression by CMA-Mediated CAV1 Degradation.

BRAF V600E attracts wide attention in the treatment of colorectal cancer (CRC) as stratifying and predicting a refractory classification of CRC. Recent evidence indicates that Wnt/ß-catenin signaling is broadly activated and participates in the refractoriness of BRAF V600E CRC, but the underlying molecular mechanism needs to be elucidated. Here, heat shock 70 kDa protein 8 (HSPA8), an essential regulator in chaperone-mediated autophagy (CMA), is identified as a potential therapeutic target for advanced BRAF V600E CRC. These results show that HSPA8 is transcriptionally upregulated in BRAF V600E CRC, which promotes CMA-dependent degradation of caveolin-1 (CAV1) to release ß-catenin into the nucleus and thus activates the Wnt/ß-catenin pathway, contributing to metastasis and progression of BRAF V600E CRC. Of note, HSPA8 directly interacts with the KIFSN motif on CAV1, the interaction can be enhanced by p38 MAPK-mediated CAV1 S168 phosphorylation. Furthermore, pharmacological targeting HSPA8 by VER155008 exhibits synergistic effects with BRAF inhibitors on CRC mouse models. In summary, these findings discover the important role of the HSPA8/CAV1/ß-catenin axis in the development of refractory BRAF V600E CRC and highlight HSPA8 as a predictive biomarker and therapeutic target in clinical practice.

Comprehensive pan-cancer analysis reveals NUSAP1 is a novel predictive biomarker for prognosis and immunotherapy response.

Nucleolar and spindle-associated protein 1 (NUSAP1) is a microtubule-associated protein that plays a crucial role in mitosis. Despite initial reports suggesting a potential involvement of NUSAP1 in tumor progression and malignant cell regulation, there has been no systematic analysis of its role in the tumor immune microenvironment, nor its predictive value for prognosis and immunotherapy response across different cancer types. In this study, we analyze NUSAP1 mRNA and protein expression levels in various human normal and tumor tissues, using data from TCGA, GTEx, CPTAC, HPA databases, and clinical samples. Our findings reveal that NUSAP1 is highly expressed in multiple tumor tissues across most cancer types and is primarily expressed in malignant and immune cells, according to single-cell sequencing data from the TISCH database. Prognostic analysis based on curated survival data from the TCGA database indicates that NUSAP1 expression levels can predict clinical outcomes for 26 cancer types. Furthermore, Gene Set Enrichment Analysis (GSEA) suggests that NUSAP1 promotes cell proliferation, tumor cell invasion, and regulation of anti-tumor response. Analysis of immune score, immune cell infiltration, and anti-cancer immunity cycle using ESTIMATE, TIMER, and TIP databases show that high NUSAP1 levels are associated with low CD4+T and NKT cell infiltration but high Th2 and MDSC infiltration, inversely correlated with antigen-presenting molecules and positively correlated with a variety of immune negative regulatory molecules. Notably, patients with melanoma, lung, and kidney cancer with high NUSAP1 expression levels have shorter survival times and lower immunotherapy response rates. Using Cmap analysis, we identify Entinostat and AACOCF3 as potential inhibitors of NUSAP1-mediated pro-oncogenic effects. In vitro and in vivo experiments further confirm that NUSAP1 knockdown significantly reduces the proliferation ability of A549 and MCF-7 cells. Overall, our study highlights the potential of NUSAP1 expression as a novel biomarker for predicting prognosis and immuno-therapeutic efficacy across different human cancers and suggests its potential for developing novel antitumor drugs or improving immunotherapy.

The prolyl isomerase Pin1 stabilizes NeuroD during differentiation of mechanoreceptors.

The peptidyl prolyl cis-trans isomerase Pin1 plays vital roles in diverse cellular processes and pathological conditions. NeuroD is a differentiation and survival factor for a subset of neurons and pancreatic endocrine cells. Although multiple phosphorylation events are known to be crucial for NeuroD function, their mechanisms remain elusive. In this study, we demonstrate that zebrafish embryos deficient in Pin1 displayed phenotypes resembling those associated with NeuroD depletion, characterized by defects in formation of mechanosensory hair cells. Furthermore, zebrafish Pin1 interacts with NeuroD in a phosphorylation-dependent manner. In Pin1-deficient cell lines, NeuroD is rapidly degraded. However, the protein stability of NeuroD is restored upon overexpression of Pin1. These findings suggest that Pin1 functionally regulates NeuroD protein levels by post-phosphorylation cis-trans isomerization during neuronal specification.

Mitochondrial dysfunction and mitophagy: crucial players in burn trauma and wound healing.

Burn injuries are a significant cause of death worldwide, leading to systemic inflammation, multiple organ failure and sepsis. The progression of burn injury is explicitly correlated with mitochondrial homeostasis, which is disrupted by the hyperinflammation induced by burn injury, leading to mitochondrial dysfunction and cell death. Mitophagy plays a crucial role in maintaining cellular homeostasis by selectively removing damaged mitochondria. A growing body of evidence from various disease models suggest that pharmacological interventions targeting mitophagy could be a promising therapeutic strategy. Recent studies have shown that mitophagy plays a crucial role in wound healing and burn injury. Furthermore, chemicals targeting mitophagy have also been shown to improve wound recovery, highlighting the potential for novel therapeutic strategies based on an in-depth exploration of the molecular mechanisms regulating mitophagy and its association with skin wound healing.

Purinergic signalling in cancer therapeutic resistance: From mechanisms to targeting strategies.

Purinergic signalling, consisting of extracellular purines and purinergic receptors, modulates cell proliferation, invasion and immunological reaction during cancer progression. Here, we focus on current evidence that suggests the crucial role of purinergic signalling in mediating cancer therapeutic resistance, the major obstacle in cancer treatment. Mechanistically, purinergic signalling can modulate the tumor microenvironment (TME), epithelial-mesenchymal transition (EMT) and anti-tumor immunity, thus affecting drug sensitivity of tumor cells. Currently, some agents attempting to target purinergic signalling either in tumor cells or in tumor-associated immune cells are under preclinical or clinical investigation. Moreover, nano-based delivery technologies significantly improve the efficacy of agents targeting purinergic signalling. In this review article, we summarize the mechanisms of purinergic signalling in promoting cancer therapeutic resistance and discuss the potentials and challenges of targeting purinergic signalling in future cancer treatment.

NUSAP1-LDHA-Glycolysis-Lactate feedforward loop promotes Warburg effect and metastasis in pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by hypoxia and hypovascular tumor microenvironment. Nucleolar and spindle associated protein 1 (NUSAP1) is a microtubule-associated protein that is known to be involved in cancer biology. Our study aimed to investigate the role of NUSAP1 in glycolytic metabolism and metastasis in PDAC. Expression and prognostic value of NUSAP1 in PDAC and common gastrointestinal tumors was evaluated. The function of NUSAP1 in PDAC progression was clarified by single-cell RNA-seq and further experiments in vitro, xenograft mouse model, spontaneous PDAC mice model and human tissue microarray. The downstream genes and signaling pathways regulated by NUSAP1 were explored by RNA-Seq. And the regulation of NUSAP1 on Lactate dehydrogenase A (LDHA)-mediated glycolysis and its underlying mechanism was further clarified by CHIP-seq. NUSAP1 was an independent unfavorable predictor of PDAC prognosis that playing a critical role in metastasis of PDAC by regulating LDHA-mediated glycolysis. Mechanically, NUSAP1 could bind to c-Myc and HIF-1α that forming a transcription regulatory complex localized to LDHA promoter region and enhanced its expression. Intriguingly, lactate upregulated NUSAP1 expression by inhibiting NUSAP1 protein degradation through lysine lactylated (Kla) modification, thus forming a NUSAP1-LDHA-glycolysis-lactate feedforward loop. The NUSAP1-LDHA-glycolysis-lactate feedforward loop is one of the underlying mechanisms to explain the metastasis and glycolytic metabolic potential in PDAC, which also provides a novel insights to understand the Warburg effect in cancer. Targeting NUSAP1 would be an attractive paradigm for PDAC treatment.

Ribosomal proteins regulate 2-cell-stage transcriptome in mouse embryonic stem cells.

A rare sub-population of mouse embryonic stem cells (mESCs), the 2-cell-like cell, is defined by the expression of MERVL and 2-cell-stage-specific transcript (2C transcript). Here, we report that the ribosomal proteins (RPs) RPL14, RPL18, and RPL23 maintain the identity of mESCs and regulate the expression of 2C transcripts. Disregulation of the RPs induces DUX-dependent expression of 2C transcripts and alters the chromatin landscape. Mechanically, knockdown (KD) of RPs triggers the binding of RPL11 to MDM2, an interaction known to prevent P53 protein degradation. Increased P53 protein upon RP KD further activates its downstream pathways, including DUX. Our study delineates the critical roles of RPs in 2C transcript activation, ascribing a novel function to these essential proteins.

The kingdom of the prolyl-isomerase Pin1: The structural and functional convergence and divergence of Pin1.

More than 20 years since its discovery, our understanding of Pin1 function in various diseases continues to improve. Pin1 plays a crucial role in pathogenesis and has been implicated in metabolic disorders, cardiovascular diseases, inflammatory diseases, viral infection, cancer and neurodegenerative diseases such as Alzheimer's, Parkinson's and Huntington's disease. In particular, the role of Pin1 in neurodegenerative diseases and cancer has been extensively studied. Our understanding of Pin1 in cancer also led to the development of cancer therapeutic drugs targeting Pin1, with some currently in clinical trial phases. However, identifying a Pin1-specific drug with good cancer therapeutic effect remains elusive, thus leading to the continued efforts in Pin1 research. The importance of Pin1 is highlighted by the presence of Pin1 orthologs across various species: from vertebrates to invertebrates and Kingdom Animalia to Plantae. Among these Pin1 orthologs, their sequence and structural similarity demonstrate the presence of conservation. Moreover, their similar functionality between species further highlights the conservancy of Pin1. As researchers continue to unlock the mysteries of Pin1 in various diseases, using different Pin1 models might shed light on how to better target Pin1 for disease therapeutics. This review aims to highlight the various Pin1 orthologs in numerous species and their divergent functional roles. We will examine their sequence and structural similarities and discuss their functional similarities and uniqueness to demonstrate the interconnectivity of Pin1 orthologs in multiple diseases.

Dendritic epidermal T cells secreting exosomes promote the proliferation of epidermal stem cells to enhance wound re-epithelialization.

BACKGROUND: Efficient re-epithelialization is important for successful skin wound healing. The proportion of epidermal stem cells (EpSCs) and dendritic epidermal T cells (DETCs) determines the extent of wound re-epithelialization, especially in large areas of skin tissue loss. However, it remains unknown whether and how DETCs regulate the status of EpSCs to impact wound re-epithelialization. METHODS: To investigate how DETCs regulate EpSCs in skin re-epithelialization, we utilized normal or full-thickness skin deficient wide type (WT) mice and Tcrσ knockout (Tcrσ-/-) mice with DETCs or DETCs-derived exosomes (Exos) treatment. Flow cytometry analysis (FCAS), BrdU labelled experiments, immunofluorescence and immunohistochemical assays were performed to detect the proportion of EpSCs in the epidermis. Wound closure rate and re-epithelialization were assayed by a macroscopical view and hematoxylin-eosin (H&E) staining. EpSCs in vitro were co-cultured with DETCs in a transwell-dependent or -independent manner, or supplement with GW4869 or Exos (5 µg/mL, 15 µg/mL and 45 µg/mL), and the proliferation of EpSCs was detected by means of FCAS and CFSE. RESULTS: Our data showed that the proportion of CD49fbriCD71dim cells, K15+ cells and BrdU+ cells in the normal epidermis of Tcrδ-/- mice had no significant difference compared to WT mice. For wounded Tcrδ-/- mice, DETCs treatment increase the proportion of CD49fbriCD71dim cells, K15+ cells and BrdU+ cells in the epidermis around the wound in comparison to PBS treatment. DETCs significantly increased the number of CD49fbriCD7dim cells and K15+ cells through transwell-dependent or -independent manners relative to control group. Furthermore, Exos stimuli remarkedly promote the proliferation of EpSCs compared to control group, while the increasement was suppressed when DETCs were interfered with GW4869. Gross observation and H&E staining showed that Exos significantly accelerated wound closure and increased re-epithelialization length in Tcrδ-/- mice when compared to control mice. Additionally, we found in vivo that Exos observably facilitated the proliferation of CD49fbriCD7dim cells and K15+ cells. CONCLUSIONS: We revealed that DETCs enhanced the proliferation of EpSCs in the epidermis around the wounds to accelerate re-epithelialization in which Exos played important roles in the remote regulation of EpSCs proliferation. Together, these findings suggest a mechanistic link among DETC-derived exosomes, the proliferation of EpSCs, and wound re-epithelialization in the skin.

P311 Facilitates the Angiogenesis and Wound Healing Function of MSCs by Increasing VEGF Production.

As a potential clinical therapeutic cell for injured tissue repair, mesenchymal stem cells (MSCs) have attracted increasing attention. Enhancing the pro-healing function of MSCs has gradually become an essential topic in improving the clinical efficacy of MSCs. Recently, studies have shown that neuronal protein 3.1 (P311) plays a crucial role in promoting skin wound healing, suggesting P311 gene modification may improve the pro-healing function of MSCs. In this study, we demonstrated that increasing the in vivo expression of P311 could significantly enhance the ability of MSCs to lessen the number of inflammatory cells, increase the expression of IL10, reduce the levels of TNF-α and IFN-γ, increase collagen deposition, promote angiogenesis, and ultimately accelerate skin wound closure and improve the quality of wound healing. Importantly, we uncovered that P311 enhanced the pro-angiogenesis function of MSCs by increasing the production of vascular endothelial growth factor (VEGF) in vitro and in vivo. Mechanistically, we revealed that the mTOR signalling pathway was closely related to the regulation of P311 on VEGF production in MSCs. Together, our data displayed that P311 gene modification in MSCs augments their capabilities to promote skin wound closure, which might bring the dawn for its clinical application in the future.

Redox-sensitive cyclophilin A elicits chemoresistance through realigning cellular oxidative status in colorectal cancer.

Cancer cells utilize rapidly elevated cellular antioxidant programs to accommodate chemotherapy-induced oxidative stress; however, the underlying mechanism remains largely unexplored. Here we screen redox-sensitive effectors as potential therapeutic targets for colorectal cancer (CRC) treatment and find that cyclophilin A (CypA) is a compelling candidate. Our results show that CypA forms an intramolecular disulfide bond between Cys115 and Cys161 upon oxidative stress and the oxidized cysteines in CypA are recycled to a reduced state by peroxiredoxin-2 (PRDX2). Furthermore, CypA reduces cellular reactive oxygen species levels and increases CRC cell survival under insults of H2O2 and chemotherapeutics through a CypA-PRDX2-mediated antioxidant apparatus. Notably, CypA is upregulated in chemoresistant CRC samples, which predicts poor prognosis. Moreover, targeting CypA by cyclosporine A exhibits promising efficacy against chemoresistant CRC when combined with chemotherapeutics. Collectively, our findings highlight CypA as a component of cellular noncanonical antioxidant defense and as a potential druggable therapeutic target to ameliorate CRC chemoresistance.

Photodynamic therapy accelerates skin wound healing through promoting re-epithelialization.

BACKGROUND: Epidermal stem cells (EpSCs) that reside in cutaneous hair follicles and the basal layer of the epidermis are indispensable for wound healing and skin homeostasis. Little is known about the effects of photochemical activation on EpSC differentiation, proliferation and migration during wound healing. The present study aimed to determine the effects of photodynamic therapy (PDT) on wound healing in vivo and in vitro. METHODS: We created mouse full-thickness skin resection models and applied 5-aminolevulinic acid (ALA) for PDT to the wound beds. Wound healing was analysed by gross evaluation and haematoxylin-eosin staining in vivo. In cultured EpSCs, protein expression was measured using flow cytometry and immunohistochemistry. Cell migration was examined using a scratch model; apoptosis and differentiation were measured using flow cytometry. RESULTS: PDT accelerated wound closure by enhancing EpSC differentiation, proliferation and migration, thereby promoting re-epithelialization and angiogenesis. PDT inhibited inflammatory infiltration and expression of proinflammatory cytokines, whereas the secretion of growth factors was greater than in other groups. The proportion of transient amplifying cells was significantly greater in vivo and in vitro in the PDT groups. EpSC migration was markedly enhanced after ALA-induced PDT. CONCLUSIONS: Topical ALA-induced PDT stimulates wound healing by enhancing re-epithelialization, promoting angiogenesis as well as modulating skin homeostasis. This work provides a preliminary theoretical foundation for the clinical administration of topical ALA-induced PDT in skin wound healing.

Hyaluronan-Mediated Motility Receptor Governs Chromosome Segregation by Regulating Microtubules Sliding Within the Bridging Fiber.

Accurate segregation of chromosomes during anaphase relies on the central spindle and its regulators. A newly raised concept of the central spindle, the bridging fiber, shows that sliding of antiparallel microtubules (MTs) within the bridging fiber promotes chromosome segregation. However, the regulators of the bridging fiber and its regulatory mechanism on MTs sliding remain largely unknown. In this study, the non-motor microtubule-associated protein, hyaluronan-mediated motility receptor (HMMR), is identified as a novel regulator of the bridging fiber. It then identifies that HMMR regulates MTs sliding within the bridging fiber by cooperating with its binding partner HSET. By utilizing a laser-based cell ablation system and photoactivation approach, the study's results reveal that depletion of HMMR causes an inhibitory effect on MTs sliding within the bridging fiber and disrupts the forced uniformity on the kinetochore-attached microtubules-formed fibers (k-fibers). These are created by suppressing the dynamics of HSET, which functions in transiting the force from sliding of bridging MTs to the k-fiber. This study sheds new light on the novel regulatory mechanism of MTs sliding within the bridging fiber by HMMR and HSET and uncovers the role of HMMR in chromosome segregation during anaphase.

The pathogenesis and diagnosis of sepsis post burn injury.

Burn is an under-appreciated trauma that is associated with unacceptably high morbidity and mortality. Although the survival rate after devastating burn injuries has continued to increase in previous decades due to medical advances in burn wound care, nutritional and fluid resuscitation and improved infection control practices, there are still large numbers of patients at a high risk of death. One of the most common complications of burn is sepsis, which is defined as "severe organ dysfunction attributed to host's disordered response to infection" and is the primary cause of death in burn patients. Indeed, burn injuries are accompanied by a series of events that lead to sepsis and multiple organ dysfunction syndrome, such as a hypovolaemic state, immune and inflammatory responses and metabolic changes. Therefore, clear diagnostic criteria and predictive biomarkers are especially important in the prevention and treatment of sepsis and septic shock. In this review, we focus on the pathogenesis of burn wound infection and the post-burn events leading to sepsis. Moreover, the clinical and promising biomarkers of burn sepsis will also be summarized.

The redox language in neurodegenerative diseases: oxidative post-translational modifications by hydrogen peroxide.

Neurodegenerative diseases, a subset of age-driven diseases, have been known to exhibit increased oxidative stress. The resultant increase in reactive oxygen species (ROS) has long been viewed as a detrimental byproduct of many cellular processes. Despite this, therapeutic approaches using antioxidants were deemed unsuccessful in circumventing neurodegenerative diseases. In recent times, it is widely accepted that these toxic by-products could act as secondary messengers, such as hydrogen peroxide (H2O2), to drive important signaling pathways. Notably, mitochondria are considered one of the major producers of ROS, especially in the production of mitochondrial H2O2. As a secondary messenger, cellular H2O2 can initiate redox signaling through oxidative post-translational modifications (oxPTMs) on the thiol group of the amino acid cysteine. With the current consensus that cellular ROS could drive important biological signaling pathways through redox signaling, researchers have started to investigate the role of cellular ROS in the pathogenesis of neurodegenerative diseases. Moreover, mitochondrial dysfunction has been linked to various neurodegenerative diseases, and recent studies have started to focus on the implications of mitochondrial ROS from dysfunctional mitochondria on the dysregulation of redox signaling. Henceforth, in this review, we will focus our attention on the redox signaling of mitochondrial ROS, particularly on mitochondrial H2O2, and its potential implications with neurodegenerative diseases.

Functions of outer mitochondrial membrane proteins: mediating the crosstalk between mitochondrial dynamics and mitophagy.

Most cellular stress responses converge on the mitochondria. Consequently, the mitochondria must rapidly respond to maintain cellular homeostasis and physiological demands by fine-tuning a plethora of mitochondria-associated processes. The outer mitochondrial membrane (OMM) proteins are central to mediating mitochondrial dynamics, coupled with continuous fission and fusion. These OMM proteins also have vital roles in controlling mitochondrial quality and serving as mitophagic receptors for autophagosome enclosure during mitophagy. Mitochondrial fission segregates impaired mitochondria in smaller sizes from the mother mitochondria and may favor mitophagy for eliminating damaged mitochondria. Conversely, mitochondrial fusion mixes dysfunctional mitochondria with healthy ones to repair the damage by diluting the impaired components and consequently prevents mitochondrial clearance via mitophagy. Despite extensive research efforts into deciphering the interplay between fission-fusion and mitophagy, it is still not clear whether mitochondrial fission essentially precedes mitophagy. In this review, we summarize recent breakthroughs concerning OMM research, and dissect the functions of these proteins in mitophagy from their traditional roles in fission-fusion dynamics, in response to distinct context, at the intersection of the OMM platform. These insights into the OMM proteins in mechanistic researches would lead to new aspects of mitochondrial quality control and better understanding of mitochondrial homeostasis intimately tied to pathological impacts.