Sclerostin inhibition in rare bone diseases: Molecular understanding and therapeutic perspectives.

Sclerostin emerges as a novel target for bone anabolic therapy in bone diseases. Osteogenesis imperfecta (OI) and X-linked hypophosphatemia (XLH) are rare bone diseases in which therapeutic potential of sclerostin inhibition cannot be ignored. In OI, genetic/pharmacologic sclerostin inhibition promoted bone formation of mice, but responses varied by genotype and age. Serum sclerostin levels were higher in young OI-I patients, while lower in adult OI-I/III/IV. It's worth investigating whether therapeutic response of OI to sclerostin inhibition could be clinically predicted by genotype and age. In XLH, preclinical/clinical data suggested factors other than identified FGF23 contributing to XLH. Higher levels of circulating sclerostin were detected in XLH. Sclerostin inhibition promoted bone formation in Hyp mice, while restored phosphate homeostasis in age-/gender-dependent manner. The role of sclerostin in regulating phosphate metabolism deserves investigation. Sclerostin/FGF23 levels of XLH patients with/without response to FGF23-antibody warrants study to develop precise sclerostin/FGF23 inhibition strategy or synergistic/additive strategy. Notably, OI patients were associated with cardiovascular abnormalities, so were XLH patients receiving conventional therapy. Targeting sclerostin loop3 promoted bone formation without cardiovascular risks. Further, blockade of sclerostin loop3-LRP4 interaction while preserving sclerostin loop2-ApoER2 interaction could be a potential precise sclerostin inhibition strategy for OI and XLH with cardiovascular safety. The Translational Potential of this Article. Preclinical data on the molecular understanding of sclerostin inhibition in OI and therapeutic efficacy in mouse models of different genotypes, as well as clinical data on serum sclerostin levels in patients with different phenotypes of OI, were reviewed and discussed. Translationally, it would facilitate to develop clinical prediction strategies (e.g. based on genotype and age, not just phenotype) for OI patients responsive to sclerostin inhibition. Both preclinical and clinical data suggested sclerostin as another factor contributing to XLH, in addition to the identified FGF23. The molecular understanding and therapeutic effects of sclerostin inhibition on both promoting bone anabolism and improving phosphate homostasis in Hyp mice were reviewed and discussed. Translationaly, it would facilitate the development of precise sclerostin/FGF23 inhibition strategy or synergistic/additive strategy for the treatment of XLH. Cardiovascular risk could not be ruled out during sclerostin inhibition treatment, especially for OI and XLH patients with cardiovascular diseases history and cardiovascular abnormalities. Studies on the role of sclerostin in inhiting bone formation and protecting cardiovascular system were reviewed and discussed. Translationaly, blockade of sclerostin loop3-LRP4 interaction while preserving sclerostin loop2-ApoER2 interaction could be a potential precise sclerostin inhibition strategy for OI and XLH with cardiovascular safety.

A strategy to distinguish similar traditional Chinese medicines by liquid chromatography-mass spectrometry, electronic senses, and gas chromatography-ion mobility spectrometry: Marsdeniae tenacissimae Caulis and Paederiae scandens Caulis as examples.

INTRODUCTION: Marsdeniae tenacissimae Caulis (MTC), a popular traditional Chinese medicine, has been widely used in the treatment of tumor diseases. Paederiae scandens Caulis (PSC), which is similar in appearance to MTC, is a common counterfeit product. It is difficult for traditional methods to effectively distinguish between MTC and PSC. Therefore, there is an urgent need for a rapid and accurate method to identify MTC and PSC. OBJECTIVES: The aim is to distinguish between MTC and PSC by analyzing the differences in nonvolatile organic compounds (NVOCs), taste, odor, and volatile organic compounds (VOCs). METHODS: Liquid chromatography-mass spectrometry (LC-MS) was utilized to analyze the NVOCs of MTC and PSC. Electronic tongue (E-tongue) and electronic nose (E-nose) were used to analyze their taste and odor respectively. Gas chromatography-ion mobility spectrometry (GC-IMS) was applied to analyze VOCs. Finally, multivariate statistical analyses were conducted to further investigate the differences between MTC and PSC, including principal component analysis, orthogonal partial least squares discriminant analysis, discriminant factor analysis, and soft independent modeling of class analysis. RESULTS: The results of this study indicate that the integrated strategy of LC-MS, E-tongue, E-nose, GC-IMS, and multivariate statistical analysis can be effectively applied to distinguish between MTC and PSC. Using LC-MS, 25 NVOCs were identified in MTC, while 18 NVOCs were identified in PSC. The major compounds in MTC are steroids, while the major compounds in PSC are iridoid glycosides. Similarly, the distinct taste difference between MTC and PSC was precisely revealed by the E-tongue. Specifically, the pronounced bitterness in PSC was proven to stem from iridoid glycosides, whereas the bitterness evident in MTC was intimately tied to steroids. The E-nose detected eight odor components in MTC and six in PSC, respectively. The subsequent statistical analysis uncovered notable differences in their odor profiles. GC-IMS provided a visual representation of the differences in VOCs between MTC and PSC. The results indicated a relatively high relative content of 82 VOCs in MTC, contrasted with 32 VOCs exhibiting a similarly high relative content in PSC. CONCLUSION: In this study, for the first time, the combined use of LC-MS, E-tongue, E-nose, GC-IMS, and multivariate statistical analysis has proven to be an effective method for distinguishing between MTC and PSC from multiple perspectives. This approach provides a valuable reference for the identification of other visually similar traditional Chinese medicines.

Ile-Pro-Pro attenuates sympathetic activity and hypertension.

Isoleucine-proline-proline (Ile-Pro-Pro, IPP) is a natural food source tripeptide that inhibits angiotensin-converting enzyme (ACE) activity. The aim of this study was to determine the central and peripheral roles of IPP in attenuating sympathetic activity, oxidative stress and hypertension. Male Sprague-Dawley rats were subjected to sham-operated surgery (Sham) or two-kidney one-clip (2K1C) surgery to induce renovascular hypertension. Renal sympathetic nerve activity and blood pressure were recorded. Bilateral microinjections of IPP to hypothalamic paraventricular nucleus (PVN) attenuated sympathetic activity (-16.1 ± 2.5%, P < 0.001) and hypertension (-8.7 ± 1.5 mmHg, P < 0.01) in 2K1C rats by inhibiting ACE activity and subsequent angiotensin II and superoxide production in the PVN. Intravenous injections of IPP also attenuated sympathetic activity (-15.1 ± 2.1%, P < 0.001) and hypertension (-16.8 ± 2.3 mmHg, P < 0.001) via inhibiting ACE activity and oxidative stress in both PVN and arteries of 2K1C rats. The duration of the effects of the intravenous IPP was longer than those of the PVN microinjection, but the sympatho-inhibitory effect of intravenous injections occurred later than that of the PVN microinjection. Intraperitoneal injection of IPP (400 pmol/day for 20 days) attenuated hypertension and vascular remodeling via inhibiting ACE activity and oxidative stress in both PVN and arteries of 2K1C rats. These results indicate that IPP attenuates hypertension and sympathetic activity by inhibiting ACE activity and oxidative stress. The sympathoinhibitory effect of peripheral IPP is mainly caused by the ACE inhibition in PVN, and the antihypertensive effect is related to the sympathoinhibition and the arterial ACE inhibition. Long-term intraperitoneal IPP therapy attenuates hypertension, oxidative stress and vascular remodeling.

Portal Venous and Hepatic Arterial Coefficients Predict Post-Hepatectomy Overall and Recurrence-Free Survival in Patients with Hepatocellular Carcinoma: A Retrospective Study.

Background: The dominant artery blood supply is a characteristic of hepatocellular carcinoma (HCC). However, it is not known whether the blood supply can predict the post-hepatectomy prognosis of patients with HCC. This retrospective study investigated the prognostic value of the portal venous and arterial blood supply estimated on triphasic liver CT (as a portal venous coefficient, PVC, and hepatic arterial coefficient, HAC, respectively) in patients with HCC following hepatectomy. Methods: HCC patients who were tested by triphasic liver CT 2 weeks before hepatectomy and received R0 hepatectomy at the Second Affiliated Hospital, Kunming Medical University between January 1, 2016 and December 31, 2020, were retrospectively screened. Their PVC and HAC, and other variables were analyzed for the prediction of overall survival (OS) and recurrence-free survival (RFS) using the least absolute shrinkage and selection operator and Cox proportional hazard regression models. Results: Four hundred and nineteen patients (53.2 ± 10.6 years of age and 370 men) were evaluated. A shorter OS was independently associated with higher blood albumin and total bilirubin grade [hazard ratio (HR) 2.020, 95% confidence interval (CI) 1.534-2.660], higher Barcelona Clinic Liver Cancer (BCLC) stage (HR 1.514, 95% CI 1.290-1.777), PVC ≤ 0.386 (HR 1.628, 95% CI 1.149-2.305), and HAC > 0.029 (HR 1.969, 95% CI 1.380-2.809). A shorter RFS was independently associated with male (HR 1.652, 95% CI 1.005-2.716), higher serum α-fetoprotein ≥ 400 ng/mL (HR 1.672, 95% CI 1.236-2.263), higher BCLC stage (HR 1.516, 95% CI 1.300-1.768), tumor PVC ≤ 0.386 (HR 1.641, 95% CI 1.198-2.249), and tumor HAC > 0.029 (HR 1.455, 95% CI 1.060-1.997). Conclusion: Tumor PVC or HAC before hepatectomy is valuable for independently predicting postoperative survival of HCC patients.

Museomics help resolving the phylogeny of snowfinches (Aves, Passeridae, Montifringilla and allies).

Historical specimens from museum collections provide a valuable source of material also from remote areas or regions of conflict that are not easily accessible to scientists today. With this study, we are providing a taxon-complete phylogeny of snowfinches using historical DNA from whole skins of an endemic species from Afghanistan, the Afghan snowfinch, Pyrgilauda theresae. To resolve the strong conflict between previous phylogenetic hypotheses, we generated novel mitogenome sequences for selected taxa and genome-wide SNP data using ddRAD sequencing for all extant snowfinch species endemic to the Qinghai-Tibet Plateau (QTP) and for an extended intraspecific sampling of the sole Central and Western Palearctic snowfinch species (Montifringilla nivalis). Our phylogenetic reconstructions unanimously refuted the previously suggested paraphyly of genus Pyrgilauda. Misplacement of one species-level taxon (Onychostruthus tazcanowskii) in previous snowfinch phylogenies was undoubtedly inferred from chimeric mitogenomes that included heterospecific sequence information. Furthermore, comparison of novel and previously generated sequence data showed that the presumed sister-group relationship between M. nivalis and the QTP endemic M. henrici was suggested based on flawed taxonomy. Our phylogenetic reconstructions based on genome-wide SNP data and on mitogenomes were largely congruent and supported reciprocal monophyly of genera Montifringilla and Pyrgilauda with monotypic Onychostruthus being sister to the latter. The Afghan endemic P. theresae likely originated from a rather ancient Pliocene out-of-Tibet dispersal probably from a common ancestor with P. ruficollis. Our extended trans-Palearctic sampling for the white-winged snowfinch, M. nivalis, confirmed strong lineage divergence between an Asian and a European clade dated to 1.5 - 2.7 million years ago (mya). Genome-wide SNP data suggested subtle divergence among European samples from the Alps and from the Cantabrian mountains.

Asprosin promotes vascular inflammation via TLR4-NFκB-mediated NLRP3 inflammasome activation in hypertension.

Objective: and design Mild vascular inflammation promotes the pathogenesis of hypertension. Asprosin, a newly discovered adipokine, is closely associated with metabolic diseases. We hypothesized that asprosin might led to vascular inflammation in hypertension via NLRP3 inflammasome formation. This study shows the importance of asprosin in the vascular inflammation of hypertension. Methods: Primary vascular smooth muscle cells (VSMCs) were obtained from the aorta of animals, including spontaneously hypertensive rats (SHR), Wistar-Kyoto rats (WKY), NLRP3-/- and wild-type mice. Studies were performed in VSMCs in vitro, as well as WKY and SHR in vivo. Results: Asprosin expressions were up-regulated in VSMCs and media of arteries in SHR. Asprosin overexpression promoted NLRP3 inflammasome activation via Toll-like receptor 4 (TLR4), accompanied with activation of NFκB signaling pathway in VSMCs. Exogenous asprosin protein showed similar roles in promoting NLRP3 inflammasome activation. Knockdown of asprosin restrained NLRP3 inflammasome and p65-NFκB activation in VSMCs of SHR. NLRP3 inhibitor MCC950 or NFκB inhibitor BAY11-7082 attenuated asprosin-caused VSMC proliferation and migration. Asprosin-induced interleukin-1ß production, proliferation and migration were attenuated in NLRP3-/- VSMCs. Local asprosin knockdown in common carotid artery of SHR attenuated inflammation and vascular remodeling. Conclusions: Asprosin promoted NLRP3 inflammasome activation in VSMCs by TLR4-NFκB pathway, and thereby stimulates VSMCs proliferation, migration, and vascular remodeling of SHR.

Maternal Oxidative Balance Score during Pregnancy and Congenital Heart Defects.

The relationship between maternal oxidative balance score (OBS) in pregnancy, representing overall oxidative balance status by integrating dietary and lifestyle factors, and congenital heart defects (CHD) remains unclear; therefore, this study attempted to explore their associations among the Chinese population. We conducted a case-control study including 474 cases and 948 controls in Northwest China. Pregnant women were interviewed to report diets and lifestyles in pregnancy by structured questionnaires. Logistic regression models were used to estimate the adjusted ORs (95%CIs). Maternal OBS ranged from 6 to 34 among cases, and 5 to 37 among controls. Comparing the highest with the lowest tertile group, the adjusted OR for CHD was 0.31 (0.19-0.50). The CHD risk was reduced by 7% (OR = 0.93, 95%CI = 0.90-0.95) in association with per 1 higher score of OBS during pregnancy. The inverse relationship between maternal OBS and CHD risk appeared to be more pronounced among participants in urban areas (OR = 0.89, 95%CI = 0.86-0.93). Maternal OBS during pregnancy showed good predictive values for fetal CHD, with the areas under the receiver operating characteristic curve 0.78 (0.76-0.81). These findings highlighted the importance of reducing oxidative stress through antioxidant-rich diets and healthy lifestyles among pregnant women to prevent fetal CHD.

Organic light-emitting diode therapy promotes longevity through the upregulation of SIRT1 in senescence-accelerated mouse prone 8 mice.

Phototherapy has been extensively used to prevent and treat signs of aging and stimulate wound healing, and phototherapy through light-emitting diodes (LEDs). In contrast to LED, organic LED (OLED) devices are composed of organic semiconductors that possess novel characteristics. We investigated the regenerative potential of OLED for restoring cellular potential from senescence and thus delaying animal aging. Bone marrow-derived stem cells (BMSCs) and adipose-derived stem cells (ADSCs) were isolated from the control and OLED- treated groups to evaluate their proliferation, migration, and differentiation potentials. Cellular senescence was evaluated using a senescence-associated ß-galactosidase (SA-ß-gal) activity assay and gene expression biomarker assessment. OLED treatment significantly increased the cell proliferation, colony formation, and migration abilities of stem cells. SA-ß-gal activity was significantly decreased in both ADSCs and BMSCs in the OLED-treated group. Gene expression biomarkers from treated mice indicated a significant upregulation of IGF-1 (insulin growthfactor-1). The upregulation of the SIRT1 gene inhibited the p16 and p19 genes then to downregulate the p53 expressions for regeneration of stem cells in the OLED-treated group. Our findings indicated that the survival rates of 10-month aging senescence-accelerated mouse prone 8 mice were prolonged and that their gross appearance improved markedly after OLED treatment. Histological analysis of skin and brain tissue also indicated significantly greater collagen fibers density, which prevents ocular abnormalities and ß-amyloid accumulation. Lordokyphosis and bone characteristics were observed to resemble those of younger mice after OLED treatment. In conclusion, OLED therapy reduced the signs of aging and enhanced stem-cell senescence recovery and then could be used for tissue regeneration.

Intervention of Asprosin Attenuates Oxidative Stress and Neointima Formation in Vascular Injury.

Aims: Asprosin, a newly discovered hormone, is linked to insulin resistance. This study shows the roles of asprosin in vascular smooth muscle cell (VSMC) proliferation, migration, oxidative stress, and neointima formation of vascular injury. Methods: Mouse aortic VSMCs were cultured, and platelet-derived growth factor-BB (PDGF-BB) was used to induce oxidative stress, proliferation, and migration in VSMCs. Vascular injury was induced by repeatedly moving a guidewire in the lumen of the carotid artery in mice. Results: Asprosin overexpression promoted VSMC oxidative stress, proliferation, and migration, which were attenuated by toll-like receptor 4 (TLR4) knockdown, antioxidant (N-Acetylcysteine, NAC), NADPH oxidase 1 (NOX1) inhibitor ML171, or NOX2 inhibitor GSK2795039. Asprosin overexpression increased NOX1/2 expressions, whereas asprosin knockdown increased heme oxygenase-1 (HO-1) and NADPH quinone oxidoreductase-1 (NQO-1) expressions. Asprosin inhibited nuclear factor E2-related factor 2 (Nrf2) nuclear translocation. Nrf2 activator sulforaphane increased HO-1 and NQO-1 expressions and prevented asprosin-induced NOX1/2 upregulation, oxidative stress, proliferation, and migration. Exogenous asprosin protein had similar roles to asprosin overexpression. PDGF-BB increased asprosin expressions. PDGF-BB-induced oxidative stress, proliferation, and migration were enhanced by Nrf2 inhibitor ML385 but attenuated by asprosin knockdown. Vascular injury increased asprosin expression. Local asprosin knockdown in the injured carotid artery promoted HO-1 and NQO-1 expressions but attenuated the NOX1 and NOX2 upregulation, oxidative stress, neointima formation, and vascular remodeling in mice. Innovation and Conclusion: Asprosin promotes oxidative stress, proliferation, and migration of VSMCs via TLR4-Nrf2-mediated redox imbalance. Inhibition of asprosin expression attenuates VSMC proliferation and migration, oxidative stress, and neointima formation in the injured artery. Asprosin might be a promising therapeutic target for vascular injury.

Attention deficit hyperactivity disorder in children with epilepsy: a multicenter cross-sectional analysis in China.

BACKGROUND: The diagnosis and treatment of attention deficit hyperactivity disorder (ADHD) comorbid with epilepsy have been insufficiently addressed in China. We conducted a study in China to investigate the current status, diagnosis, and treatment of ADHD in children to further our understanding of ADHD comorbid with epilepsy, strengthen its management, and improve patients' quality of life. METHODS: We carried out a multicenter cross-sectional survey of children with epilepsy across China between March 2022 and August 2022. We screened all patients for ADHD and compared various demographic and clinical factors between children with and without ADHD, including gender, age, age at epilepsy onset, duration of epilepsy, seizure types, seizure frequency, presence of epileptiform discharges, and treatment status. Our objective was to explore any possible associations between these characteristics and the prevalence of ADHD. RESULTS: Overall, 395 epilepsy patients aged 6-18 years were enrolled. The age at seizure onset and duration of epilepsy ranged from 0.1-18 to 0.5-15 years, respectively. Focal onset seizures were observed in 212 (53.6%) patients, while 293 (76.3%) patients had epileptiform interictal electroencephalogram (EEG) abnormalities. Among the 370 patients treated with anti-seizure medications, 200 (54.1%) had monotherapy. Although 189 (47.8%) patients had ADHD, only 31 received treatment for it, with the inattentive subtype being the most common. ADHD was more common in children undergoing polytherapy compared to those on monotherapy. Additionally, poor seizure control and the presence of epileptiform interictal EEG abnormalities may be associated with a higher prevalence of ADHD. CONCLUSIONS: While the prevalence of ADHD was higher in children with epilepsy than in normal children, the treatment rate was notably low. This highlights the need to give more importance to the diagnosis and treatment of ADHD in children with epilepsy.

CircPIAS1 promotes hepatocellular carcinoma progression by inhibiting ferroptosis via the miR-455-3p/NUPR1/FTH1 axis.

BACKGROUND: The role of circRNAs in hepatocellular carcinoma (HCC) progression remains unclear. CircPIAS1 (circBase ID: hsa_circ_0007088) was identified as overexpressed in HCC cases through bioinformatics analysis. This study aimed to investigate the oncogenic properties and mechanisms of circPIAS1 in HCC development. METHODS: Functional analyses were conducted to assess circPIAS1's impact on HCC cell proliferation, migration, and ferroptosis. Xenograft mouse models were employed to evaluate circPIAS1's effects on tumor growth and pulmonary metastasis in vivo. Bioinformatics analysis, RNA immunoprecipitation, and luciferase reporter assays were utilized to elucidate the molecular pathways influenced by circPIAS1. Additional techniques, including RNA pulldown, fluorescence in situ hybridization (FISH), chromatin immunoprecipitation (ChIP), qPCR, and western blotting, were used to further explore the underlying mechanisms. RESULTS: CircPIAS1 expression was elevated in HCC tissues and cells. Silencing circPIAS1 suppressed HCC cell proliferation and migration both in vitro and in vivo. Mechanically, circPIAS1 overexpression inhibited ferroptosis by competitively binding to miR-455-3p, leading to upregulation of Nuclear Protein 1 (NUPR1). Furthermore, NUPR1 promoted FTH1 transcription, enhancing iron storage in HCC cells and conferring resistance to ferroptosis. Treatment with ZZW-115, an NUPR1 inhibitor, reversed the tumor-promoting effects of circPIAS1 and sensitized HCC cells to lenvatinib. CONCLUSION: This study highlights the critical role of circPIAS1 in HCC progression through modulation of ferroptosis. Targeting the circPIAS1/miR-455-3p/NUPR1/FTH1 regulatory axis may represent a promising therapeutic strategy for HCC.

A novel model combining genes associated with disulfidptosis and glycolysis to predict breast cancer prognosis, molecular subtypes, and treatment response.

Breast cancer (BC) is a heterogeneous malignancy with a dismal prognosis. Disulfidptosis is a novel type of regulated cell death that happens in the presence of glucose deficiency and is linked to the metabolic process of glycolysis. However, the mechanism of action of disulfidptosis and glycolysis-related genes (DGRG) in BC, as well as their prognostic value in BC patients, remain unknown. After identifying the differentially expressed DGRG in normal and BC tissues, a number of machine learning algorithms were utilized to select essential prognostic genes to develop a model, including SLC7A11, CACNA1H, SDC1, CHST1, and TFF3. The expression characteristics of these genes were then examined using single-cell RNA sequencing, and BC was classified into three clusters using "ConsensusClusterPlus" based on these genes. The DGRG model's median risk score can categorize BC patients into high-risk and low-risk groups. Furthermore, we investigated variations in clinical landscape, immunoinvasion analysis, tumor immune dysfunction and rejection (TIDE), and medication sensitivity in patients in the DGRG model's high- and low-risk groups. Patients in the low-risk group performed better on immunological and chemotherapeutic therapies and had lower TIDE scores. In conclusion, the DGRG model we developed has significant clinical application potential because it can accurately predict the prognosis of BC, TME, and pharmacological treatment responses.

BMP signaling maintains auricular chondrocyte identity and prevents microtia development by inhibiting protein kinase A.

Elastic cartilage constitutes a major component of the external ear, which functions to guide sound to the middle and inner ears. Defects in auricle development cause congenital microtia, which affects hearing and appearance in patients. Mutations in several genes have been implicated in microtia development, yet, the pathogenesis of this disorder remains incompletely understood. Here, we show that Prrx1 genetically marks auricular chondrocytes in adult mice. Interestingly, BMP-Smad1/5/9 signaling in chondrocytes is increasingly activated from the proximal to distal segments of the ear, which is associated with a decrease in chondrocyte regenerative activity. Ablation of Bmpr1a in auricular chondrocytes led to chondrocyte atrophy and microtia development at the distal part. Transcriptome analysis revealed that Bmpr1a deficiency caused a switch from the chondrogenic program to the osteogenic program, accompanied by enhanced protein kinase A activation, likely through increased expression of Adcy5/8. Inhibition of PKA blocked chondrocyte-to-osteoblast transformation and microtia development. Moreover, analysis of single-cell RNA-seq of human microtia samples uncovered enriched gene expression in the PKA pathway and chondrocyte-to-osteoblast transformation process. These findings suggest that auricle cartilage is actively maintained by BMP signaling, which maintains chondrocyte identity by suppressing osteogenic differentiation.

Necroptosis contributes to non-alcoholic fatty liver disease pathoetiology with promising diagnostic and therapeutic functions.

Nonalcoholic fatty liver disease (NAFLD) is the most prevalent type of chronic liver disease. However, the disease is underappreciated as a remarkable chronic disorder as there are rare managing strategies. Several studies have focused on determining NAFLD-caused hepatocyte death to elucidate the disease pathoetiology and suggest functional therapeutic and diagnostic options. Pyroptosis, ferroptosis, and necroptosis are the main subtypes of non-apoptotic regulated cell deaths (RCDs), each of which represents particular characteristics. Considering the complexity of the findings, the present study aimed to review these types of RCDs and their contribution to NAFLD progression, and subsequently discuss in detail the role of necroptosis in the pathoetiology, diagnosis, and treatment of the disease. The study revealed that necroptosis is involved in the occurrence of NAFLD and its progression towards steatohepatitis and cancer, hence it has potential in diagnostic and therapeutic approaches. Nevertheless, further studies are necessary.

Solitary bone plasmacytoma: Long-term clinical outcomes in a single center.

BACKGROUND: A solitary plasmacytoma is classified into a solitary plasmacytoma of the bone (SBP) and a solitary extramedullary (soft tissue mass) plasmacytoma, based on the site of the lesion. Despite the high local control rate with radiotherapy, approximately half of patients' conditions progress to multiple myeloma (MM) within 3-5 years after diagnosis, with SBP having a worse prognosis. PATIENTS AND METHODS: We retrospectively assessed the treatment and outcomes of patients with SBP in a hospital in China from 2008 to 2021. Twenty-four patients treated over 13 years with SBP were enrolled in this retrospective study. RESULTS: The most common sites for SBP were the axial skeleton and femur. The M protein was detected in 11 patients (46 %), of which 8 (33 %) had light chains, 2 (8 %) had immunoglobulin G kappa and 1 (4 %) had immunoglobulin D kappa. Flow cytometry revealed that 5 patients (21 %) had minimal bone marrow involvement. The treatment included chemotherapy, surgery, and radiotherapy in 18 (75 %), 12 (50 %), and 9 (38 %) patients, respectively, of whom 13 (54 %) received combined treatment. Over a median follow-up period of 67.2 months, 9 patients (38 %) developed MM in a median time of 101.5 months. The 5- and 10-year progression-free survival rates were 67.3 % and 37.4 %, respectively. One patient died due to pneumonia without progression and the other died due to relapse. CONCLUSION: This study confirmed the high rate of progression of SBP to MM, indicating a need for adjunct chemotherapy for the management of SBP.

GLP-1 in the Hypothalamic Paraventricular Nucleus Promotes Sympathetic Activation and Hypertension.

Glucagon-like peptide-1 (GLP-1) and its analogs are widely used for diabetes treatment. The paraventricular nucleus (PVN) is crucial for regulating cardiovascular activity. This study aims to determine the roles of GLP-1 and its receptors (GLP-1R) in the PVN in regulating sympathetic outflow and blood pressure. Experiments were carried out in male normotensive rats and spontaneously hypertensive rats (SHR). Renal sympathetic nerve activity (RSNA) and mean arterial pressure (MAP) were recorded. GLP-1 and GLP-1R expressions were present in the PVN. PVN microinjection of GLP-1R agonist recombinant human GLP-1 (rhGLP-1) or EX-4 increased RSNA and MAP, which were prevented by GLP-1R antagonist exendin 9-39 (EX9-39) or GLP-1R antagonist 1, superoxide scavenger tempol, antioxidant N-acetylcysteine, NADPH oxidase (NOX) inhibitor apocynin, adenylyl cyclase (AC) inhibitor SQ22536 or protein kinase A (PKA) inhibitor H89. PVN microinjection of rhGLP-1 increased superoxide production, NADPH oxidase activity, cAMP level, AC, and PKA activity, which were prevented by SQ22536 or H89. GLP-1 and GLP-1R were upregulated in the PVN of SHR. PVN microinjection of GLP-1 agonist increased RSNA and MAP in both WKY and SHR, but GLP-1 antagonists caused greater effects in reducing RSNA and MAP in SHR than in WKY. The increased superoxide production and NADPH oxidase activity in the PVN of SHR were augmented by GLP-1R agonists but attenuated by GLP-1R antagonists. These results indicate that activation of GLP-1R in the PVN increased sympathetic outflow and blood pressure via cAMP-PKA-mediated NADPH oxidase activation and subsequent superoxide production. GLP-1 and GLP-1R upregulation in the PVN partially contributes to sympathetic overactivity and hypertension.

Comprehensive pan-cancer analysis reveals prognostic implications of TMEM92 in the tumor immune microenvironment.

BACKGROUND: Transmembrane protein 92 (TMEM92) has been implicated in the facilitation of tumor progression. Nevertheless, comprehensive analyses concerning the prognostic significance of TMEM92, as well as its role in immunological responses across diverse cancer types, remain to be elucidated. METHODS: In this study, data was sourced from a range of publicly accessible online platforms and databases, including TCGA, GTEx, UCSC Xena, CCLE, cBioPortal, HPA, TIMER2.0, GEPIA, CancerSEA, GDSC, exoRBase, and ImmuCellAI. We systematically analyzed the expression patterns of TMEM92 at both mRNA and protein levels across diverse human organs, tissues, extracellular vesicles (EVs), and cell lines associated with multiple cancer types. Subsequently, analyses were conducted to determine the relationship between TMEM92 and various parameters such as prognosis, DNA methylation, copy number variation (CNV), the tumor microenvironment (TME), immune cell infiltration, genes with immunological relevance, tumor mutational burden (TMB), microsatellite instability (MSI), mismatch repair (MMR), and half-maximal inhibitory concentration (IC50) values. RESULTS: In the present study, we observed a pronounced overexpression of TMEM92 across a majority of cancer types, which was concomitantly associated with a less favorable prognosis. A notable association emerged between TMEM92 expression and both DNA methylation and CNV. Furthermore, a pronounced relationship was discerned between TMEM92 expression, the TME, and the degree of immune cell infiltration. Intriguingly, while TMEM92 expression displayed a positive correlation with macrophage presence, it inversely correlated with the infiltration level of CD8 + T cells. Concurrently, significant associations were identified between TMEM92 and the major histocompatibility complex, TMB, MSI, and MMR. Results derived from Gene Set Enrichment Analysis and Gene Set Variation Analysis further substantiated the nexus of TMEM92 with both immune and metabolic pathways within the oncogenic context. CONCLUSIONS: These findings expanded the understanding of the roles of TMEM92 in tumorigenesis and progression and suggest that TMEM92 may have an immunoregulatory role in several malignancies.