BACKGROUND:Gradient artificial bone repair scaffolds can mimic unique anatomical features in musculoskeletal tissues,showing great potential for repairing injured musculoskeletal tissues. OBJECTIVE:To review the latest research advances in gradient artificial bone repair scaffolds for tissue engineering in the musculoskeletal system and describe their advantages and fabrication strategies. METHODS:The first author of the article searched the Web of Science and PubMed databases for articles published from 2000 to 2023 with search terms"gradient,bone regeneration,scaffold".Finally,76 papers were analyzed and summarized after the screening. RESULTS AND CONCLUSION:(1)As an important means of efficient and high-quality repair of skeletal system tissues,gradient artificial bone repair scaffolds are currently designed bionically for the natural gradient characteristics of bone tissue,bone-cartilage,and tendon-bone tissue.These scaffolds can mimic the extracellular matrix of native tissues to a certain extent in terms of structure and composition,thus promoting cell adhesion,migration,proliferation,differentiation,and regenerative recovery of damaged tissues to their native state.(2)Advanced manufacturing technology provides more possibilities for gradient artificial bone repair scaffold preparation:Gradient electrospun fiber scaffolds constructed by spatially differentiated fiber arrangement and loading of biologically active substances have been developed;gradient 3D printed scaffolds fabricated by layered stacking,graded porosity,and bio-3D printing technology;gradient hydrogel scaffolds fabricated by in-situ layered injections,simple layer-by-layer stacking,and freeze-drying method;and in addition,there are also scaffolds made by other modalities or multi-method coupling.These scaffolds have demonstrated good biocompatibility in vitro experiments,were able to accelerate tissue regeneration in small animal tests,and were observed to have significantly improved histological structure.(3)The currently developed gradient artificial bone repair scaffolds have problems such as mismatch of gradient scales,unclear material-tissue interactions,and side effects caused by degradation products,which need to be further optimized by combining the strengths of related disciplines and clinical needs in the future.

Background: s/Aims: Non-invasive models stratifying clinically significant portal hypertension (CSPH) are limited. Herein, we developed a new non-invasive model for predicting CSPH in patients with compensated cirrhosis and investigated whether carvedilol can prevent hepatic decompensation in patients with high-risk CSPH stratified using the new model. Methods: Non-invasive risk factors of CSPH were identified via systematic review and meta-analysis of studies involving patients with hepatic venous pressure gradient (HVPG). A new non-invasive model was validated for various performance aspects in three cohorts, i.e., a multicenter HVPG cohort, a follow-up cohort, and a carvediloltreating cohort. Results: In the meta-analysis with six studies (n=819), liver stiffness measurement and platelet count were identified as independent risk factors for CSPH and were used to develop the new “CSPH risk” model. In the HVPG cohort (n=151), the new model accurately predicted CSPH with cutoff values of 0 and –0.68 for ruling in and out CSPH, respectively. In the follow-up cohort (n=1,102), the cumulative incidences of decompensation events significantly differed using the cutoff values of <–0.68 (low-risk), –0.68 to 0 (medium-risk), and >0 (high-risk). In the carvediloltreated cohort, patients with high-risk CSPH treated with carvedilol (n=81) had lower rates of decompensation events than non-selective beta-blockers untreated patients with high-risk CSPH (n=613 before propensity score matching [PSM], n=162 after PSM). Conclusions Treatment with carvedilol significantly reduces the risk of hepatic decompensation in patients with high-risk CSPH stratified by the new model.

Background: s/Aims: Non-invasive models stratifying clinically significant portal hypertension (CSPH) are limited. Herein, we developed a new non-invasive model for predicting CSPH in patients with compensated cirrhosis and investigated whether carvedilol can prevent hepatic decompensation in patients with high-risk CSPH stratified using the new model. Methods: Non-invasive risk factors of CSPH were identified via systematic review and meta-analysis of studies involving patients with hepatic venous pressure gradient (HVPG). A new non-invasive model was validated for various performance aspects in three cohorts, i.e., a multicenter HVPG cohort, a follow-up cohort, and a carvediloltreating cohort. Results: In the meta-analysis with six studies (n=819), liver stiffness measurement and platelet count were identified as independent risk factors for CSPH and were used to develop the new “CSPH risk” model. In the HVPG cohort (n=151), the new model accurately predicted CSPH with cutoff values of 0 and –0.68 for ruling in and out CSPH, respectively. In the follow-up cohort (n=1,102), the cumulative incidences of decompensation events significantly differed using the cutoff values of <–0.68 (low-risk), –0.68 to 0 (medium-risk), and >0 (high-risk). In the carvediloltreated cohort, patients with high-risk CSPH treated with carvedilol (n=81) had lower rates of decompensation events than non-selective beta-blockers untreated patients with high-risk CSPH (n=613 before propensity score matching [PSM], n=162 after PSM). Conclusions Treatment with carvedilol significantly reduces the risk of hepatic decompensation in patients with high-risk CSPH stratified by the new model.

Background: s/Aims: Non-invasive models stratifying clinically significant portal hypertension (CSPH) are limited. Herein, we developed a new non-invasive model for predicting CSPH in patients with compensated cirrhosis and investigated whether carvedilol can prevent hepatic decompensation in patients with high-risk CSPH stratified using the new model. Methods: Non-invasive risk factors of CSPH were identified via systematic review and meta-analysis of studies involving patients with hepatic venous pressure gradient (HVPG). A new non-invasive model was validated for various performance aspects in three cohorts, i.e., a multicenter HVPG cohort, a follow-up cohort, and a carvediloltreating cohort. Results: In the meta-analysis with six studies (n=819), liver stiffness measurement and platelet count were identified as independent risk factors for CSPH and were used to develop the new “CSPH risk” model. In the HVPG cohort (n=151), the new model accurately predicted CSPH with cutoff values of 0 and –0.68 for ruling in and out CSPH, respectively. In the follow-up cohort (n=1,102), the cumulative incidences of decompensation events significantly differed using the cutoff values of <–0.68 (low-risk), –0.68 to 0 (medium-risk), and >0 (high-risk). In the carvediloltreated cohort, patients with high-risk CSPH treated with carvedilol (n=81) had lower rates of decompensation events than non-selective beta-blockers untreated patients with high-risk CSPH (n=613 before propensity score matching [PSM], n=162 after PSM). Conclusions Treatment with carvedilol significantly reduces the risk of hepatic decompensation in patients with high-risk CSPH stratified by the new model.

BACKGROUND: Generalized pustular psoriasis (GPP), a rare and recurrent autoinflammatory disease, imposes a substantial burden on patients and society. Awareness of GPP in China remains limited. METHODS: This cross-sectional survey, conducted between September 2021 and May 2023 across 14 hospitals in China, included GPP patients of all ages and disease phases. Data collected encompassed demographics, clinical characteristics, economic impact, disease severity, quality of life, and treatment-related complications. Risk factors for GPP recurrence were analyzed. RESULTS: Among 127 patients (female/male ratio = 1.35:1), the mean age of disease onset was 25 years (1st quartile [Q1]-3rd quartile [Q3]: 11-44 years); 29.2% had experienced GPP for more than 10 years. Recurrence occurred in 75.6% of patients, and nearly half reported no identifiable triggers. Younger age at disease onset ( P  = 0.021) and transitioning to plaque psoriasis ( P  = 0.022) were associated with higher recurrence rates. The median diagnostic delay was 8 months (Q1-Q3: 2-41 months), and 32.3% of patients reported misdiagnoses. Comorbidities were present in 53.5% of patients, whereas 51.1% experienced systemic complications during treatment. Depression and anxiety affected 84.5% and 95.6% of patients, respectively. During GPP flares, the median Dermatology Life Quality Index score was 19.0 (Q1-Q3: 13.0-23.5). This score showed significant differences between patients with and without systemic symptoms; it demonstrated correlations with both depression and anxiety scores. Treatment costs caused financial hardship in 55.9% of patients, underscoring the burden associated with GPP. CONCLUSIONS The substantial disease and economic burdens among Chinese GPP patients warrant increased attention. Patients with early onset disease and those transitioning to plaque psoriasis require targeted interventions to mitigate the high recurrence risk.
Humans ; Male ; Female ; Psoriasis/pathology* ; Adult ; Cross-Sectional Studies ; Adolescent ; Child ; Young Adult ; Quality of Life ; Middle Aged ; China/epidemiology* ; Recurrence ; Risk Factors ; Surveys and Questionnaires ; East Asian People

BACKGROUND: The protective effect of mesenchymal stem cells (MSCs) on cardiac ischemia-reperfusion (I/R) injury has been widely reported. Dental pulp-derived mesenchymal stem cells (DP-MSCs) have therapeutic effects on various diseases, including diabetes and cirrhosis. This study aimed to determine the therapeutic effects of DP-MSCs on I/R injury and elucidate the underlying mechanism. METHODS: Myocardial I/R injury model mice were treated with DP-MSCs or a miR-19a-3p mimic. The infarct volume, fibrotic area, pyroptosis, inflammation level, and cardiac function were measured. Cardiomyocytes exposed to hypoxia-reoxygenation were transfected with the miR-19a-3p mimic, miR-19a-3p inhibitor, or negative control. Pyroptosis and protein expression in the interferon regulatory factor 8/mitogen-activated protein kinase (IRF-8/MAPK) pathway were measured. RESULTS: DP-MSCs protected cardiac function in cardiac I/R-injured mice and inhibited cardiomyocyte pyroptosis. The upregulation of miR-19a-3p protected cardiac function, inhibited cardiomyocyte pyroptosis, and inhibited IRF-8/MAPK signaling in cardiac I/R-injured mice. DP-MSCs inhibited cardiomyocyte pyroptosis and the IRF-8/MAPK signaling by upregulating the miR-19a-3p levels in cardiomyocytes injured by I/R. CONCLUSION DP-MSCs protected cardiac function by inhibiting cardiomyocyte pyroptosis through miR-19a-3p under I/R conditions.
Animals ; MicroRNAs/metabolism* ; Pyroptosis/genetics* ; Mesenchymal Stem Cells/metabolism* ; Myocytes, Cardiac/cytology* ; Mice ; Male ; Mice, Inbred C57BL ; Dental Pulp/cytology* ; Myocardial Reperfusion Injury/therapy* ; MAP Kinase Signaling System/physiology*

A primary hallmark of pathological cardiac hypertrophy is excess protein synthesis due to enhanced translational activity. However, regulatory mechanisms at the translational level under cardiac stress remain poorly understood. Here we examined the translational regulations in a mouse cardiac hypertrophy model induced by transaortic constriction (TAC) and explored the conservative networks versus the translatome pattern in human dilated cardiomyopathy (DCM). The results showed that the heart weight to body weight ratio was significantly elevated, and the ejection fraction and fractional shortening significantly decreased 8 weeks after TAC. Puromycin incorporation assay showed that TAC significantly increased protein synthesis rate in the left ventricle. RNA-seq revealed 1,632 differentially expressed genes showing functional enrichment in pathways including extracellular matrix remodeling, metabolic processes, and signaling cascades associated with pathological cardiomyocyte growth. When combined with ribosome profiling analysis, we revealed that translation efficiency (TE) of 1,495 genes was enhanced, while the TE of 933 genes was inhibited following TAC. In DCM patients, 1,354 genes were upregulated versus 1,213 genes were downregulated at the translation level. Although the majority of the genes were not shared between mouse and human, we identified 93 genes, including Nos3, Kcnj8, Adcy4, Itpr1, Fasn, Scd1, etc., with highly conserved translational regulations. These genes were remarkably associated with myocardial function, signal transduction, and energy metabolism, particularly related to cGMP-PKG signaling and fatty acid metabolism. Motif analysis revealed enriched regulatory elements in the 5' untranslated regions (5'UTRs) of transcripts with differential TE, which exhibited strong cross-species sequence conservation. Our study revealed novel regulatory mechanisms at the translational level in cardiac hypertrophy and identified conserved translation-sensitive targets with potential applications to treat cardiac hypertrophy and heart failure in the clinic.
Animals ; Humans ; Cardiomegaly/physiopathology* ; Ribosomes/physiology* ; Protein Biosynthesis/physiology* ; Mice ; Cardiomyopathy, Dilated/genetics* ; Ribosome Profiling

This study investigated the effects of total flavonoids of Dracocephalum moldavica(TFDM) on apoptosis in rat H9c2 cells induced by endoplasmic reticulum stress(ERS) established by oxygen-glucose deprivation and reoxygenation(OGD/R) injury and tunicamycin(TM), and explored the potential mechanisms. After successful modeling, the following groups were set in this experiment: control group, model(OGD/R or TM) group, and TFDM low-, medium-, and high-dose groups(12.5, 25, and 50 μg·mL~(-1)). The OGD/R injury model was constructed in vitro. Cell proliferation was assessed using the cell counting kit-8(CCK-8) method. The levels of lactate dehydrogenase(LDH) and creatine kinase MB isoenzyme(CKMB) in the cell supernatant were detected. Western blot was used to assess the expression of ERS-related proteins, including glucose regulatory protein 78(GRP78), C/EBP homologous protein(CHOP), activating transcription factor 6(ATF6), and apoptotic proteins B-cell lymphoma 2(Bcl-2) and Bcl-2-associated X protein(Bax). Apoptosis was detected using the terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling(TUNEL) method. In the TM-induced ERS model, Western blot was used to measure the expression of ERS pathway-related proteins GRP78, CHOP, inositol-requiring enzyme 1(IRE1), X-box binding protein 1(XBP1), protein kinase RNA-like endoplasmic reticulum kinase(PERK), eukaryotic initiation factor 2α(eIF2α), ATF6, p-ATF6, and apoptotic proteins Bcl-2, Bax, cysteinyl aspartate specific proteinase-12(caspase-12), and cleaved caspase-12. Gene expression of GRP78, CHOP, PERK, and ATF6 was detected by real-time fluorescence quantitative PCR(RT-qPCR). Apoptosis was again detected using the TUNEL method. The results showed that in the OGD/R model, compared with the control group, the levels of LDH and CKMB in the cell supernatant were significantly increased in the OGD/R group. Compared with the OGD/R group, the levels of LDH and CKMB in the TFDM group were significantly reduced. Western blot results revealed that compared with the control group, the expression of ERS-related proteins and Bax in the OGD/R group was significantly increased, while the expression of Bcl-2 was significantly decreased. Compared with the OGD/R group, the expression of ERS-related proteins and Bax in the TFDM groups was significantly reduced, and the expression of Bcl-2 was significantly increased. TUNEL assay showed that apoptosis was significantly decreased after TFDM treatment. In the TM-induced ERS experiment, compared with the control group, the expression of ERS-related genes, ERS-related proteins, and apoptotic proteins in the TM group was significantly increased, while the expression of Bcl-2 was significantly decreased. Compared with the TM group, the expression of ERS-related genes, ERS-related proteins, and apoptotic proteins in the TFDM group was significantly reduced, and the expression of Bcl-2 was significantly increased. These results suggest that ERS exists in the OGD/R-injured H9c2 cell model, and TFDM can effectively inhibit ERS-induced apoptosis. The mechanism may be related to the downregulation of ERS pathway-related proteins and apoptotic proteins.
Animals ; Endoplasmic Reticulum Stress/drug effects* ; Apoptosis/drug effects* ; Rats ; Flavonoids/pharmacology* ; Glucose/metabolism* ; Cell Line ; Lamiaceae/chemistry* ; Drugs, Chinese Herbal/pharmacology* ; Oxygen/metabolism* ; Reperfusion Injury/physiopathology* ; Myocytes, Cardiac/cytology*