Search

Mitochondria are crucial organelles that play a central role in cellular metabolism and programmed cell death in eukaryotic cells. Mitochondrial autophagy (mitophagy) is a selective process where damaged mitochondria are encapsulated and degraded through autophagic mechanisms, ensuring the maintenance of both mitochondrial and cellular homeostasis. Excessive programmed cell death in neurons can result in functional impairments following cerebral ischemia and trauma, as well as in chronic neurodegenerative diseases, leading to irreversible declines in motor and cognitive functions. Neuroinflammation, an inflammatory response of the central nervous system to factors disrupting homeostasis, is a common feature across various neurological events, including ischemic, infectious, traumatic, and neurodegenerative conditions. Emerging research suggests that regulating autophagy may offer a promising therapeutic avenue for treating certain neurological diseases. Furthermore, existing literature indicates that various small molecule autophagy regulators have been tested in animal models and are linked to neurological disease outcomes. This review explores the role of mitophagy in programmed neuronal death and its connection to neuroinflammation.

Ovarian cancer is one of the most common gynecological malignancies. The current first-line treatment strategies for advanced ovarian cancer include surgery, chemotherapy, and maintenance therapy. Bevacizumab and poly (ADP-ribose) polymerase inhibitors (PARPi) are primary maintenance treatments for advanced ovarian cancer. Previously, many patients declined these therapies before medicare coverage because of high costs. Bevacizumab and apatinib are anti-tumor angiogenic agents. In this case study, we describe a patient with advanced ovarian cancer who underwent neoadjuvant chemotherapy, interval debulking surgery, and adjuvant chemotherapy. She declined bevacizumab and PARPi maintenance therapy owing to the prohibitive expenses. The patient was administered off-label apatinib and achieved a progression-free survival of 54 months. Thus, apatinib may offer substantial therapeutic value as a first-line maintenance therapy in advanced ovarian cancer.

An open critical-size bone defect is a major medical problem because of the difficulty in self-healing, leading to an increased risk of bacterial infection owing to wound exposure, resulting in treatment failure. Herein, a composite hydrogel was synthesized by chitosan, gallic acid, and hyaluronic acid, termed “CGH.” Hydroxyapatite was modified with polydopamine (PDA@HAP) and introduced to CGH to obtain a mussel-inspired mineralized hydrogel (CGH/PDA@HAP). The CGH/PDA@HAP hydrogel exhibited excellent mechanical performances, including self-healing and injectable properties. Owing to its three-dimensional porous structure and polydopamine modifications, the cellular affinity of the hydrogel was enhanced. When adding PDA@HAP into CGH, Ca2+ and PO43- could release and then promoted differentiation of BMSCs into osteoblasts. Without any osteogenic agent or stem cells, the area of new bone at the site of defect was enhanced and the newly formed bone had a dense trabecular structure after implanting of the CGH/PDA@HAP hydrogel for 4 and 8 weeks. Moreover, the growth of Staphylococcus aureus and Escherichia coli was effectively inhibited through the grafting of gallic acid onto chitosan. Above, this study provides a reasonable alternative strategy to manage open bone defects.

Background: The limited regenerative potential of periodontal tissue remains a challenge in orthodontic treatment, especially with respect to alveolar bone remodeling. The dynamic balance between the bone formation of osteoblasts and the bone resorption of osteoclasts controls bone homeostasis. The osteogenic effect of low-intensity pulsed ultrasound (LIPUS) is widely accepted, so LIPUS is expected to be a promising method for alveolar bone regeneration. Osteogenesis is regulated by the acoustic mechanical effect of LIPUS, while the cellular perception, transduction mode and response regulation mechanism of LIPUS stimuli are still unclear. This study aimed to explore the effects of LIPUS on osteogenesis by osteoblast-osteoclast crosstalk and the underlying regulation mechanism.Methods: The effects of LIPUS on orthodontic tooth movement (OTM) and alveolar bone remodeling were investigated via rat model by histomorphological analysis. Mouse bone marrow mesenchymal stem cells (BMSCs) and bone marrow monocytes (BMMs) were purified and used as BMSC-derived osteoblasts and BMM-derived osteoclasts, respectively. The osteoblast-osteoclast co-culture system was used to evaluate the effect of LIPUS on cell differentiation and intercellular crosstalk by Alkaline phosphatase (ALP), Alizarin Red S (ARS), tartrate-resistant acid phosphatase (TRAP) staining, real-time quantitative PCR, western blotting and immunofluorescence.Results: LIPUS was found to improve OTM and alveolar bone remodeling in vivo, promote differentiation and EphB4 expression in BMSC-derived osteoblasts in vitro, particularly when cells were directly co-cultured with BMM-derived osteoclasts. LIPUS enhanced EphrinB2/EphB4 interaction between osteoblasts and osteoclasts in alveolar bone, activated the EphB4 receptor on osteoblasts membrane, transduced LIPUS-related mechanical signals to the intracellular cytoskeleton, and gave rise to the nuclear translocation of YAP in Hippo signaling pathway, thus regulating cell migration and osteogenic differentiation.Conclusions: This study shows that LIPUS modulates bone homeostasis by osteoblast-osteoclast crosstalk via EphrinB2/EphB4 signaling, which benefits the balance between OTM and alveolar bone remodeling.

BackgroundBone marrow stimulation (BMS) has been considered a well-established method for treating knee and ankle osteochondral lesions. Some studies have also shown that BMS can promote healing of the repaired tendon and enhance biomechanical properties during rotator cuff repair. Our purpose was to compare the clinical outcomes of arthroscopic repair rotator cuff (ARCR) with and without BMS.MethodsA systematic review with meta-analysis was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). PubMed, Embase, Web of Science, Google scholar, ScienceDirect, and the Cochrane Library were searched from inception to March 20, 2022. Data on retear rates, shoulder functional outcomes, visual analog score and range of motion were pooled and analyzed. Dichotomous variables were presented as odds ratios (OR), and continuous variables were presented as mean differences (MD). Meta-analyses were conducted with Review Manager 5.3.ResultsEight studies involving 674 patients were included, with mean follow-up period ranging from 12 to 36.8 months. Compared to ARCR alone, the intraoperative combination of the BMS resulted in lower retear rates (P

BackgroundSpontaneous quadriceps tendon rupture (QTR) is a rare complication of uremia. Secondary hyperparathyroidism (SHPT) is considered the leading cause of QTR in uremia patients. QTR in patients with uremia and SHPT are treated with active surgical repair along with the treatment of SHPT using medication or parathyroidectomy (PTX). The impact of PTX for SHPT on tendon healing remains unclear. The purpose of this study was to introduce surgical procedures for QTR and to determine the functional recovery of the repaired quadriceps tendon (QT) after PTX.MethodsBetween Jan 2014 and Dec 2018, eight uremia patients underwent PTX after a ruptured QT was repaired by figure-of-eight trans-osseous sutures with an overlapping tightening suture technique. Biochemical indices were measured before and one year after PTX to evaluate the control of SHPT. The changes in bone mineral density (BMD) were determined by comparing x-ray images at pre-PTX and during follow-up. The assessment of the functional recovery of the repaired QT was conducted at the last follow-up using multiple functional parameters.ResultsEight patients (fourteen tendons) were retrospectively evaluated at an average follow-up of 3.46 ± 1.37 years after PTX. ALP and iPTH levels one year after PTX were significantly lower than at pre-PTX (P = 0.017, P

BackgroundPancreatic ductal adenocarcinoma (PDAC), the most prevalent type of pancreatic cancer, is a highly lethal malignancy with poor prognosis. Polypeptide N-acetylgalactosaminyltransferase-6 (GALNT6) is frequently overexpressed in PDAC. However, the role of GALNT6 in the PDAC remains unclear.MethodsThe expression of GALNT6 in pancreatic cancer and normal tissues were analyzed by bioinformatic analyses and immunohistochemistry. CCK8 and colony formation were used to detect cell proliferation. Flow cytometry was applied to detect cell cycle.The pyroptosis was detected by scanning electron microscopy. The mRNA expression was detected by qRT-PCR. The protein expression and localization were detected by western blot and immunofluorescence assay. ELISA was used to detect the levels of inflammatory factors.ResultsThe expression of GALNT6 was associated with advanced tumor stage, and had an area under curve (AUC) value of 0.919 in pancreatic cancer based on the cancer genome atlas (TCGA) dataset. Knockdown of GALNT6 inhibited cell proliferation, migration, invasion and cell cycle arrest of PDAC cells. Meanwhile, knockdown of GALNT6 increased the expression levels of interleukin-1β (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) and interleukin-18 (IL-18), the release of inflammasome and an increasing of Gasdermin D (GSDMD), N-terminal of GSDMD (GSDMD-N), Gasdermin E (GSDME) and N-terminal of GSDME (GSDME-N) in PDAC cells. GALNT6 suppressed the expression of NOD-like receptor thermal protein domain associated protein 3 (NLRP3) and GSDMD by glycosylation of NF-κB and inhibiting the nucleus localization of NF-κB. Additionally, GALNT6 promotes the degradation of GSDME by O-glycosylation.ConclusionWe found that GALNT6 is highly expressed in pancreatic cancer and plays a carcinogenic role. The results suggested that GALNT6 regulates the pyroptosis of PDAC cells through NF-κB/NLRP3/GSDMD and GSDME signaling. Our study might provides novel insights into the roles of GALNT6 in PDAC progression.

IntroductionPediatric growth hormone deficiency (GHD) is a disease resulting from impaired growth hormone/insulin-like growth factor-1 (IGF-1) axis but the effects of GHD on children’s cognitive function, brain structure and brain function were not yet fully illustrated.MethodsFull Wechsler Intelligence Scales for Children, structural imaging, diffusion tensor imaging, and resting-state functional magnetic resonance imaging were assessed in 11 children with GHD and 10 matched healthy controls.Results(1) The GHD group showed moderate cognitive impairment, and a positive correlation existed between IGF-1 levels and cognitive indices. (2) Mean diffusivity was significantly increased in both corticospinal tracts in GHD group. (3) There were significant positive correlations between IGF-1 levels and volume metrics of left thalamus, left pallidum and right putamen but a negative correlation between IGF-1 levels and cortical thickness of the occipital lobe. And IGF-1 levels negatively correlated with fractional anisotropy in the superior longitudinal fasciculus and right corticospinal tract. (4) Regional homogeneity (ReHo) in the left hippocampus/parahippocampal gyrus was negatively correlated with IGF-1 levels; the amplitude of low-frequency fluctuation (ALFF) and ReHo in the paracentral lobe, postcentral gyrus and precentral gyrus were also negatively correlated with IGF-1 levels, in which region ALFF fully mediates the effect of IGF-1 on working memory index.ConclusionMultiple subcortical, cortical structures, and regional neural activities might be influenced by serum IGF-1 levels. Thereinto, ALFF in the paracentral lobe, postcentral gyrus and precentral gyrus fully mediates the effect of IGF-1 on the working memory index.

Background: The treatment of cartilage damage is a hot topic at present, and cell therapy is an emerging alternative therapy. Stem cells derived from peripheral blood have become the focus of current research due to the ease of obtaining materials and a wide range of sources.Methods: We used a text search strategy using the [“mesenchymal stem cells” (MeSH term) OR “MSC” OR “BMMSC” OR “PBMSC” OR” PBMNC” OR “peripheral blood stem cells”] AND (cartilage injury [MeSH term] OR “cartilage” OR “chondral lesion”). After searching the literature, through the inclusion and exclusion criteria, the last included articles were systematically reviewed.Result: We found that peripheral blood-derived stem cells have chondrogenic differentiation ability and can induce chondrogenic differentiation and repair in vivo and have statistical significance in clinical and imaging prognosis. It is an improvement of academic differences. Compared with the bone marrow, peripheral blood is easier to obtain, widely sourced, and simple to obtain. In the future, peripheral blood will be a more potential cell source for cell therapy in the treatment of cartilage damage.Conclusion: Stem cells derived from peripheral blood can repair cartilage and are an important resource for the treatment of cartilage damage in the future. The specific mechanism and way of repairing cartilage need further study.

The repairment of critical-sized bone defects is a serious problem that stimulates the development of new biomaterials. In this study, nanohydroxyapatite (nHA)-doped porous polyetheretherketone (pPEEK) were successfully fabricated by the thermally induced phase separation method and hydrothermal treatment. Structural analysis was performed by X-ray diffraction. The water contact angles and scanning electron microscopy were measured to assess physical properties of surfaces. The mechanical strength of the composites is also determined. Microcomputed tomography is used to characterize the nHA content of the composites. The in vitro bioactivity of the composites with or without nHA was investigated by using murine pre-osteoblasts MC3T3-E1, and the results of cytotoxicity and cell proliferation assays revealed that the cytocompatibility of all specimens was good. Adherence assays were employed to examine the adhesion and morphology of cells on different materials. However, nHA-doped composites induced cell attachment and cell spreading more significantly. Osteogenic differentiation was investigated using alkaline phosphatase activity and alizarin red staining, and these in vitro results demonstrated that composites containing nHA particles enhanced osteoblast differentiation. Its effectiveness for promoting osteogenesis was also confirmed in an in vivo animal experiment using a tibial defective rat model. After 8 weeks of implantation, compared to the pure PEEK and pPEEK without nHA groups, the nHA-pPEEK group showed better osteogenic activity. The results indicate that the nHA-pPEEK composites are possibly a well-designed bone substitute for critical-sized bone defects by promoting bone regeneration and osteointegration successfully.

BackgroundMyocardial fibrosis is an important pathophysiologic mechanism of cardiac involvement that leads to increased mortality in patients with autoimmune diseases (AIDs). The aim of this study was to evaluate the association between myocardial strain from speckle-tracking echocardiography (STE) and fibrosis on cardiovascular magnetic resonance (CMR) and to further explore their prognostic implications in patients with AIDs.MethodsWe prospectively included 102 AIDs patients with clinically suspected cardiac involvement and 102 age- and sex-matched healthy individuals. Patients underwent CMR for evaluation of myocardial fibrosis by late gadolinium enhancement (LGE) and T1 mapping. A semiquantitative evaluation based on the extent of LGE was used to calculate the total (tLGEs) and segmental (sLGEs) LGE score. Global longitudinal strain (GLS) was evaluated by STE in all subjects. All patients were regularly followed up every 6 months. The primary endpoint was the composite incidence of all-cause death and cardiovascular hospitalization.ResultsCompared to healthy controls, AIDs patients had impaired GLS (−17.9 ± 5.1% vs. −21.2 ± 2.5%, p < 0.001). LGE was detected in 70% of patients. Patients with LGE presented worse GLS (−17.1 ± 5.3% vs. −19.6 ± 4.1%, p = 0.018) than those without LGE. On multivariate logistic analysis, GLS ≥ −15% was an independent predictor of LGE presence (OR = 4.98, 95%CI 1.35–18.33, p = 0.016). Moreover, a marked and stepwise impairment of segmental longitudinal strain (−19.3 ± 6.6 vs. −14.9 ± 6.5 vs. −8.9 ± 6.3, p < 0.001) was observed as sLGEs increased. During a median follow-up time of 25 months, 6 patients died, and 14 patients were hospitalized for cardiovascular reasons. Both GLS ≥ −15% (HR 3.56, 95%CI 1.28–9.86, p = 0.015) and tLGEs ≥ 6 (HR 4.13, 95%CI 1.43–11.92, p = 0.009) were independently associated with the primary endpoint.ConclusionsIn AIDs patients, impaired myocardial strain on STE could reflect the presence and extent of myocardial fibrosis and provide incremental prognostic value in addition to LGE in the prediction of adverse outcomes.

BackgroundThe transcriptional factor peroxisome proliferator–activated receptor γ (PPARγ) is an important therapeutic target for the treatment of type 2 diabetes. However, the role of the PPARγ transcriptional activity remains ambiguous in its metabolic regulation.MethodsBased on the crystal structure of PPARγ bound with the DNA target of PPARγ response element (PPRE), Arg134, Arg135, and Arg138, three crucial DNA binding sites for PPARγ, were mutated to alanine (3RA), respectively. In vitro AlphaScreen assay and cell-based reporter assay validated that PPARγ 3RA mutant cannot bind with PPRE and lost transcriptional activity, while can still bind ligand (rosiglitazone) and cofactors (SRC1, SRC2, and NCoR). By using CRISPR/Cas9, we created mice that were heterozygous for PPARγ-3RA (PPARγ3RA/+). The phenotypes of chow diet and high-fat diet fed PPARγ3RA/+ mice were investigated, and the molecular mechanism were analyzed by assessing the PPARγ transcriptional activity.ResultsHomozygous PPARγ-3RA mutant mice are embryonically lethal. The mRNA levels of PPARγ target genes were significantly decreased in PPARγ3RA/+ mice. PPARγ3RA/+ mice showed more severe adipocyte hypertrophy, insulin resistance, and hepatic steatosis than wild type mice when fed with high-fat diet. These phenotypes were ameliorated after the transcription activity of PPARγ was restored by rosiglitazone, a PPARγ agonist.ConclusionThe current report presents a novel mouse model for investigating the role of PPARγ transcription in physiological functions. The data demonstrate that the transcriptional activity plays an indispensable role for PPARγ in metabolic regulation.

Non-alcoholic fatty liver disease (NAFLD) has become the most common chronic liver disorder, and yet with no pharmacological treatment approved worldwide. The repositioning of old drugs provides a safe approach for drug development. Vidofludimus, an inhibitor for dihydroorotate dehydrogenase (DHODH) for the treatment of autoimmune disorders, is herein uncovered as a novel modulator for farnesoid X receptor (FXR) by biochemical and crystallographic analysis. We further revealed that vidofludimus exerts in vivo therapeutic effects on dextran sodium sulfate (DSS)-induced colitis in an FXR-dependent manner. Notably, vidofludimus also possesses remarkable beneficial effects in reducing NAFLD by targeting FXR, which may represent a unique approach in developing the treatment for NAFLD. Our findings not only reveal a promising template for the design of novel FXR ligands in treating autoimmune disorders, but also uncover a novel therapeutic effect for vidofludimus on NAFLD based on the newly established relationships among drugs, targets, and diseases.

Background: Pancreatic ductal adenocarcinoma (PDAC), the most prevalent type of pancreatic cancer, is a highly lethal malignancy with poor prognosis. Polypeptide N-acetylgalactosaminyltransferase-6 (GALNT6) is frequently overexpressed in PDAC. However, the role of GALNT6 in the PDAC remains unclear. Methods: The expression of GALNT6 in pancreatic cancer and normal tissues were analyzed by bioinformatic analyses and immunohistochemistry. CCK8 and colony formation were used to detect cell proliferation. Flow cytometry was applied to detect cell cycle. The pyroptosis was detected by scanning electron microscopy. The mRNA expression was detected by qRT-PCR. The protein expression and localization were detected by western blot and immunofluorescence assay. ELISA was used to detect the levels of inflammatory factors. Results: The expression of GALNT6 was associated with advanced tumor stage, and had an area under curve (AUC) value of 0.919 in pancreatic cancer based on the cancer genome atlas (TCGA) dataset. Knockdown of GALNT6 inhibited cell proliferation, migration, invasion and cell cycle arrest of PDAC cells. Meanwhile, knockdown of GALNT6 increased the expression levels of interleukin-1β (IL-β), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) and interleukin-18 (IL-18), the release of inflammasome and an increasing of Gasdermin D (GSDMD), N-terminal of GSDMD (GSDMD-N), Gasdermin E (GSDME) and N-terminal of GSDME (GSDME-N) in PDAC cells. GALNT6 suppressed the expression of NOD-like receptor thermal protein domain associated protein 3 (NLRP3) and GSDMD by glycosylation of NF-κB and inhibiting the nucleus localization of NF-κB. Additionally, GALNT6 promotes the degradation of GSDME by O-glycosylation. Conclusion: We found that GALNT6 is highly expressed in pancreatic cancer and plays a carcinogenic role. The results suggested that GALNT6 regulates the pyroptosis of PDAC cells through NF-kB/NLRP3/GSDMD and GSDME signaling. Our studymight provides novel insights into the roles of GALNT6 in PDAC progression. [ABSTRACT FROM AUTHOR]