USP26 Combats Age-Related Declines in Self-Renewal and Multipotent Differentiation of BMSC by Maintaining Mitochondrial Homeostasis.

Age-related declines in self-renewal and multipotency of bone marrow mesenchymal stem cells (BMSCs) limit their applications in tissue engineering and clinical therapy. Thus, understanding the mechanisms behind BMSC senescence is crucial for maintaining the rejuvenation and multipotent differentiation capabilities of BMSCs. This study reveals that impaired USP26 expression in BMSCs leads to mitochondrial dysfunction, ultimately resulting in aging and age-related declines in the self-renewal and multipotency of BMSCs. Specifically, decreased USP26 expression results in decreased protein levels of Sirtuin 2 due to its ubiquitination degradation, which leads to mitochondrial dysfunction in BMSCs and ultimately resulting in aging and age-related declines in self-renewal and multilineage differentiation potentials. Additionally, decreased USP26 expression in aging BMSCs is a result of dampened hypoxia-inducible factor 1α (HIF-1α) expression. HIF-1α facilitates USP26 transcriptional expression by increasing USP26 promoter activity through binding to the -191 - -198 bp and -262 - -269 bp regions on the USP26 promoter. Therefore, the identification of USP26 as being correlated with aging and age-related declines in self-renewal and multipotency of BMSCs, along with understanding its expression and action mechanisms, suggests that USP26 represents a novel therapeutic target for combating aging and age-related declines in the self-renewal and multipotent differentiation of BMSCs.

IL-4 promotes chondrogenesis of bone marrow mesenchymal stem cells and blockade of IL-4Rα retards the endochondral ossification during rat embryonic bone development.

Interleukin-4 (IL-4)/IL-4 receptor alpha (IL-4Rα) signalling pathways play important roles in the complex process of bone formation and bone remodelling. However, whether IL-4/IL-4Rα participates in skeletogenesis during embryonic development is not completely understood. We used the anti-IL-4Rα monoclonal antibody (anti-IL-4Rα mAb) as a powerful investigational tool to evaluate the potential roles of IL-4/IL-4Rα in the chondrogenic differentiation of rat bone marrow mesenchymal stem cells (BMSCs) in vitro. Simultaneously, we explored the effect of IL-4/IL-4Rα on bone ossification during rat embryo-fetal development. In this study, we found that, compared to the control group, IL-4 can significantly promote the chondrogenic differentiation of BMSCs. Furthermore, following exposure to anti-IL-4Rα mAb in pregnant rats, unexpected phenomena were observed in fetal bone development, including non-ossification of the fetal sternum, an incomplete ossification centre in long bones and a reduced number of ossification points in digit (toe) bones. To further investigate the underlying mechanism of the phenotype, we studied the rat sternum as the target organ, starting from different time points of sternum development in the embryonic stage. The results indicated that the retardation mainly occurred in the middle and late stages of embryonic development. This retardation was characterized by the inhibition of the differentiation process of mesenchymal stem cells into chondrocytes, resulting in reduced angiogenesis near the ossification centre, failure of osteoblasts to invade the centre of the cartilage body with the blood vessels and delayed formation of the primary ossification centre (POC). Overall, our study demonstrated the significant function of IL-4/IL-4Rα in chondrogenic differentiation of BMSCs and bone ossification during embryo-fetal development.

Nucleus accumbens ghrelin signaling controls anxiety-like behavioral response to acute stress.

BACKGROUND: Anxiety disorders are one of the most common mental disorders. Ghrelin is a critical orexigenic brain-gut peptide that regulates food intake and metabolism. Recently, the ghrelin system has attracted more attention for its crucial roles in psychiatric disorders, including depression and anxiety. However, the underlying neural mechanisms involved have not been fully investigated. METHODS: In the present study, the effect and underlying mechanism of ghrelin signaling in the nucleus accumbens (NAc) core on anxiety-like behaviors were examined in normal and acute stress rats, by using immunofluorescence, qRT-PCR, neuropharmacology, molecular manipulation and behavioral tests. RESULTS: We reported that injection of ghrelin into the NAc core caused significant anxiolytic effects. Ghrelin receptor growth hormone secretagogue receptor (GHSR) is highly localized and expressed in the NAc core neurons. Antagonism of GHSR blocked the ghrelin-induced anxiolytic effects. Moreover, molecular knockdown of GHSR induced anxiogenic effects. Furthermore, injection of ghrelin or overexpression of GHSR in the NAc core reduced acute restraint stress-induced anxiogenic effects. CONCLUSIONS: This study demonstrates that ghrelin and its receptor GHSR in the NAc core are actively involved in modulating anxiety induced by acute stress, and raises an opportunity to treat anxiety disorders by targeting ghrelin signaling system.

Activation of the osteoblastic HIF-1α pathway partially alleviates the symptoms of STZ-induced type 1 diabetes mellitus via RegIIIγ.

The hypoxia-inducible factor-1α (HIF-1α) pathway coordinates skeletal bone homeostasis and endocrine functions. Activation of the HIF-1α pathway increases glucose uptake by osteoblasts, which reduces blood glucose levels. However, it is unclear whether activating the HIF-1α pathway in osteoblasts can help normalize glucose metabolism under diabetic conditions through its endocrine function. In addition to increasing bone mass and reducing blood glucose levels, activating the HIF-1α pathway by specifically knocking out Von Hippel‒Lindau (Vhl) in osteoblasts partially alleviated the symptoms of streptozotocin (STZ)-induced type 1 diabetes mellitus (T1DM), including increased glucose clearance in the diabetic state, protection of pancreatic ß cell from STZ-induced apoptosis, promotion of pancreatic ß cell proliferation, and stimulation of insulin secretion. Further screening of bone-derived factors revealed that islet regeneration-derived protein III gamma (RegIIIγ) is an osteoblast-derived hypoxia-sensing factor critical for protection against STZ-induced T1DM. In addition, we found that iminodiacetic acid deferoxamine (SF-DFO), a compound that mimics hypoxia and targets bone tissue, can alleviate symptoms of STZ-induced T1DM by activating the HIF-1α-RegIIIγ pathway in the skeleton. These data suggest that the osteoblastic HIF-1α-RegIIIγ pathway is a potential target for treating T1DM.

Ghrelin/GHSR signaling in the lateral septum ameliorates chronic stress-induced depressive-like behaviors.

Ghrelin is a gastrointestinal hormone on feeding and metabolism regulation, and acts through its receptor-growth hormone secretagogue receptor (GHSR), which is widely distributed throughout the central nervous system. Recent studies have suggested that ghrelin plays an important role in the regulation of depression, but the underlying mechanisms remain uncertain. Lateral septum (LS) is a critical brain region in modulating depression. Therefore, we investigated the role of ghrelin/GHSR signaling in the LS on the depressive-like behaviors of mice under conditions of chronic stress by using behavioral tests, neuropharmacology, and molecular biology techniques. We found that infusion of ghrelin into the LS produced antidepressant-like responses in mice. Activation of LS GABAergic neurons was involved in the antidepressant effect of ghrelin. Importantly, GHSR was highly expressed and distributed in the LS neurons. Blockade of GHSR in the LS reversed the ghrelin-induced antidepressant-like effects. Molecular knockdown of GHSR in the LS induced depressive-like symptoms in mice. Furthermore, administration of ghrelin into the LS alleviated depressive-like behaviors induced by chronic social defeat stress (CSDS). Consistent with the neuropharmacological results, overexpression of GHSR in the LS reversed CSDS-induced depressive-like behaviors. Our findings clarify a key role for ghrelin/GHSR signaling in the regulation of chronic stress-induced depressive-like behaviors, which could provide new strategies for the treatment of depression.

Histamine signaling in the bed nucleus of the stria terminalis modulates stress-induced anxiety.

BACKGROUND: Anxiety disorder is one of the most prevalent psychiatric disorders. Intriguingly, dysfunction of the central histaminergic system, which is recognized as a general regulator for whole-brain activity, may result in anxiety, suggesting an involvement of the central histaminergic signaling in the modulation of anxiety. However, the neural mechanisms involved have not been fully identified. METHODS: Here, we examined the effect of histaminergic signaling in the bed nucleus of the stria terminalis (BNST) on anxiety-like behaviors both in normal and acute restraint stressed male rats by using anterograde tracing, immunofluorescence, qPCR, neuropharmacology, molecular manipulation and behavioral tests. RESULTS: We found that histaminergic neurons in the hypothalamus send direct projections to the BNST, which forms a part of the circuitry involved in stress and anxiety. Infusion of histamine into the BNST produced anxiogenic effect. Moreover, histamine H1 and H2 receptors are expressed and distributed in the BNST neurons. Blockade of histamine H1 or H2 receptors in the BNST did not affect anxiety-like behaviors in normal rats, but ameliorated anxiogenic effect induced by acute restraint stress. Furthermore, knockdown of H1 or H2 receptors in the BNST induced anxiolytic effect in acute restraint stressed rats, which confirmed the pharmacological results. LIMITATIONS: A single dose of histamine receptor antagonist was used. CONCLUSIONS: Together, these findings demonstrate a novel mechanism for the central histaminergic system in the regulation of anxiety, and suggest that inhibition of histamine receptors may be a useful strategy for treating anxiety disorder.

Desferrioxamine alleviates UHMWPE particle-induced osteoclastic osteolysis by inhibiting caspase-1-dependent pyroptosis in osteocytes.

BACKGROUND: Cell death and inflammation are the two important triggers of wear particle-induced osteolysis. Particles, including cobalt-chromium-molybdenum and tricalcium phosphate, have been reported to induce pyroptosis in macrophages and osteocytes. Although macrophage pyroptosis facilitates osteoclastic bone resorption and osteolysis, whether osteocyte pyroptosis is involved in osteoclastic osteolysis still needs further investigation. Desferrioxamine (DFO), an FDA-approved medication and a powerful iron chelator, has been proven to reduce ultrahigh-molecular-weight polyethylene (UHMWPE) particle-induced osteolysis. However, whether DFO can ameliorate UHMWPE particle-induced osteolysis by decreasing pyroptosis in osteocytes is unknown. RESULTS: A mouse calvarial osteolysis model and the mouse osteocyte cell line MLO-Y4 was used, and we found that pyroptosis in osteocytes was significantly induced by UHMWPE particles. Furthermore, our findings uncovered a role of caspase-1-dependent pyroptosis in osteocytes in facilitating osteoclastic osteolysis induced by UHMWPE particles. In addition, we found that DFO could alleviate UHMWPE particle-induced pyroptosis in osteocytes in vivo and in vitro. CONCLUSIONS: We uncovered a role of caspase-1-dependent pyroptosis in osteocytes in facilitating osteoclastic osteolysis induced by UHMWPE particles. Furthermore, we found that DFO alleviated UHMWPE particle-induced osteoclastic osteolysis partly by inhibiting pyroptosis in osteocytes. Schematic of DFO reducing UHMWPE particle-induced osteolysis by inhibiting osteocytic pyroptosis. Wear particles, such as polymers, generated from prosthetic implant materials activate canonical inflammasomes and promote the cleavage and activation of caspase-1. This is followed by caspase-1-dependent IL-ß maturation and GSDMD cleavage. The N-terminal fragment of GSDMD binds to phospholipids on the cell membrane and forms holes in the membrane, resulting in the release of mature IL-ß and inflammatory intracellular contents. This further facilitates osteoclastic differentiation of BMMs, resulting in excessive bone resorption and ultimately leading to prosthetic osteolysis. DFO reduces UHMWPE particle-induced osteolysis by inhibiting osteocytic pyroptosis.

Data-Driven Thyroid Nodule Diagnosis Using Belief Rule Base.

Doctors' diagnosis preferences are different, which makes them adopt different assumptions in medical decision making. Taking the diagnosis of thyroid nodules as an example, this study compares three assumptions, namely deletion, imputation based on the distribution (distribution), and benign by default (benign). For deletion, which is the most used assumption, the clinical reports with missing features would be deleted. For distribution, the missing features would be replaced with a distribution of features with respective probabilities. Besides the two assumptions, certain doctors have also stated that they leave benign features unrecorded because they think that such benign features are irrelevant to the final diagnosis. Under the benign assumption, the missing features would be replaced with benign features. The three assumptions are tested comparatively. Moreover, the belief rule base (BRB) is used to construct the diagnostic model under the three assumptions since it is essentially a white-box approach that can provide good interpretability and direct access to doctors and patients. A total of 3766 clinical reports on thyroid nodule diagnosis were collected from ten radiologists over a seven-year period. Case study results validate that the benign by default assumption has produced the optimal results, although different doctors could present varied tendencies towards different assumptions. Guidance and suggestions for doctors' practical work have been made based on the study results to improve work efficiency and diagnostic accuracy.

The osteoprotective role of USP26 in coordinating bone formation and resorption.

Bone homeostasis is maintained through a balance of bone formation by osteoblasts and bone resorption by osteoclasts. Ubiquitin-specific proteases (USPs) are involved in regulating bone metabolism by preserving bone formation or antagonizing bone resorption. However, the specific USPs that maintain bone homeostasis by orchestrating bone formation and bone resorption simultaneously are poorly understood. Here, we identified USP26 as a previously unknown regulator of bone homeostasis that coordinates bone formation and resorption. Mechanistically, USP26 stabilizes ß-catenin to promote the osteogenic activity of mesenchymal cells (MSCs) and impairs the osteoclastic differentiation of bone myelomonocytes (BMMs) by stabilizing inhibitors of NF-κBα (IκBα). Gain-of-function experiments revealed that Usp26 supplementation significantly increased bone regeneration in bone defects in aged mice and decreased bone loss resulting from ovariectomy. Taken together, these data show the osteoprotective effect of USP26 via the coordination of bone formation and resorption, suggesting that USP26 represents a potential therapeutic target for osteoporosis.

Periosteal CD68+ F4/80+ Macrophages Are Mechanosensitive for Cortical Bone Formation by Secretion and Activation of TGF-ß1.

Mechanical force regulates bone density, modeling, and homeostasis. Substantial periosteal bone formation is generated by external mechanical stimuli, yet its mechanism is poorly understood. Here, it is shown that myeloid-lineage cells differentiate into subgroups and regulate periosteal bone formation in response to mechanical loading. Mechanical loading on tibiae significantly increases the number of periosteal myeloid-lineage cells and the levels of active transforming growth factor ß (TGF-ß), resulting in cortical bone formation. Knockout of Tgfb1 in myeloid-lineage cells attenuates mechanical loading-induced periosteal bone formation in mice. Moreover, CD68+ F4/80+ macrophages, a subtype of myeloid-lineage cells, express and activate TGF-ß1 for recruitment of osteoprogenitors. Particularly, mechanical loading induces the differentiation of periosteal CD68+ F4/80- myeloid-lineage cells to the CD68+ F4/80+ macrophages via signaling of piezo-type mechanosensitive ion channel component 1 (Piezo1) for TGF-ß1 secretion. Importantly, CD68+ F4/80+ macrophages activate TGF-ß1 by expression and secretion of thrombospondin-1 (Thbs1). Administration of Thbs1 inhibitor significantly impairs loading-induced TGF-ß activation and recruitment of osteoprogenitors in the periosteum. The results suggest that periosteal myeloid-lineage cells respond to mechanical forces and consequently produce and activate TGF-ß1 for periosteal bone formation.

Transparent Digital Twin for Output Control Using Belief Rule Base.

A transparent digital twin (DT) is designed for output control using the belief rule base (BRB), namely, DT-BRB. The goal of the transparent DT-BRB is not only to model the complex relationships between the system inputs and output but also to conduct output control by identifying and optimizing the key parameters in the model inputs. The proposed DT-BRB approach is composed of three major steps. First, BRB is adopted to model the relationships between the inputs and output of the physical system. Second, an analytical procedure is proposed to identify only the key parameters in the system inputs with the highest contribution to the output. Being consistent with the inferencing, integration, and unification procedures of BRB, there are also three parts in the contribution calculation in this step. Finally, the data-driven optimization is performed to control the system output. A practical case study on the Wuhan Metro System is conducted for reducing the building tilt rate (BTR) in tunnel construction. By comparing the results following different standards, the 80% contribution standard is proved to have the highest marginal contribution that identifies only 43.5% parameters as the key parameters but can reduce the BTR by 73.73%. Moreover, it is also observed that the proposed DT-BRB approach is so effective that iterative optimizations are not necessarily needed.

Orexin 2 receptor in the nucleus accumbens is critical for the modulation of acute stress-induced anxiety.

Orexin is a neuropeptide mainly synthesized in the lateral hypothalamus/perifornical area and has been traditionally implicated in feeding, sleep-wake cycles, and reward. Intriguingly, patients with anxiety have increased levels of orexin in the cerebrospinal fluid. Pharmacological or genetic manipulation of orexin receptors affects anxiety-like behaviors in rodents, suggesting an involvement of the orexin signaling in the regulation of anxiety. Yet, the neural substrates involved remain largely unknown. The nucleus accumbens (NAc) shell holds a key position in the modulation of anxiety-related behaviors. Therefore, in the present study, by using neuropharmacology, molecular approaches and behavioral tests in rats, the role of orexin/orexin receptors in the NAc shell on the anxiety-like behaviors was investigated. We found that microinjection of orexin-A into the NAc shell induced an anxiogenic-like effect. Quantitative real-time PCR and immunofluorescence showed that the orexin 2 receptor (OX2R) is expressed and distributed in the NAc shell neurons. Activation of OX2R mimicked the anxiogenic effect of orexin-A. Moreover, infusion of an OX2R antagonist had no effect on anxiety-like behaviors in normal rats, but reversed anxiogenic effect induced by acute restraint stress. Finally, we found that downregulation of OX2R in the NAc shell caused an anxiolytic-like effect in acute restraint stressed rats, which was consistent with the pharmacological results. Together, this study suggests that OX2R in the NAc shell is involved in the regulation of acute stress-induced anxiety, and raises the possibility that OX2R antagonist may serve as an effective mean to treat anxiety disorders.

TRIM21 drives intervertebral disc degeneration induced by oxidative stress via mediating HIF-1α degradation.

The onset and progression of intervertebral disc degeneration (IVDD) is strictly associated with oxidative stress. TRIM21 (Tripartite motif-containing protein 21), a ubiquitin E3 ligase, has been shown to play an essential role in liver redox homeostasis; however, whether TRIM21 is involved in IVDD, especially in oxidative stress-induced IVDD, is unknown. Here, we reported that TRIM21 was upregulated in nucleus pulposus (NPs) with increasing severity of IVDD, and that oxidative stress was a stimulator of TRIM21 expression. Furthermore, we found that TRIM21 deficiency significantly protected NP cells from degeneration induced by oxidative stress as well as ameliorated disc degeneration in aged mice. Mechanistically, TRIM21 facilitated NP cells degeneration induced by oxidative stress via HIF-1α. TRIM21 could physically interact with HIF-1α and facilitated its degradation via its ubiquitylating activity. Taken together, these findings revealed that TRIM21 drived IVDD induced by oxidative stress by increasing HIF-1α degradation. These findings implicates the potential of TRIM21 as a therapeutic target in IVDD, especially in oxidative stress-induced IVDD.

Osteocytic HIF-1α Pathway Manipulates Bone Micro-structure and Remodeling via Regulating Osteocyte Terminal Differentiation.

The activation of hypoxia-inducible factor 1α (HIF-1α) signaling has promising implications for the treatment of bone diseases such as osteoporosis and skeletal fractures. However, the effects of manipulating HIF-1α pathway on bone micro-structure and remodeling should be fully studied before the clinical application of therapeutics that interfere with the HIF-1α pathway. In this study, we found that osteocyte-specific HIF-1α pathway had critical role in manipulating bone mass accrual, bone material properties and micro-structures, including bone mineralization, bone collagen fiber formation, osteocyte/canalicular network, and bone remodeling. In addition, our results suggest that osteocyte-specific HIF-1α pathway regulates bone micro-structure and remodeling via impairing osteocyte differentiation and maturation.

Neurotensin 1 receptor in the prelimbic cortex regulates anxiety-like behavior in rats.

The central neurotensin system has been implicated in reward, memory processes, also in the regulation of anxiety. However, the neural substrates where neurotensin acts to regulate anxiety have not been fully identified. The prelimbic region of medial prefrontal cortex (PrL) holds a key position in the modulation of anxiety-related behaviors and expresses neurotensin 1 receptor (NTS1). This study investigated the effects of activation or blockade of NTS1 in the PrL on anxiety-like behaviors of rats. Our results demonstrated that infusion of a selective NTS1 agonist or neurotensin into the PrL produced anxiogenic-like effects. Administration of a NTS1 antagonist into the PrL did not affect anxiety-like behaviors of normal rats, but attenuated anxiogenic effects induced by restraint stress. Moreover, we employed molecular approaches to downregulate the expression of NTS1 in the PrL, and found that downregulation of NTS1 in the PrL induced anxiolytic effects in restraint stress rats, also confirming the pharmacological results. Together, these findings suggest that NTS1 in the PrL is actively involved in the regulation of anxiety.

Data-Driven Analysis of Radiologists' Behavior for Diagnosing Thyroid Nodules.

Thyroid nodule has been a common and serious threaten to human health. With the identification and diagnosis of thyroid nodules in the general population, large volumes of examination reports in clinical practice have been accumulated. They provide data basics of analyzing radiologists' behavior of diagnosing thyroid nodules. To conduct data-driven analysis of radiologists' behavior, an experimental framework is designed based on belief rule base, which is essentially a white box for knowledge representation and uncertain reasoning. Under the framework, with 2744 examination reports of thyroid nodules in the period from January 2012 to February 2019 that have been collected from a tertiary hospital located in Hefei, Anhui, China, experimental results are obtained from conducting missing validation, self-validation, and mutual validation. Three principles are then concluded from the results and corresponding analysis. The first is that missing features on some criteria are considered as benign ones by default, the second is that there is generally inconsistency between the recorded features on criteria and the overall diagnosis, and the third is that different radiologists have different diagnostic preferences. These three principles reflect three diagnostic behavioral characteristics of radiologists, namely reliability, inconsistency, and independence. Based on the three principles and radiologists' behavioral characteristics, managerial insights in a general case are concluded to make the findings in this study available in other situations.

Mapping international collaboration in tuberculosis research from 1998 to 2017: A scientometric study.

BACKGROUND: TB is one of the top 10 causes of death and the leading cause from a single infectious agent. The study characterize the developmental trends and collaboration features in the field of tuberculosis (TB) at the national level and identify high-impact countries. METHODS: Scientometrics and social network analysis methods were used to analyze the research situation and collaboration behaviors based on TB research indexed in Web of Science from 1998 to 2017. RESULTS: The publication output, national collaborative rate, and collaborative level have steadily increased from 1998 to 2017. However, domestic publications still account for a substantial proportion of a nation's publications. Over time, the numbers of national publications and international collaborative publications have increased in total, but the growth trend of their share as a proportion of total national publications is not significant. The United States of America has the largest number of highly cited publications, while Denmark, the Netherlands, Switzerland, and Sweden have higher values of average relative citation than do other countries. Notably, the United Kingdom and South Africa have established the strongest and most stable collaboration. CONCLUSIONS: There was increasing research activity and collaboration in the field of TB during the period 1998 to 2017, but growth shows wide variability between countries. Further comprehensive and full collaboration should be promoted.

Ghrelin improves muscle function in dystrophin-deficient mdx mice by inhibiting NLRP3 inflammasome activation.

AIMS: Immuno-inflammation contributes to the pathogenesis of Duchenne muscular dystrophy (DMD), characterized by progressive muscle degeneration and weakness. The nucleotide-binding oligomerization domain (NOD)-like receptor family pyrin domain containing 3 (NLRP3) inflammasome is crucial for initiating innate immunity. Ghrelin is a circulating hormone that exerts anti-inflammatory activity in several inflammatory diseases. However, the role of ghrelin in DMD and underlying mechanism are still unstated. Therefore, we investigated the effect and potential mechanism of ghrelin on muscle morphology and muscular function of mdx mice, a mouse model of DMD. MAIN METHODS: 4-Week-old male mdx mice were injected intraperitoneally with ghrelin (100 µg/kg of body weight/day) or saline for 4 weeks. Then, muscle performance was evaluated by behavioral tests. Skeletal muscles samples were collected and relevant parameters were measured by using histopathological analysis and molecular biology techniques both in mdx muscles and primary myoblasts. KEY FINDINGS: Ghrelin significantly improved motor performance, alleviated muscle pathology and decreased inflammatory cell infiltration in mdx mice. Importantly, ghrelin dramatically inhibited NLRP3 inflammasome activation and reduced the production of mature IL-1ß both in dystrophic muscles and in lipopolysaccharide (LPS)-primed primary myoblasts induced by the NLRP3 inflammasome activator benzylated ATP (BzATP). Furthermore, the inhibition of NLRP3 inflammasome by ghrelin was partly mediated by the suppression of JAK2-STAT3 and p38 MAPK signaling pathway. SIGNIFICANCE: Our findings reveal that ghrelin suppresses muscle inflammation and ameliorates disease phenotype through inhibition of NLRP3 inflammasome activation and the production of IL-1ß in mdx mice, which suggests new therapeutic potential of ghrelin in DMD.

IL-36γ Induced by the TLR3-SLUG-VDR Axis Promotes Wound Healing via REG3A.

IL-36 family members are highly expressed in hyperproliferative keratinocytes and play an important role in the pathogenesis of skin diseases such as psoriasis. However, whether and how IL-36 cytokines are induced to promote wound healing remains unknown. Here we showed that skin injury increased the expression of IL-36γ to promote wound healing. Mechanistically, the expression of IL-36γ was induced by RNAs from damaged cells via the activation of toll-like receptor 3 (TLR3) and TIR-domain-containing adapter-inducing IFN-ß (TRIF) followed by the induction of a zinc finger protein SLUG to abrogate the inhibitory effect of vitamin D receptor (VDR) on the promoter of IL-36γ gene. IL-36γ acted back on keratinocytes to induce REG3A, which regulated keratinocyte proliferation and differentiation, thus promoting wound re-epithelialization. These observations show that skin injury increases IL-36γ via the activation of TLR3-SLUG-VDR axis and that IL-36γ induces REG3A to promote wound healing. These findings also provide insights into pathways contributing to wound repair.

Mitochondrial dysfunction and cerebral metabolic abnormalities in patients with mitochondrial encephalomyopathy subtypes: Evidence from proton MR spectroscopy and muscle biopsy.

AIMS: Accumulated evidence indicates that cerebral metabolic features, evaluated by proton magnetic resonance spectroscopy (1 H-MRS), are sensitive to early mitochondrion dysfunction associated with mitochondrial encephalomyopathy (ME). The metabolite ratios of lactate (lac)/Cr, N-acetyl aspartate (NAA)/creatine (Cr), total choline (tCho)/Cr, and myoinositol (mI)/Cr are measured in the infarct-like lesions by 1 H-MRS and may reveal metabolic changes associated with ME. However, the application of this molecular imaging technique in the investigation of the pathology of ME subtypes is unknown. METHODS: In this study, cerebral metabolic features of pathologically diagnosed ME cases, that is, 19 mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS); nine chronic progressive external ophthalmoplegia (CPEO); and 23 healthy controls, were investigated using 1 H-MRS. Receiver operating characteristics (ROC) analysis was used to evaluate the diagnostic power of the cerebral metabolites. Histochemical evaluation was carried out on muscle tissues derived from biopsy to assess the abnormal mitochondrial proliferation. The association between cerebral metabolic and mitochondrial cytopathy was examined by correlation analysis. RESULTS: Patients with MELAS or CPEO exhibited a significantly higher Lac/Cr ratio and a lower NAA/Cr ratio compared with controls. The ROC curve of Lac/Cr ratio indicated prominent discrimination between MELAS or CPEO and healthy control subjects, whereas the NAA/Cr ratio may present diagnostic power in the distinction of MELAS from CPEO. Lower NAA/Cr ratio was associated with higher Lac/Cr in MELAS, but not in CPEO. Furthermore, higher ragged-red fibers (RRFs) percentages were associated with elevated Lac/Cr and reduced NAA/Cr ratios, notably in MELAS. This association was not noted in the case of mI/Cr ratio. CONCLUSIONS: Mitochondrial cytopathy (lactic acidosis and RRFs on muscle biopsy) was associated with neuronal viability but not glial proliferation, notably in MELAS. Mitochondrial neuronopathy and neuronal vulnerability are considered significant causes in the pathogenesis of MELAS, particularly with regard to stroke-like episodes.