BMP4 inhibits myogenic differentiation of bone marrow–derived mesenchymal stromal cells in mdx mice

AbstractBackground aimsBone marrow–derived mesenchymal stromal cells (BMSCs) are a promising therapeutic option for treating Duchenne muscular dystrophy (DMD). Myogenic differentiation occurs in the skeletal muscle of the mdx mouse (a mouse model of DMD) after BMSC transplantation. The transcription factor bone morphogenic protein 4 (BMP4) plays a crucial role in growth regulation, differentiation and survival of many cell types, including BMSCs. We treated BMSCs with BMP4 or the BMP antagonist noggin to examine the effects of BMP signaling on the myogenic potential of BMSCs in mdx mice.MethodsWe added BMP4 or noggin to cultured BMSCs under myogenic differentiation conditions. We then injected BMP4- or noggin-treated BMSCs into the muscles of mdx mice to determine their myogenic potential.ResultsWe found that the expression levels of desmin and myosin heavy chain decreased after treating BMSCs with BMP4, whereas the expression levels of phosphorylated Smad, a downstream target of BMP4, were higher in these BMSCs than in the controls. Mdx mouse muscles injected with BMSCs pretreated with BMP4 showed decreased dystrophin expression and increased phosphorylated Smad levels compared with muscles injected with non-treated BMSCs. The opposite effects were seen after pretreatment with noggin, as expected.ConclusionsOur results identified BMP/Smad signaling as an essential negative regulator of promyogenic BMSC activity; inhibition of this pathway improved the efficiency of BMSC myogenic differentiation, which suggests that this pathway might serve as a target to regulate BMSC function for better myogenic differentiation during treatment of DMD and degenerative skeletal muscle diseases

Molecular differences in brain regional vulnerability to aging between males and females

BackgroundAging-related cognitive decline is associated with brain structural changes and synaptic loss. However, the molecular mechanisms of cognitive decline during normal aging remain elusive.ResultsUsing the GTEx transcriptomic data from 13 brain regions, we identified aging-associated molecular alterations and cell-type compositions in males and females. We further constructed gene co-expression networks and identified aging-associated modules and key regulators shared by both sexes or specific to males or females. A few brain regions such as the hippocampus and the hypothalamus show specific vulnerability in males, while the cerebellar hemisphere and the anterior cingulate cortex regions manifest greater vulnerability in females than in males. Immune response genes are positively correlated with age, whereas those involved in neurogenesis are negatively correlated with age. Aging-associated genes identified in the hippocampus and the frontal cortex are significantly enriched for gene signatures implicated in Alzheimer’s disease (AD) pathogenesis. In the hippocampus, a male-specific co-expression module is driven by key synaptic signaling regulators including VSNL1, INA, CHN1 and KCNH1; while in the cortex, a female-specific module is associated with neuron projection morphogenesis, which is driven by key regulators including SRPK2, REPS2 and FXYD1. In the cerebellar hemisphere, a myelination-associated module shared by males and females is driven by key regulators such as MOG, ENPP2, MYRF, ANLN, MAG and PLP1, which have been implicated in the development of AD and other neurodegenerative diseases.ConclusionsThis integrative network biology study systematically identifies molecular signatures and networks underlying brain regional vulnerability to aging in males and females. The findings pave the way for understanding the molecular mechanisms of gender differences in developing neurodegenerative diseases such as AD

Resveratrol Regulates Mitochondrial Biogenesis and Fission/Fusion to Attenuate Rotenone-Induced Neurotoxicity

It has been confirmed that mitochondrial impairment may underlie both sporadic and familial Parkinson’s disease (PD). Mitochondrial fission/fusion and biogenesis are key processes in regulating mitochondrial homeostasis. Therefore, we explored whether the protective effect of resveratrol in rotenone-induced neurotoxicity was associated with mitochondrial fission/fusion and biogenesis. The results showed that resveratrol could not only promote mitochondrial mass and DNA copy number but also improve mitochondrial homeostasis and neuron function in rats and PC12 cells damaged by rotenone. We also observed effects with alterations in proteins known to regulate mitochondrial fission/fusion and biogenesis in rotenone-induced neurotoxicity. Therefore, our findings suggest that resveratrol may prevent rotenone-induced neurotoxicity through regulating mitochondrial fission/fusion and biogenesis

Advances in developing novel therapeutic strategies for Alzheimer’s disease

Abstract Alzheimer’s Disease (AD), the most prevalent neurodegenerative disease of aging, affects one in eight older Americans. Nearly all drug treatments tested for AD today have failed to show any efficacy. There is a great need for therapies to prevent and/or slow the progression of AD. The major challenge in AD drug development is lack of clarity about the mechanisms underlying AD pathogenesis and pathophysiology. Several studies support the notion that AD is a multifactorial disease. While there is abundant evidence that amyloid plays a role in AD pathogenesis, other mechanisms have been implicated in AD such as tangle formation and spread, dysregulated protein degradation pathways, neuroinflammation, and loss of support by neurotrophic factors. Therefore, current paradigms of AD drug design have been shifted from single target approach (primarily amyloid-centric) to developing drugs targeted at multiple disease aspects, and from treating AD at later stages of disease progression to focusing on preventive strategies at early stages of disease development. Here, we summarize current strategies and new trends of AD drug development, including pre-clinical and clinical trials that target different aspects of disease (mechanism-based versus non-mechanism based, e.g. symptomatic treatments, lifestyle modifications and risk factor management)

Research on the Design of Industry and Education Integration Capability Maturity Model

This article introduces the design and evaluation method of the capability Maturity Model for the Integration of Industry and Education. Based on the interpretation of the industry-education integration documents issued by the country and major provinces and cities, the capability model architecture is designed into four levels: Dimension, Process Area Group, Process Area, and Capability Practice. Each maturity level and its objectives are defined, and a capability dictionary is established according to different requirements for the different maturity levels. The evaluation method sets weights for Dimensions and Process Areas based on their importance, and designs scoring rules for Capability Practice to determine the current capability maturity level of the organization

Cloning and characterization of a CCoAOMT gene involved in rapid lignification of endocarp in dove tree (Davidia involucrata Baill.)

The long period of seed dormancy is one of the most important reasons leading to the low fertility of dove tree (Davidia involucrata Baill., Davidia hereinafter). During the fruit development process of Davidia, the endocarps will become particularly compact and hard, which was considered as a critical reason for the long seed dormancy of Davidia. However, the biological significance and regulatory mechanism of this process remain unclear. In this study, we identified a CCoAOMT gene, a key member of the lignin biosynthesis pathway, from Davidia endocarp. The gene named DiCCoAOMT1 has an ORF (open reading frame) of 744 bp and encodes a predicted protein of 239 amino acids. The expression of DiCCoAOMT1 is endocarp-specific and the expression levels increased along with the fruit development process. The encoding protein of DiCCoAOMT1 demonstrated a relatively high O-methyltransferase activity when using caffeic acid as a substrate in vitro. The tissue-specific CCoAOMT gene identified in this study might play a key role in specifically regulating the rapid lignification process in Davidia endocarp

Hormonal Regulation and Transcriptomic Insights into Flower Development in <i>Hydrangea paniculata</i> ‘Vanilla Strawberry’

Understanding the molecular mechanisms that regulate flower growth, development, and opening is of paramount importance, yet these processes remain less explored at the genetic level. Flower development in Hydrangea paniculata ‘Vanilla Strawberry’ is finely tuned through hormonal signals, yet the genetic underpinnings are not well defined. This study addresses the gap by examining the influence of gibberellic acid (GA3), salicylic acid (SA), and ethylene (ETH) on the flowering traits and underlying molecular responses. Treatment with 100 mg/L SA significantly improved chlorophyll content and bolstered the accumulation of soluble sugars and proteins, advancing the flowering onset by 6 days and lengthening the flowering period by 11 days. Concurrently, this treatment enhanced inflorescence dimensions, increasing length, width, and petal area by 22.76%, 26.74%, and 27.45%, respectively. Contrastingly, 100 mg/L GA3 expanded inflorescence size but postponed flowering initiation and decreased inflorescence count. Higher concentrations of SA and GA3, as well as any concentration of ETH, resulted in delayed flowering and inferior inflorescence attributes. A physiological analysis over 50 days revealed that these regulators variably affected sugar and protein levels and modified antioxidant enzyme activities. An RNA-seq analysis during floral development highlighted significant transcriptomic reprogramming, with SA treatment downregulating Myb transcription factors, implicating them in the modulation of flowering timing and stress adaptation. These findings illuminate the complex interplay between hormonal treatments, gene expression, and flowering phenotypes in Hydrangea paniculata, offering valuable perspectives for ornamental horticulture optimization

Abnormal Neural Progenitor Cells Differentiated from Induced Pluripotent Stem Cells Partially Mimicked Development of TSC2 Neurological Abnormalities

Summary: Tuberous sclerosis complex (TSC) is a disease featuring devastating and therapeutically challenging neurological abnormalities. However, there is a lack of specific neural progenitor cell models for TSC. Here, the pathology of TSC was studied using primitive neural stem cells (pNSCs) from a patient presenting a c.1444-2A>C mutation in TSC2. We found that TSC2 pNSCs had higher proliferative activity and increased PAX6 expression compared with those of control pNSCs. Neurons differentiated from TSC2 pNSCs showed enlargement of the soma, perturbed neurite outgrowth, and abnormal connections among cells. TSC2 astrocytes had increased saturation density and higher proliferative activity. Moreover, the activity of the mTOR pathway was enhanced in pNSCs and induced in neurons and astrocytes. Thus, our results suggested that TSC2 heterozygosity caused neurological malformations in pNSCs, indicating that its heterozygosity might be sufficient for the development of neurological abnormalities in patients. : In this article, Cheng and colleagues isolated primitive neural stem cells from a patient presenting a c.1444-2A>C mutation in TSC2. These iPSC-derived neural cells recapitulated the pathophysiology of TSC2-deficient patients and could be used for screening appropriate drugs for personalized therapies. Keywords: induced pluripotent stem cells, mTOR, neural differentiation, neurological abnormalities, primitive neural stem cells, tuberous sclerosis comple

Serum Creatinine Distinguishes Duchenne Muscular Dystrophy from Becker Muscular Dystrophy in Patients Aged ≤3 Years: A Retrospective Study

Here, we investigated correlations between serum creatinine (SCRN) levels and clinical phenotypes of dystrophinopathy in young patients. Sixty-eight patients with dystrophinopathy at the Neuromuscular Clinic, The First Affiliated Hospital, Sun Yat-sen University, were selected for this study. The diagnosis of dystrophinopathy was based on clinical manifestation, biochemical changes, and molecular analysis. Some patients underwent muscle biopsies; SCRN levels were tested when patients were ≤3 years old, and reading frame changes were analyzed. Each patient was followed up, and motor function and clinical phenotype were assessed when the same patients were ≥4 years old. Our findings indicated that in young patients, lower SCRN levels were associated with increased disease severity (p &lt; 0.01) and that SCRN levels were the highest in patients exhibiting mild Becker muscular dystrophy (BMD) (p &lt; 0.001) and the lowest in patients with Duchenne muscular dystrophy (DMD) (p &lt; 0.01) and were significantly higher in patients carrying in-frame mutations than in patients carrying out-of-frame mutations (p &lt; 0.001). SCRN level cutoff values for identifying mild BMD [18 µmol/L; area under the curve (AUC): 0.947; p &lt; 0.001] and DMD (17 µmol/L; AUC: 0.837; p &lt; 0.001) were established. These results suggest that SCRN might be a valuable biomarker for distinguishing DMD from BMD in patients aged ≤3 years and could assist in the selection of appropriate treatment strategies