MaC2H2-IDD regulates fruit softening and involved in softening disorder induced by cold stress in banana.

Chilling stress causes banana fruit softening disorder and severely impairs fruit quality. Various factors, such as transcription factors, regulate fruit softening. Herein, we identified a novel regulator, MaC2H2-IDD, whose expression is closely associated with fruit ripening and softening disorder. MaC2H2-IDD is a transcriptional activator located in the nucleus. The transient and ectopic overexpression of MaC2H2-IDD promoted "Fenjiao" banana and tomato fruit ripening. However, transient silencing of MaC2H2-IDD repressed "Fenjiao" banana fruit ripening. MaC2H2-IDD modulates fruit softening by activating the promoter activity of starch (MaBAM3, MaBAM6, MaBAM8, MaAMY3, and MaISA2) and cell wall (MaEXP-A2, MaEXP-A8, MaSUR14-like, and MaGLU22-like) degradation genes. DLR, Y1H, EMSA, and ChIP-qPCR assays validated the expression regulation. MaC2H2-IDD interacts with MaEBF1, enhancing the regulation of MaC2H2-IDD to MaAMY3, MaEXP-A2, and MaGLU22-like. Overexpressing/silencing MaC2H2-IDD in banana and tomato fruit altered the transcript levels of the cell wall and starch (CWS) degradation genes. Several differentially expressed genes (DEGs) were authenticated between the overexpression and control fruit. The DEGs mainly enriched biosynthesis of secondary metabolism, amino sugar and nucleotide sugar metabolism, fructose and mannose metabolism, starch and sucrose metabolism, and plant hormones signal transduction. Overexpressing MaC2H2-IDD also upregulated protein levels of MaEBF1. MaEBF1 does not ubiquitinate or degrade MaC2H2-IDD. These data indicate that MaC2H2-IDD is a new regulator of CWS degradation in "Fenjiao" banana and cooperates with MaEBF1 to modulate fruit softening, which also involves the cold softening disorder.

Identification of DNA methylation episignature for the intellectual developmental disorder, autosomal dominant 21 syndrome, caused by variants in the CTCF gene.

PURPOSE: The main objective of this study was to assess clinical features and genome-wide DNA methylation profiles in individuals affected by intellectual developmental disorder, autosomal dominant 21 (IDD21) syndrome, caused by variants in the CCCTC-binding factor (CTCF) gene. METHODS: DNA samples were extracted from peripheral blood of 16 individuals with clinical features and genetic findings consistent with IDD21. DNA methylation analysis was performed using the Illumina Infinium Methylation EPIC Bead Chip microarrays. The methylation levels were fitted in a multivariate linear regression model to identify the differentially methylated probes. A binary support vector machine classification model was constructed to differentiate IDD21 samples from controls. RESULTS: We identified a highly specific, reproducible, and sensitive episignature associated with CTCF variants. Six variants of uncertain significance were tested, of which 2 mapped to the IDD21 episignature and clustered alongside IDD21 cases in both heatmap and multidimensional scaling plots. Comparison of the genomic DNA methylation profile of IDD21 with that of 56 other neurodevelopmental disorders provided insights into the underlying molecular pathophysiology of this disorder. CONCLUSION: The robust and specific CTCF/IDD21 episignature expands the growing list of neurodevelopmental disorders with distinct DNA methylation profiles, which can be applied as supporting evidence in variant classification.

Ephrin B2 (EFNB2) potentially protects against intervertebral disc degeneration through inhibiting nucleus pulposus cell apoptosis.

Nucleus pulposus (NP) cell apoptosis is a significant indication of accelerated intervertebral disc degeneration; however, the precise mechanism is unelucidated as of yet. Ephrin B2 (EFNB2), the only gene down-regulated in the three degraded intervertebral disc tissue microarray groups (GSE70362, GSE147383 and GSE56081), was screened for examination in this study. Subsequently, EFNB2 was verified to be down-regulated in degraded NP tissue samples. Interleukin-1 (IL-1ß) treatment of NP cells to simulate the IDD environment indicated that IL-1ß treatment decreased EFNB2 expression. In degenerative NP cells stimulated by IL-1ß, EFNB2 knockdown significantly increased the rate of apoptosis as well as the apoptosis-related molecules cleaved-caspase-3 and the Bax to Bcl-2 ratio. EFNB2 was found to promote AKT, PI3K, and mTOR phosphorylation; the PI3K/AKT signaling role was investigated using the PI3K inhibitor LY294002. EFNB2 overexpression significantly increased PI3K/AKT pathway activity in IL-1ß-stimulated NP cells than the normal control. Moreover, EFNB2 partially alleviated NP cell apoptosis induced by IL-1ß, reduced the cleaved-cas3 level, and decreased the Bax/Bcl-2 ratio after the addition of the inhibitor LY294002. Additionally, EFNB2 overexpression inhibited the ERK1/2 phosphorylation; the effects of EFNB2 overexpression on ERK1/2 phosphorylation, degenerative NP cell viability, and cell apoptosis were partially reversed by ERK signaling activator Ceramide C6. EFNB2 comprehensively inhibited the apoptosis of NP cells by activating the PI3K/AKT signaling and inhibiting the ERK signaling, obviating the exacerbation of IDD. EFNB2 could be a potential target to protect against degenerative disc changes.

Environmental iodine as a natural iodine intake in humans and environmental pollution index: a scientometric and updated mini review.

Although almost a third of the world's population is exposed to iodine deficiency (ID), and supplementation programs such as enriching table salt have been carried out or are being carried out at the global and national level, in many regions of the world, people are facing an increase in iodine intake, which is mainly due to the presence of large amounts of iodine in water, soil, agricultural products, or high consumption of seafood. Published articles were indexed in the Scopus database (from 2000 to 1 April 2023) were reviewed and analyzed by VOSviewer software. The results showed the growing interest of researchers over the last 20 years in environmental iodine intake. The results of this study can have a significant impact on the planning and policy-making of relevant officials and communities to supply the needed iodine.

ICE1 interacts with IDD14 to transcriptionally activate QQS to increase pollen germination and viability.

In flowering plants, sexual reproductive success depends on the production of viable pollen grains. However, the mechanisms by which QUA QUINE STARCH (QQS) regulates pollen development and how transcriptional activators facilitate the transcription of QQS in this process remain poorly understood. Here, we demonstrate that INDUCER OF CBF EXPRESSION 1 (ICE1), a basic helix-loop-helix (bHLH) transcription factor, acts as a key transcriptional activator and positively regulates QQS expression to increase pollen germination and viability in Arabidopsis thaliana by interacting with INDETERMINATE DOMAIN14 (IDD14). In our genetic and biochemical experiments, overexpression of ICE1 greatly promoted both the activation of QQS and high pollen viability mediated by QQS. IDD14 additively enhanced ICE1 function by promoting the binding of ICE1 to the QQS promoter. In addition, mutation of ICE1 significantly repressed QQS expression; the impaired function of QQS and the abnormal anther dehiscence jointly affected pollen development of the ice1-2 mutant. Our results also showed that the enhancement of pollen activity by ICE1 depends on QQS. Furthermore, QQS interacted with CUT1, the key enzyme for long-chain lipid biosynthesis. This interaction both promoted CUT1 activity and regulated pollen lipid metabolism, ultimately determining pollen hydration and fertility. Our results not only provide new insights into the key function of QQS in promoting pollen development by regulating pollen lipid metabolism, but also elucidate the mechanism that facilitates the transcription of QQS in this vital developmental process.

Magnetic resonance imaging approaches for studying mouse models of multiple sclerosis: A mini review.

Given that multiple sclerosis (MS) is a complex disease with an unclear etiology, a single animal model is unlikely to accurately represent all aspects of pathology and clinical features of the human condition. However, the availability of three major types of murine models of MS, that is, experimental autoimmune encephalomyelitis (EAE), viral models, and toxic models, enables studies of several relevant features of this debilitating disease. Researchers have recently begun to combine magnetic resonance imaging (MRI) technologies with other experimental strategies to acquire complementary information, for example, anatomical and functional, and study the effect of experimental manipulations longitudinally in a noninvasive way. This review summarizes the latest MRI studies investigating critical aspects of MS, such as atrophy, demyelination, neuroaxonal damage, and neuroinflammation, in mouse models of MS. Advanced techniques will be briefly discussed, providing references to specialized literature for the readers. Thus, this review aims to describe different imaging protocols used to study critical aspects of MS in a research laboratory, discussing the main related findings in the most significant murine models of the disease.

High throughput method for detecting murine brain atrophy using a clinical 3T MRI.

BACKGROUND: There is a lack of understanding of the mechanisms by which the CNS is injured in multiple sclerosis (MS). Since Theiler's murine encephalomyelitis virus (TMEV) infection in SJL/J mice is an established model of progressive disability in MS, and CNS atrophy correlates with progressive disability in MS, we used in vivo MRI to quantify total ventricular volume in TMEV infection. We then sought to identify immunological and virological biomarkers that correlated with increased ventricular size. METHODS: Mice, both infected and control, were followed for 6 months. Cerebral ventricular volumes were determined by MRI, and disability was assessed by Rotarod. A range of immunological and virological measures was obtained using standard techniques. RESULTS: Disability was present in infected mice with enlarged ventricles, while infected mice without enlarged ventricles had Rotarod performance similar to sham mice. Ventricular enlargement was detected as soon as 1 month after infection. None of the immunological and virological measures correlated with the development of ventricular enlargement. CONCLUSIONS: These results support TMEV infection with brain MRI monitoring as a useful model for exploring the biology of disability progression in MS, but they did not identify an immunological or virological correlate with ventricular enlargement.

Cognitive dysfunction and psychopathology: a cohort study of adults with intellectual developmental disorder.

BACKGROUND: Cognitive impairment of intellectual developmental disorders (IDD) is determined by several different combinations of specific cognitive alterations. People with IDD present a rate of mental health problems that is up to 4 times higher than that of the general population. Despite this, the relationship between specific cognitive dysfunctions and co-occurring mental disorders has not been adequately studied. The aim of the present paper is to investigate the association between specific cognitive dysfunctions and specific psychiatric symptoms and syndromes in people with IDD. METHODS: One hundred and twenty adults with mild to moderate IDD living in residential facilities underwent a clinical and instrumental assessment for specific cognitive and psychopathological features. RESULTS: Participants with IDD and ASD have significantly lower scores compared to those without respect to who has not the diagnosis on the Processing Speed Index (PSI) and Perceptual Reasoning Index (PRI) on the WAIS-IV and higher time scores on the TMT A. Moreover, there is a significant association between years of hospitalisation and TMT B and TMT B A time scores; the longer a participant with IDD was hospitalised, the worse their performance on the TMT. Although not statistically significant, many psychopathological clusters showed substantial cognitive profiles. CONCLUSIONS: Although further research is needed, neuropsychological and IQ tests scores seem to be differently associated to various psychopathological conditions co-occurring with IDD, and with ASD especially. Cognitive assessment seems to support diagnosis and treatment of psychopathological co-occurrences in persons with IDD, also in consideration of indirect implications including a better knowledge of the patient's characteristics beyond IQ deficit.

Baicalin suppresses interleukin-1ß-induced apoptosis, inflammatory response, oxidative stress, and extracellular matrix degradation in human nucleus pulposus cells.

OBJECTIVE: To explore the effect of baicalin on human nucleus pulposus cells (NPCs) in response to interleukin (IL)-1ß stimulation. METHODS: Viability of NPCs was measured by cell counting kit-8 (CCK-8) assay. TUNEL staining assay and flow cytometry were performed to detect apoptotic cell death of NPCs. Western blot analysis was conducted to detect the expression levels of proteins. Enzyme-linked immunosorbent assay (ELISA) was applied for the determination of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), tumor necrosis factor alpha (TNF-α), and IL-6. Oxidative stress indicators including reactive oxygen species (ROS) production, malondialdehyde (MDA) level, and superoxide dismutase (SOD) activity were measured. RESULTS: Baicalin attenuated IL-1ß-caused cell viability reduction and apoptosis in NPCs. IL-1ß-induced increase in Bax expression and decrease in Bcl-2 expression were attenuated by baicalin treatment. IL-1ß-induced production of iNOS, COX-2, IL-6, and TNF-α in NPCs was inhibited by baicalin treatment. Baicalin treatment reversed IL-1ß-induced increase in ROS production and MDA level, as well as decrease in SOD activity. Furthermore, baicalin treatment elevated the expression levels of Col II and Aggrecan and downregulated the expression levels of MMP3, MMP13, and ADAMTS5 in IL-1ß-induced NPCs. A total of 402 related targets of baicalin and 134 related targets of intervertebral disk degeneration were found, and nine intersection targets were screened out. The Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed that mitogen-activated protein kinase (MAPK) pathway was found to be involved in the effects of baicalin. CONCLUSIONS: Baicalin exhibited protective effects on IL-1ß-caused cell viability reduction, apoptosis, oxidative stress, inflammation, and extracellular matrix degradation in NPCs. In addition, we found c-Jun N-terminal kinase (JNK) and p38 MAPK pathways as targets of baicalin through bioinformatic analysis.

Comprehensive Analysis of the INDETERMINATE DOMAIN (IDD) Gene Family and Their Response to Abiotic Stress in Zea mays.

Transcription factors (TFs) are important regulators of numerous gene expressions due to their ability to recognize and combine cis-elements in the promoters of target genes. The INDETERMINATE DOMAIN (IDD) gene family belongs to a subfamily of C2H2 zinc finger proteins and has been identified only in terrestrial plants. Nevertheless, little study has been reported concerning the genome-wide analysis of the IDD gene family in maize. In total, 22 ZmIDD genes were identified, which can be distributed on 8 chromosomes in maize. On the basis of evolutionary relationships and conserved motif analysis, ZmIDDs were categorized into three clades (1, 2, and 3), each owning 4, 6, and 12 genes, respectively. We analyzed the characteristics of gene structure and found that 3 of the 22 ZmIDD genes do not contain an intron. Cis-element analysis of the ZmIDD promoter showed that most ZmIDD genes possessed at least one ABRE or MBS cis-element, and some ZmIDD genes owned the AuxRR-core, TCA-element, TC-rich repeats, and LTR cis-element. The Ka:Ks ratio of eight segmentally duplicated gene pairs demonstrated that the ZmIDD gene families had undergone a purifying selection. Then, the transcription levels of ZmIDDs were analyzed, and they showed great differences in diverse tissues as well as abiotic stresses. Furthermore, regulatory networks were constructed through the prediction of ZmIDD-targeted genes and miRNAs, which can inhibit the transcription of ZmIDDs. In total, 6 ZmIDDs and 22 miRNAs were discovered, which can target 180 genes and depress the expression of 9 ZmIDDs, respectively. Taken together, the results give us valuable information for studying the function of ZmIDDs involved in plant development and climate resilience in maize.

Multiple indeterminate domain (IDD)-DELLA1 complexes participate in gibberellin feedback regulation in peach.

KEY MESSAGE: Peach encodes 14 INDETERMINATE DOMAIN (IDD) transcription factors. PpIDD4, -12 and -13 mediated PpDELLA1 binding to the PpGA20ox1 promoter. Each of these three PpIDD-DELLA1 complexes activated transcription of PpGA20ox1. PpTPR1 and -4 interrupted the interaction of PpIDDs with PpDELLA1. The plant growth regulator gibberellin (GA) plays an important role in the rapid growth of annual shoots in peach. Our previous study showed that the peach cultivar 'FenHuaShouXingTao' (FHSXT), a gibberellic acid receptor (gid1) mutant, accumulates active GAs in annual shoot tips. This mutant enhances GA feedback regulation in peach. The results of this study suggested that the PpIDD-DELLA1 complex is the underlying mechanism of GA feedback regulation in peach. Fourteen IDD genes were identified in peach, and three PpIDDs (PpIDD4, -12 and -13, all from group IV) interacted with PpDELLA1, an important component in GA signaling pathway. Truncation, segmentation and site mutation of the promoter of PpGA20ox1 (a GA biosynthesis gene) showed that all three PpIDD proteins recognized the core motif TTGTC. PpIDD4 and -13 mainly bind to site 3, while PpIDD12 binds to site 5 of the PpGA20ox1 promoter. All three PpIDD-DELLA1 complexes activated the PpGA20ox1 promoter-LUC fusion. These data suggested that PpIDDs bridge PpDELLA1 and the promoter of PpGA20ox1, which then activated the transcription of PpGA20ox1. In addition, PpTPR1 and -4 disrupted the interaction of PpIDDs with PpDELLA1. Our research will be helpful for understanding and possibly modifying the regulation of annual shoot growth and GA biosynthesis.

Vascular anatomy-based localization of intervertebral discs assisting needle puncture for constructing a mouse model of mechanical injury-induced lumbar intervertebral disc degeneration.

Intervertebral disc degeneration (IDD) may be the primary cause of low back pain. Potential therapeutics for IDD must be validated in animal models, and their effectiveness quantified using functional metrics. Needle puncture of intervertebral discs (IVDs) has been used to induce IDD in mice and rats. Due to operational challenges, most animal IDD models are constructed using needle puncture of the caudal IVDs in mice, or by using larger animals, such as rats and rabbits. However, mouse IDD models involving lumbar IVD puncture are preferable because mice are genetically similar to humans and are the most commonly used transgenic animals, and because human IDD commonly affects the lumbar spine. We constructed a needle puncture-based mouse IDD model that relies on vascular anatomy to pinpoint lumbar IVDs. We evaluated the morphological and molecular changes in this model by using radiological, pathological, and immunostaining examinations. In our mechanical injury-induced IDD model, lumbar IVDs were accurately localized by injecting colored perfusates into the common iliac artery and vein, and right iliolumbar vein, which helped to visualize puncture positions, avoid neuromuscular injury, shorten the operation time, and decrease bleeding. Nucleus pulposus cells, defined by Krt19, and the disc height index gradually decreased after the surgery, and the degenerative effects peaked at 1 week. In conclusion, we established a mouse IDD model by performing precise puncture of lumbar IVDs via the ventral anterior approach assisted by vessel position. Our model effectively simulated the effects of IDD, and may serve as an efficient research tool.

LncRNA MIR155HG functions as a ceRNA of miR-223-3p to promote cell pyroptosis in human degenerative NP cells.

Nucleus pulposus (NP) cell pyroptosis plays a critical role in the pathogenesis of intervertebral disk degeneration (IDD). MIR155 host gene (MIR155HG) is a long non-coding RNA with pro-inflammatory activity. However, very little is known about its role in NP cell pyroptosis. This study aimed to observe the impact of MIR155HG on cell pyroptosis and to explore the underlying mechanism in human degenerative NP cells. Our results demonstrated that MIR155HG expression was significantly increased in human degenerative NP tissue samples and showed a positive correlation with Pfirrmann score. Overexpression of MIR155HG through a lentiviral vector decreased miR-223-3p levels, up-regulated NLRP3 expression and induced cell pyroptosis in human degenerative NP cells. A ceRNA action mode was identified among MIR155HG, miR-223-3p, and NLRP3. The stimulatory effect of MIR155HG on human degenerative NP cell pyroptosis was significantly reversed by pretreatment with miR-223-3p mimic or NLRP3 siRNA. In summary, these data suggest that MIR155HG sponges miR-223-3p to promote NLRP3 expression, leading to induction of cell pyroptosis in human degenerative NP cells. Targeting MIR155HG could be a novel and promising strategy to slow down the progression of IDD.

The Arabidopsis IDD14 transcription factor interacts with bZIP-type ABFs/AREBs and cooperatively regulates ABA-mediated drought tolerance.

The INDETERMINATE DOMAIN (IDD) transcription factors mediate various aspects of plant growth and development. We previously reported that an Arabidopsis IDD subfamily regulates spatial auxin accumulation, and thus organ morphogenesis and gravitropic responses. However, its functions in stress responses are not well defined. Here, we use a combination of physiological, biochemical, molecular, and genetic approaches to provide evidence that the IDD14 cooperates with basic leucine zipper-type binding factors/ABA-responsive element (ABRE)-binding proteins (ABRE-binding factors (ABFs)/AREBs) in ABA-mediated drought tolerance. idd14-1D, a gain-of-function mutant of IDD14, exhibits decreased leaf water loss and improved drought tolerance, whereas inactivation of IDD14 in idd14-1 results in increased transpiration and reduced drought tolerance. Altered IDD14 expression affects ABA sensitivity and ABA-mediated stomatal closure. IDD14 can physically interact with ABF1-4 and subsequently promote their transcriptional activities. Moreover, ectopic expression and mutation of ABFs could, respectively, suppress and enhance plant sensitivity to drought stress in the idd14-1 mutant. Our results demonstrate that IDD14 forms a functional complex with ABFs and positively regulates drought-stress responses, thus revealing a previously unidentified role of IDD14 in ABA signaling and drought responses.

IL-17 in intervertebral disc degeneration: Mechanistic insights and therapeutic implications.

Intervertebral disc degeneration (IDD) serves as an independent risk factor for lower back pain and is closely associated with spinal musculoskeletal disorders, including lumbar disc herniation, radiculopathy, and myelopathy. Interleukin-17 (IL-17), also named IL-17A, is a critical signature cytokine of T-helper 17 cells. Upon binding to the IL-17 receptor A/C heterodimeric complex, IL-17 can trigger multiple signal transduction pathways to stimulate gene transcription and increase messenger RNA stability. IL-17 expression is significantly increased in degenerative disc tissue and shows a positive correlation with disease severity. IL-17 has been shown to accelerate the development of IDD by promoting extracellular matrix degradation, enhancing inflammatory response, inducing neoangiogenesis, and inhibiting nucleus pulposus cell autophagy and proliferation. Targeting IL-17 represents a novel and promising approach for the therapeutic intervention of IDD. In this review, we summarized the recent progression about the role of IL-17 in IDD and highlighted its therapeutic implications.

Iodine in household cooking salt no longer plays a crucial role in iodine status of residents in Tianjin, China.

PURPOSE: The contribution of household cooking salt to population iodine status is decreasing in China, the applicability of the coverage rate of iodized salt (IS), proportion of adequately iodized salt (AIS), and salt iodine concentration (SIC) of household cooking salt used for iodine status assessment of residents requires further investigation. METHODS: Through the IDD control project, 16,445 children and 4848 pregnant women were recruited from Tianjin, China and the relationship between the coverage rate of IS, proportion of AIS, SIC, and population iodine status was analyzed. Additionally, through the thyroid health survey project, 856 children with IS or noniodized salt were recruited. The effects of different household cooking salts on individual iodine status and thyroid health were analyzed. RESULTS: After adjusting for confounding factors, no relationship was found between the coverage rate of IS, proportion of AIS, SIC of household cooking salt, and iodine status of children and pregnant women (all P > 0.05). No differences in levels of thyroid function and structural indicators were found in children with different household cooking salts (all P > 0.05). Additionally, no relationship was found between noniodized salt exposure and goiter, overt hyperthyroidism, overt hypothyroidism, thyroid nodules, antibody single positivity, or subclinical hypothyroidism (all P > 0.05). CONCLUSION: Iodine in household cooking salt no longer plays a crucial role in iodine status in Tianjin, China. Other indicators must be identified as beneficial supplements for precise iodine status evaluation not only in Tianjin but also in other large cities in China.

Cyanidin-3-glucoside protects against high glucose-induced injury in human nucleus pulposus cells by regulating the Nrf2/HO-1 signaling.

Cyanidin-3-glucoside (C3G) is a well-known natural anthocyanin with antioxidant and anti-inflammatory properties. In this study, we explored the role and action mechanism of C3G in high glucose (HG)-induced damage of human nucleus pulposus cells (HNPCs). Cell viability was assessed by CCK-8 assay. TUNEL assay was performed for detecting apoptotic rate. Western blot was performed to determine the expression levels of cl-caspase-3, caspase-3, Bax, Bim, collagen II, aggrecan, MMP-3, MMP-13, and ADAMTS5. Reactive oxygen species (ROS) generation was analyzed using DCFH-DA staining. The Nrf2 was knocked down or overexpressed in HNPCs through transfection with si-Nrf2 or pcDNA3.0-Nrf2. C3G treatment (12.5, 25, and 50 µM) improved cell viability of HNPCs under HG condition. HG-induced cell apoptosis of HNPCs was attenuated by C3G with decreased apoptotic rate and relative levels of cl-caspase-3/caspase-3, Bax, and Bim. C3G treatment caused significant increase in expression levels of collagen II and aggrecan and decrease in the relative levels of MMP-3, MMP-13, and ADAMTS5. After treatment with C3G, ROS generation in HNPCs was markedly reduced. Treatment with N-acetylcysteine (NAC) reversed HG-induced cell apoptosis and extracellular matrix (ECM) degradation. C3G treatment induced the expression of Nrf2 and HO-1 in HG-induced HNPCs. Moreover, knockdown of Nrf2 reversed the inhibitory effect of C3G on ROS production. Summarily, C3G exerted a protective effect on ROS-mediated cellular damage in HNPCs under HG condition, which was attributed to the induction of the Nrf2/HO-1 signaling pathway.

The Proteolysis of ECM in Intervertebral Disc Degeneration.

Intervertebral disc (IVD) degeneration (IDD) is a pathological process that commonly occurs throughout the human life span and is a major cause of lower back pain. Better elucidation of the molecular mechanisms involved in disc degeneration could provide a theoretical basis for the development of lumbar disc intervention strategies. In recent years, extracellular matrix (ECM) homeostasis has received much attention due to its relevance to the mechanical properties of IVDs. ECM proteolysis mediated by a variety of proteases is involved in the pathological process of disc degeneration. Here, we discuss in detail the relationship between the IVD as well as the ECM and the role of ECM proteolysis in the degenerative process of the IVD. Targeting ECM proteolysis-associated proteases may be an effective means of intervention in IDD.

Complex Diagnostics of Non-Specific Intellectual Developmental Disorder.

Intellectual development disorder (IDD) is characterized by a general deficit in intellectual and adaptive functioning. In recent years, there has been a growing interest in studying the genetic structure of IDD. Of particular difficulty are patients with non-specific IDD, for whom it is impossible to establish a clinical diagnosis without complex genetic diagnostics. We examined 198 patients with non-specific IDD from 171 families using whole-exome sequencing and chromosome microarray analysis. Hereditary forms of IDD account for at least 35.7% of non-specific IDD, of which 26.9% are monogenic forms. Variants in the genes associated with the BAF (SWI/SNF) complex were the most frequently identified. We were unable to identify phenotypic features that would allow differential diagnosis of monogenic and microstructural chromosomal rearrangements in non-specific IDD at the stage of clinical examination, but due to its higher efficiency, exome sequencing should be the diagnostic method of the highest priority study after the standard examination of patients with NIDD in Russia.

The Dual PDE7-GSK3ß Inhibitor, VP3.15, as Neuroprotective Disease-Modifying Treatment in a Model of Primary Progressive Multiple Sclerosis.

Multiple sclerosis (MS) is a chronic, inflammatory, autoimmune and degenerative disease with axonal damage and demyelination as its main features. Its dual neurological and autoimmune nature makes it a disease that is difficult to treat. Treatments that simultaneously stop the immune response while protecting and repairing the nervous system are urgent. That is of utmost importance for the primary progressive multiple sclerosis (PPMS), a rare and severe variant of MS, characterized by worsening neurological function from the onset of symptoms. In this sense, inhibitors of glycogen synthase kinase 3ß (GSK3ß) and phosphodiesterase 7 (PDE7) have recently shown great therapeutic potential for the treatment of demyelinating diseases. Here we investigated a dual inhibitor of these two targets, the small molecule VP3.15, in a preclinical model, which resembles primary-progressive MS (PPMS), the Theiler's mouse encephalomyelitis virus-induced demyelinated disease (TMEV-IDD). In our study, VP3.15 ameliorates the disease course improving motor deficits of infected mice. Chronic treatment with VP3.15 also showed significant efficacy in the immunomodulation process, as well as in the proliferation and differentiation of oligodendroglial precursors, improving the preservation of myelin and axonal integrity. Therefore, our results support a treatment with the safe VP3.15 as an integrative therapeutic strategy for the treatment of PPMS.