Search Results (32)

Background: Single-minded homolog 1 (SIM1) gene mutations with autosomal dominant inheritance have been related to hyperphagia and early-onset severe obesity. SIM1 is implicated in the development of hypothalamic nuclei, which play a crucial role in energy homeostasis. The development of melanocortin neural circuits in the hypothalamus is promoted by other factors such as Semaphorine 3 (SEMA3) and its receptors, such as PLXNA1-4 and NRP1-2. Loss-of-function across multiple SEMA3/NRP/PLXNA genes can collectively contribute to obesity onset. Case Description: A 3-year-old male was referred for the first time to Outpatient pediatric endocrinology due to early-onset and progressive severe obesity and hyperphagia. He presented neurobehavior disorders and partial diabetes insipidus. At age 6, the child was diagnosed with obesity-related complications, including hyperinsulinemia, impaired glucose tolerance, hypercholesterolemia, hepatic steatosis, and hypovitaminosis. The NGS analysis revealed four variants related to obesity: SIM1, SEMA3C, PLXNA4, and CREBBP gene mutations. Conclusions: The case presents the association of SIM-1 gene mutation with other obesity-related variants. The interactive and cumulative effects of the identified variants could coexist in the determination of severe obesity through abnormalities in the development and function of hypothalamic melanocortin circuits related to energy homeostasis. Although the pathogenic mutation of the SIM1 gene plays the main role, the complex clinical picture may be related to the possible cumulative effect of the other genetic mutations. Full article

In sepsis, a balanced pro-inflammatory and anti-inflammatory response results in the bacterial clearance and resolution of inflammation, promoting clinical recovery and survival. Semaphorins, a large family of secreted and membrane-bound glycoproteins, are newly recognized biomarkers and therapeutic targets in immunological and neoplastic disorders. Although semaphorins might also be a crucial part of host defense responses to infection, their role in sepsis is yet to be determined. This study aimed to analyze the association of serum semaphorin concentrations with sepsis severity and outcomes. Serum semaphorin concentrations (SEMA3A, SEMA3C, SEMA3F, SEMA4D, and SEMA7A) were measured in 115 adult patients with community-acquired sepsis and 50 healthy controls. While SEMA3A was decreased, SEMA3C, SEMA3F, SEMA4D, and SEMA7A were increased in sepsis patients. All analyzed SEMA showed good accuracy in identifying patients with sepsis. SEMA kinetics were related to sepsis complications; SEMA3A, SEMA3C, SEMA3F, and SEMA4D with respiratory failure; SEMA3C and SEMA7A with acute kidney injury; and SEMA3C and SEMA3F were related to septic shock. Importantly, SEMA3A, SEMA3C, SEMA4D, and SEMA7A were associated with 28-day mortality. In conclusion, we provide evidence that semaphorins are associated with sepsis course and outcomes. Full article

Background/Objectives: Bladder cancer is a very important issue in contemporary urology. The aim of this pilot study was to assess for the first time the clinical utility of semaphorin 3C (sema3C) and 4A (sema4A) in patients with non-muscle-invasive bladder cancer (NMIBC). Methods: The experiment involved 15 patients with NMIBC and 5 patients without malignancies as the control group. Plasma and urinary concentrations of sema3C and sema4A were assessed by using an enzyme-linked immunosorbent assay (ELISA). Urinary sema4A concentration was below the detection level. Results: There was no statistically significant difference between patients and controls in terms of plasma sema4A and sema3C or urinary sema3C concentrations (p > 0.05). There was a significantly higher sema3C plasma concentration in patients with low-grade tumors (p = 0.0132) and an upward trend in sema4A plasma concentration for the subjects with Ta-stage tumors. Urinary sema3C concentration positively correlated with tumor size (R = 0.57, p = 0.03). Plasma sema3C concentration correlated negatively with tumor grade (R = −0.62, p = 0.01). Conclusions: Urinary sema4A concentration, which is below the detection threshold, is unlikely to be useful as a marker of NMIBC. Plasma sema4A concentration and sema3C concentration in plasma and urine cannot be used as stand-alone markers of NMIBC at this point. The plasma concentration of sema3C can potentially be considered in the future as a marker for tumors of lower grades. Plasma sema4A concentration could potentially be considered in the future as a marker for tumors of earlier stages. All of these observations are preliminary, so they have to be assessed in larger cohorts to make reliable recommendations. Nevertheless, our study lays the groundwork for further research to develop potential tests that could be used in daily practice to monitor and predict the course of cancer. Full article

Autism spectrum disorder (ASD) is a neurodevelopmental disorder that includes autism, Asperger’s syndrome, and pervasive developmental disorder. Individuals with ASD may exhibit difficulties in social interactions, communication challenges, repetitive behaviors, and restricted interests. While genetic mutations in individuals with ASD can either activate or inactivate the activities of the gene product, impacting neuronal morphogenesis and causing symptoms, the underlying mechanism remains to be fully established. Herein, for the first time, we report that genetically conserved Rac1 guanine-nucleotide exchange factor (GEF) Dock5 signalosome molecules control process elongation in the N1E-115 cell line, a model line capable of achieving neuronal morphological changes. The increased elongation phenotypes observed in ASD and intellectual disability (ID)-associated Semaphorin-5A (Sema5A) Arg676-to-Cys [p.R676C] were also mediated by Dock5 signalosome molecules. Indeed, knockdown of Dock5 using clustered regularly interspaced short palindromic repeat (CRISPR)/CasRx-based guide(g)RNA specifically recovered the mutated Sema5A-induced increase in process elongation in cells. Knockdown of Elmo2, an adaptor molecule of Dock5, also exhibited similar recovery. Comparable results were obtained when transfecting the interaction region of Dock5 with Elmo2. The activation of c-Jun N-terminal kinase (JNK), one of the primary signal transduction molecules underlying process elongation, was ameliorated by either their knockdown or transfection. These results suggest that the Dock5 signalosome comprises abnormal signaling involved in the process elongation induced by ASD- and ID-associated Sema5A. These molecules could be added to the list of potential therapeutic target molecules for abnormal neuronal morphogenesis in ASD at the molecular and cellular levels. Full article

Semaphorin 4D (Sema4D), also known as CD100, is a multifunctional transmembrane protein with immunoregulatory functions. Upon the activation of immune cells, soluble Semaphorin 4D (sSema4D) is proteolytically cleaved from the membrane by metalloproteinases. sSema4D levels are elevated in various (auto-)inflammatory diseases. Our aim was to investigate sSema4D levels in association with sepsis and critical illnesses and to evaluate sSema4D’s potential as a prognostic biomarker. We measured sSema4D levels in 192 patients upon admission to our medical intensive care unit. We found similar levels of sSema4D in 125 patients with sepsis compared to 67 non-septic patients. sSema4D levels correlated with leukocytes but not with other markers of systemic inflammation such as C-reactive protein or procalcitonin. Most interestingly, in a subgroup of patients suffering from pre-existing liver cirrhosis, we observed significantly higher levels of sSema4D. Consistently, sSema4D was also positively correlated with markers of hepatic and cholestatic injury. Our study suggests that sSema4D is not regulated in sepsis compared to other causes of critical illness. However, sSema4D seems to be associated with hepatic injury and inflammation. Full article

Autism spectrum disorder (ASD) is a neurodevelopmental disorder that includes autism, Asperger’s syndrome, and pervasive developmental disorder. ASD is characterized by poor interpersonal relationships and strong attachment. The correlations between activated or inactivated gene products, which occur as a result of genetic mutations affecting neurons in ASD patients, and ASD symptoms are now of critical concern. Here, for the first time, we describe the process in which that the respective ASD-associated mutations (Arg676-to-Cys [R676C] and Ser951-to-Cys [S951C]) of semaphorin-5A (Sema5A) localize Sema5A proteins themselves around the plasma membrane in the N1E-115 cell line, a model line that can achieve neuronal morphological differentiation. The expression of each mutated construct resulted in the promotion of excessive elongation of neurite-like processes with increased differentiation protein markers; R676C was more effective than S951C. The differentiated phenotypes were very partially neutralized by an antibody, against Plexin-B3 as the specific Sema5A receptor, suggesting that the effects of Sema5A act in an autocrine manner. R676C greatly increased the activation of c-Jun N-terminal kinase (JNK), one of the signaling molecules underlying process elongation. In contrast, the blocking of JNK signaling, by a chemical JNK inhibitor or an inhibitory construct of the interaction of RhoG with Elmo1 as JNK upstream signaling molecules, recovered the excessive process elongation. These results suggest that ASD-associated mutations of Sema5A, acting through the JNK signaling cascade, lead to excessive differentiated phenotypes, and the inhibition of JNK signaling recovers them, revealing possible therapeutic targets for recovering the potential molecular and cellular phenotypes underlying certain ASD symptoms. Full article

According to recent evidence, some groups of semaphorins (SEMAs) have been associated with cancer progression. These proteins are able to modulate the cellular signaling of particular receptor tyrosine kinases (RTKs) via the stimulation of SEMA-specific coreceptors, namely plexins (plexin-A, -B, -C, -D) and neuropilins (Np1, Np2), which share common domains with RTKs, leading to the coactivation of the latter receptors. MET, ERBB2, VEGFR2, PFGFR, and EGFR, among others, represent acknowledged targets of semaphorins that are often associated with tumor progression or poor prognosis. In particular, higher expression of SEMA6 family proteins in cancer cells and stromal cells of the cancer niche is often associated with enhanced tumor angiogenesis, metastasis, and resistance to anticancer therapy. Notably, high SEMA6 expression in malignant tumor cells such as melanoma, pleural mesothelioma, gastric cancer, lung adenocarcinoma, and glioblastoma may serve as a prognostic biomarker of tumor progression. To date, very few studies have focused on the mechanisms of transmembrane SEMA6-driven tumor progression and its underlying interplay with RTKs within the tumor microenvironment. This review presents the growing evidence in the literature on the complex and shaping role of SEMA6 family proteins in cancer responsiveness to environmental stimuli. Full article

Regular physical activity and the use of nutritional supplements, including antioxidants, are recognized as efficacious approaches for the prevention and mitigation of obesity-related complications. This study investigated the effects of 12 weeks of CrossFit training combined with astaxanthin (ASX) supplementation on some plasma adipokines in males with obesity. Sixty-eight males with obesity (BMI: 33.6 ± 1.4 kg·m⁻²) were randomly assigned into four groups: the control group (CG; n = 11), ASX supplementation group (SG; n = 11), CrossFit group (TG; n = 11), and training plus supplement group (TSG; n = 11). Participants underwent 12 weeks of supplementation with ASX or placebo (20 mg/day capsule daily), CrossFit training, or a combination of both interventions. Plasma levels of semaphorin 3C (SEMA3C), apelin, chemerin, omentin1, visfatin, resistin, adiponectin, leptin, vaspin, and RBP4 were measured 72 h before the first training session and after the last training session. The plasma levels of all measured adipokines were significantly altered in SG, TG, and TSG groups (p < 0.05). The reduction of resistin was significantly higher in TSG than in SG (p < 0.05). The plasma levels of omentin1 were significantly higher in both training groups of TG and TSG than SG (p < 0.05), although such a meaningful difference was not observed between both training groups (p > 0.05). Significant differences were found in the reductions of plasma levels of vaspin, visfatin, apelin, RBP4, chemerin, and SEMA3C between the SG and TSG groups (p < 0.05). The study found that a 12-week intervention using ASX supplementation and CrossFit exercises resulted in significant improvements in several adipokines among male individuals with obesity. Notably, the combined approach of supplementation and training had the most pronounced results. The findings presented in this study indicate that the supplementation of ASX and participation in CrossFit exercise have the potential to be effective therapies in mitigating complications associated with obesity and enhancing metabolic health. Full article

Semaphorins have recently been recognized as crucial modulators of immune responses. In the pathogenesis of COVID-19, the activation of immune responses is the key factor in the development of severe disease. This study aimed to determine the association of serum semaphorin concentrations with COVID-19 severity and outcomes. Serum semaphorin concentrations (SEMA3A, -3C, -3F, -4D, -7A) were measured in 80 hospitalized adult patients with COVID-19 (moderate (n = 24), severe (n = 32), critical, (n = 24)) and 40 healthy controls. While SEMA3C, SEMA3F and SEMA7A serum concentrations were significantly higher in patients with COVID-19, SEMA3A was significantly lower. Furthermore, SEMA3A and SEMA3C decreased with COVID-19 severity, while SEMA3F and SEMA7A increased. SEMA4D showed no correlation with disease severity. Serum semaphorin levels show better predictive values than CRP, IL-6 and LDH for differentiating critical from moderate/severe COVID-19. SEMA3F and SEMA7A serum concentrations were associated with the time to recovery, requirement of invasive mechanical ventilation, development of pulmonary thrombosis and nosocomial infections, as well as with in-hospital mortality. In conclusion, we provide the first evidence that SEMA3A, SEMA3C, SEMA3F and SEMA7A can be considered as new biomarkers of COVID-19 severity. Full article

In recent years, olfactory dysfunction has attracted increasingly more attention as a hallmark symptom of neurodegenerative diseases (ND). Deeply understanding the molecular basis underlying the development of the olfactory bulb (OB) will provide important insights for ND studies and treatments. Now, with a genetic knockout mouse model, we show that TRIM67, a new member of the tripartite motif (TRIM) protein family, plays an important role in regulating the proliferation and development of mitral cells in the OB. TRIM67 is abundantly expressed in the mitral cell layer of the OB. The genetic deletion of TRIM67 in mice leads to excessive proliferation of mitral cells in the OB and defects in its synaptic development, resulting in reduced olfactory function in mice. Finally, we show that TRIM67 may achieve its effect on mitral cells by regulating the Semaphorin 7A/Plexin C1 (Sema7A/PlxnC1) signaling pathway. Full article

Plexins are a family of nine single-pass transmembrane receptors with a conserved GTPase activating protein (GAP) domain. The plexin family is divided into four subfamilies: Type-A, type-B, type-C, and type-D plexins. Plexins function as receptors for axon guidance factors of the semaphorin family. The semaphorin gene family contains 22 genes that are divided into eight subclasses of which subclasses three to seven represent vertebrate semaphorins. The plexins and their semaphorin ligands have important roles as regulators of angiogenesis, cancer proliferation, and metastasis. Class 3 semaphorins, with the exception of sema3E, are the only semaphorins that do not bind directly to plexins. In order to transduce their signals, they bind instead to complexes consisting of receptors of the neuropilin family and various plexins. Some plexins also form complexes with tyrosine-kinase receptors such as the epidermal growth factor receptor ErbB2, the mesenchymal epithelial transition factor receptor (MET), and the Vascular endothelial growth factor receptor 2 (VEGFR2) and, as a result, can modulate cell proliferation and tumor progression. This review focuses on the roles of the different plexins in the control of cancer cell proliferation and invasiveness. Plexins also affect tumor progression and tumor metastasis by indirect mechanisms, such as modulation of angiogenesis and immune responses. However, these topics are not covered in the present review. Full article

Neural crest (NC) is a unique vertebrate cell type arising from the border of the neural plate and epidermis that gives rise to diverse tissues along the entire body axis. Roberto Mayor and colleagues have made major contributions to our understanding of NC induction, delamination, and migration. We report that a truncating mutation of the classical tumor suppressor Adenomatous Polyposis Coli (apc) disrupts craniofacial development in zebrafish larvae, with a marked reduction in the cranial neural crest (CNC) cells that contribute to mandibular and hyoid pharyngeal arches. While the mechanism is not yet clear, the altered expression of signaling molecules that guide CNC migration could underlie this phenotype. For example, apc^mcr/mcr larvae express substantially higher levels of complement c3, which Mayor and colleagues showed impairs CNC cell migration when overexpressed. However, we also observe reduction in stroma-derived factor 1 (sdf1/cxcl12), which is required for CNC migration into the head. Consistent with our previous work showing that APC directly enhances the activity of glycogen synthase kinase 3 (GSK-3) and, independently, that GSK-3 phosphorylates multiple core mRNA splicing factors, we identify 340 mRNA splicing variations in apc mutant zebrafish, including a splice variant that deletes a conserved domain in semaphorin 3f (sema3f), an axonal guidance molecule and a known regulator of CNC migration. Here, we discuss potential roles for apc in CNC development in the context of some of the seminal findings of Mayor and colleagues. Full article

Estrogen receptor positive (ER⁺) breast cancer (BCa) accounts for the highest proportion of breast cancer-related deaths. While endocrine therapy is highly effective for this subpopulation, endocrine resistance remains a major challenge and the identification of novel targets is urgently needed. Previously, we have shown that Semaphorin 3C (SEMA3C) is an autocrine growth factor that drives the growth and treatment resistance of various cancers, but its role in breast cancer progression and endocrine resistance is poorly understood. Here, we report that SEMA3C plays a role in maintaining the growth of ER⁺ BCa cells and is a novel, tractable therapeutic target for the treatment of ER⁺ BCa patients. Analyses of publicly available clinical datasets indicate that ER⁺ BCa patients express significantly higher levels of SEMA3C mRNA than other subtypes. Furthermore, SEMA3C mRNA expression was positively correlated with ESR1 mRNA expression. ER+ BCa cell lines (MCF7 and T47D) expressed higher levels of SEMA3C mRNA and protein than a normal mammary epithelial MCF10A cell line. ER siRNA knockdown was suppressed, while dose-dependent beta-estradiol treatment induced SEMA3C expression in both MCF7 and T47D cells, suggesting that SEMA3C is an ER-regulated gene. The stimulation of ER⁺ BCa cells with recombinant SEMA3C activated MAPK and AKT signaling in a dose-dependent manner. Conversely, SEMA3C silencing inhibited Estrogen Receptor (ER) expression, MAPK and AKT signaling pathways while simultaneously inducing apoptosis, as monitored by flow cytometry and Western blot analyses. SEMA3C silencing significantly inhibited the growth of ER⁺ BCa cells, implicating a growth dependency of ER⁺ BCa cells on SEMA3C. Moreover, the analysis of tamoxifen resistant (TamR) cell models (TamC3 and TamR3) showed that SEMA3C levels remain high despite treatment with tamoxifen. Tamoxifen-resistant cells remained dependent on SEMA3C for growth and survival. Treatment with B1SP Fc fusion protein, a SEMA3C pathway inhibitor, attenuated SEMA3C-induced signaling and growth across a panel of tamoxifen sensitive and resistant ER⁺ breast cancer cells. Furthermore, SEMA3C silencing and B1SP treatment were associated with decreased EGFR signaling in TamR cells. Here, our study implicates SEMA3C in a functional role in ER⁺ breast cancer signaling and growth that suggests ER⁺ BCa patients may benefit from SEMA3C-targeted therapy. Full article

Nonalcoholic fatty liver disease (NAFLD) is associated with systemic changes in immune response linked with chronic low-grade inflammation and disease progression. Semaphorins, a large family of biological response modifiers, were recently recognized as one of the key regulators of immune responses, possibly also associated with chronic liver diseases. The aim of this study was to identify semaphorins associated with NAFLD and their relationship with steatosis and fibrosis stages. In this prospective, case-control study, serum semaphorin concentrations (SEMA3A, -3C, -4A, -4D, -5A and -7A) were measured in 95 NAFLD patients and 35 healthy controls. Significantly higher concentrations of SEMA3A, -3C and -4D and lower concentrations of SEAMA5A and -7A were found in NAFLD. While there was no difference according to steatosis grades, SEMA3C and SEMA4D significantly increased and SEMA3A significantly decreased with fibrosis stages and had better accuracy in predicting fibrosis compared to the FIB-4 score. Immunohistochemistry confirmed higher expression of SEMA4D in hepatocytes, endothelial cells and lymphocytes in NAFLD livers. The SEMA5A rs1319222 TT genotype was more frequent in the NAFLD group and was associated with higher liver stiffness measurements. In conclusion, we provide the first evidence of the association of semaphorins with fibrosis in patients with NAFLD. Full article

Endothelial cells (ECs) and neurons share a number of common signaling pathways and molecular mediators to orchestrate directional migration and guide the pattern of the vascular network and nervous system. So far, research concerning the functional coupling between vascular and neuronal pathfinding remains insufficient. Semaphorin4C (sema4C), a member of class 4 semaphorins, is initially described in the nervous system, whose role has been demonstrated in diverse biological developments. The present study focused on the role of sema4C in the vascular and neural development process in zebrafish embryos. It confirmed that sema4C is expressed in both the nervous system and intersegmental vessels (ISVs) in zebrafish embryos by diverse expression analysis. It also showed that the knockdown of sema4C caused a serious pathfinding anomaly both in the ISVs and primary motor neurons (PMNs) of zebrafish embryos. In addition, overexpressing exogenous sema4C mRNA in sema4C morphants remarkably neutralized the defective pattern of the vascular and neural system. Collectively, this report suggests that sema4C acts as a dual guiding factor regulating vascular and neuronal development. These findings elucidate a new molecular mechanism underlying blood vessel and nerve development and might serve as groundwork for future research on functional coupling between both systems. Full article