Search Results (102)

Background: The impairment of neurite outgrowth is an early pathological hallmark underlying various neurodegenerative disorders. The promotion of neurite outgrowth was considered as a feasible strategy to treat neurodegenerative disorders. 9-Methylfascaplysin (9-MF), a marine-derived, bioactive compound, has exhibited multiple neuroprotective activities. Methods and Result: In this study, 9-MF at nanomolar concentrations promoted neurite outgrowth, upregulated the expression of growth-associated protein-43 (GAP-43), and increased the mitochondrial positive area with similar efficacy as retinoic acid in PC12 cells. 9-MF-associated differentiated expressed genes were enriched in mitochondria and synapse, forming a Rho-associated coiled-coil containing a protein kinase 2 (ROCK2)-centralized network. CMap analysis further identified positive connections between 9-MF-induced perturbation and perturbations caused by the inhibition of the ROCK2 pathway. Molecular docking analysis demonstrated a high binding affinity between 9-MF and ROCK2, indicating that 9-MF could inhibit ROCK2. Furthermore, 9-MF significantly reduced the phosphorylation of ROCK2 with a similar efficacy as fasudil, a ROCK2 inhibitor. Narciclasine, a known ROCK2 activator, almost completely abolished the effects of 9-MF on the induction of neurite outgrowth in PC12 cells. Conclusions: 9-MF effectively promoted neurite outgrowth possibly via the inhibition of ROCK2, providing supporting evidence that 9-MF might be developed as a novel neurological drug. Full article

Background/Objectives: Rho small GTPases (RSG), which regulates metastasis, constitute eight subfamilies—“classical” Rho, Rac, cdc42, and “atypical” Rif, Rnd, Wrch, RhoH, and RhoBTB. Their downstream signaling requires switching between GTP-bound active and GDP-bound inactive forms. Classical RSGs, but not atypical RSGs, require regulation by guanine nucleotide exchange factors (GEF), GTPase-activating proteins (GAP) and guanine nucleotide dissociation inhibitors (GDI) to achieve this switch. The objective of this review is to summarize the roles of RSGs in metastatic prostate cancer (mPCa) and their interaction with the androgen receptor (AR), which regulates this disease. Methods: We summarize the literature that describes the role of RSGs in mPCa, and their interaction with the AR. Results: Classical RSGs mostly promote metastasis (except RhoB), whereas atypical RSGs, with exceptions, mostly prevent it. Their role, however, is context-dependent—e.g., RhoB is tumor-suppressive in AR-null PCa but oncogenic in AR-positive tumors. The AR modulates RSG expression transcriptionally, but also affects their function through modulation of GEFs, GAPs, and GDIs. In turn, RSGs also regulate AR transcriptional activity. Interestingly, RSGs and the AR have non-genomic interactions via membrane-localized AR (mAR) not affected by AR inhibitors. Conclusions: Drugs that target RSGs are needed along with AR inhibitors to prevent mPCa progression. Full article

Purpose: Adolescence is a period of increased vulnerability to addictive behaviors, and Primary Health Care (PHC) plays a crucial role in prevention and intervention (e.g., through Screening, Brief Intervention, and Referral to Treatment), but professionals often face barriers, such as inadequate training and systemic challenges, particularly within the Greek context. Given the lack of data on their needs, this study aimed to investigate the levels of self-perceived knowledge/skills, attitudes regarding communication and readiness, perceived barriers, and educational expectations among PHC professionals in Greece. Method: A cross-sectional descriptive survey was conducted using an anonymous questionnaire with a convenience sample of 331 PHC professionals from 5 Health Regions. Results: Professionals recognized the high importance of effective communication (M = 4.31/5) but reported low preparedness (M = 2.65/5) and moderate confidence in knowledge, especially in screening tools/motivational interviewing (M = 2.25/5). Lack of training was the main barrier (87.6%). A strong positive correlation was found between knowledge and preparedness (rho = 0.68, p < 0.001), but not between age/experience and readiness (p > 0.05). Discussion: The study highlights a significant readiness gap and a substantial need for specialized training for PHC professionals in Greece, regardless of experience. Targeted interventions are required to enhance skills (especially in SBIRT/MI) and self-efficacy, alongside action to address systemic barriers. Full article

It has previously been reported that the RhoA/Rho-associated kinase (ROCK) pathway is involved in depolarization-induced contraction triggered by high [K⁺] stimulation in rat caudal arterial smooth muscle. Furthermore, we reported that activation of the upstream Ca²⁺-dependent proline-rich tyrosine kinase 2 (Pyk2) leads to phosphorylation of myosin targeting subunit of myosin light chain phosphatase (MYPT1) and 20 kDa myosin light chain (LC₂₀). These findings suggest that Rho guanine nucleotide exchange factors (RhoGEFs) or Rho GTPase-activating proteins (RhoGAPs) may mediate RhoA activation downstream of Pyk2, thereby contributing to depolarization-induced contraction. However, it remains unclear whether Pyk2 directly interacts with RhoGEFs or RhoGAPs. In this study, we investigated the interaction between Pyk2 and RhoGEFs or RhoGAPs during depolarization stimulation of rat caudal arterial smooth muscle. We examined the interaction between Pyk2 and RhoGEFs or RhoGAPs, which previously were identified in smooth muscle, specifically in rat caudal arterial smooth muscle, in response to 60 mM K⁺ stimulation by immunoprecipitation analysis. ArhGEF11, ArhGEF12, phosphorylated ArhGAP42 at Tyr792 (pTyr792-ArhGAP42) and phosphorylated ArhGAP42 at Tyr376 (pTyr376-ArhGAP42) co-immunoprecipitated with Pyk2. The co-immunoprecipitation of pTyr792-ArhGAP42, but not pTyr376-ArhGAP42, with Pyk2 was inhibited by a Pyk2 inhibitor, sodium salicylate. Furthermore, 60 mM K⁺ stimulation increased ArhGAP42 phosphorylation at Tyr792, which was also suppressed by sodium salicylate. These findings indicate that Pyk2-mediated phosphorylation of ArhGAP42 at Tyr792 may play a role in depolarization-induced contraction of rat caudal arterial smooth muscle. Full article

Background/Objectives: Survivors of sepsis can develop left ventricular (LV) systolic function with focal myocardial fibrosis. The relationship between diffuse myocardial fibrosis or oedema and LV systolic function remains unknown in this patient cohort. This study sought to address this knowledge gap using cardiovascular magnetic resonance (CMR) parametric mapping methods. Methods: Sepsis survivors who underwent CMR at a UK cardiac centre were included. CMR images analysed include cines, native T1-mapping, native T2-mapping, and post-contrast T1-mapping. Synthetic extracellular volume (ECV) fraction was also estimated. Native myocardial T1 values, native myocardial T2 values, and ECV values were compared against LV ejection fraction (LVEF). Results: Of the 37 sepsis survivors (age 53 ± 16 years old; 57% males), the mean left ventricular ejection fraction (LVEF) was 55% (IQR 43–62), and 43% of the patients had LV systolic dysfunction (LVEF < 50%). Mean native myocardial T1 values were 1055 ± 65 ms (septal) and 1051 ± 60 ms (global). Mean synthetic ECV values were 0.30 ± 0.04. Mean native myocardial T2 values were 52 ± 7 ms (septal) and 53 ± 6 ms (global). Septal and global native myocardial T1 values were not significantly correlated with LVEF (rho = 0.080, p = 0.637; rho = 0.036, p = 0.831, respectively). Synthetic ECV was not significantly correlated to LVEF (rho = −0.082; p = 0.723). Septal and global native myocardial T2 values were weakly correlated with LVEF (rho = 0.261, p = 0.281; rho = 0.216, p = 0.375, respectively). On ROC analysis, the performance of native myocardial T1 values, ECV, and native myocardial T2 values for predicting LV dysfunction was modest (AUC: 0.53 ± 0.10, 0.54 ± 11, and 0.68 ± 0.14; all p > 0.05, respectively). Conclusions: CMR markers of diffuse myocardial fibrosis (native T1-mapping and ECV) and myocardial oedema (native T2-mapping) have weak relationships with left ventricular systolic function in this study cohort of sepsis survivors. Further work is needed to better assess the role of diffuse myocardial fibrosis and oedema in the pathophysiology of post-sepsis cardiomyopathy. Full article

Background: Effective doctor–patient communication is essential for high-quality care, especially for patients with chronic conditions requiring hemodialysis. However, there is a lack of validated tools in the Malay language to measure this communication. This study aimed to translate and validate the Doctor–Patient Communication Questionnaire (DPCQ) into Malay (MyD-PCQ) for use among patients receiving hemodialysis in Kelantan, Malaysia. Methods: A cross-sectional study was conducted with 300 patients receiving hemodialysis at Hospital Universiti Sains Malaysia. The original English DPCQ was translated and culturally adapted into Malay following international guidelines, including forward and backward translation, expert review, and cognitive debriefing. Data were collected using the Malay version of the questionnaire. Confirmatory factor analysis (CFA) assessed the construct validity, while Raykov’s rho measured internal consistency. Results: The Malay version of the DPCQ demonstrated excellent model fit in CFA (χ²/df = 1.25, p = 0.053; SRMR = 0.037; RMSEA = 0.029; CFI = 0.982; and TLI = 0.979). Factor loadings ranged from 0.493 to 0.640. The internal consistency was high, with Raykov’s rho of 0.887. The average total score among participants was 37.31 out of 60, indicating moderate perceived communication quality. Conclusions: The Malay Doctor–Patient Communication Questionnaire (MyD-PCQ) is a valid and reliable tool for assessing communication between doctors and patients receiving hemodialysis in Malaysia. Its use can help identify communication gaps, support training initiatives, and improve patient-centered care in clinical practice. Future research should evaluate its use in other settings and patient populations. Full article

Tensins (TNS1–4) are pivotal molecular scaffolds bridging the actin cytoskeleton to integrin-based adhesions, orchestrating signal transduction and governing cellular processes in cancer. Structurally, the N-terminal actin-binding domain (ABD) in TNS1–3 enables cytoskeletal regulation and interactions with regulators like the Rho GAP DLC1, while ABD-deficient TNS4 functions as a focal adhesion signal amplifier. Functionally, TNS1–3 exhibit context-dependent duality as tumor promoters or suppressors, dictated by tissue-specific microenvironments and signaling crosstalk. In contrast, TNS4 acts predominantly as an oncoprotein across carcinomas by stabilizing epidermal growth factor receptor (EGFR), driving epithelial–mesenchymal transition and invasion, and sustaining proliferation. Clinically, tensin dysregulation correlates with metastasis and poor prognosis: TNS2 serves as a diagnostic biomarker for gastrointestinal stromal tumors, aberrant TNS1/TNS3 expression predicts metastasis risk, and TNS4 is recurrently embedded in multi-gene prognostic signatures. This review synthesizes their structural basis, regulatory mechanisms, and clinical relevance, highlighting context-dependent switches and TNS4’s therapeutic potential. Full article

There is growing interest in the application of Rho-associated protein kinase (ROCK) inhibitors (ROCKI) to the treatment of corneal diseases. ROCK is a key regulator of several cellular processes in the cornea, including cytoskeletal organization, cell proliferation, migration, inflammation, and wound healing. ROCKI, such as ripasudil and netarsudil, enhances endothelial cell migration, and promotes repair in conditions characterized by endothelial dysfunction. These agents also exert anti-inflammatory, anti-angiogenic, and anti-fibrotic effects for wound healing. As such, ROCKI demonstrate promise as therapeutic options for conditions such as Fuchs’ endothelial corneal dystrophy, pseudophakic bullous keratopathy, and iridocorneal endothelial syndrome. Emerging data further supports ROCKI’s potential in managing corneal neovascularization and supporting recovery following cataract surgery and keratoplasty, reducing the need for donor tissue. This narrative review provides a comprehensive evaluation of ROCKI’s mechanism of action, pharmacological properties, safety profile, applications in corneal disease management, emerging clinical trials, and novel approaches. We emphasize both preclinical and clinical findings, highlight existing evidence gaps, and outline future research priorities. Full article

Background: After recovery from acute sepsis, patients can exhibit left ventricular systolic dysfunction (LVSD) and non-ischaemic myocardial fibrosis. The relationship between myocardial fibrosis and LVSD remains poorly defined. This study sought to fill this knowledge gap using quantitative late gadolinium enhancement (LGE) cardiovascular magnetic resonance (CMR). Methods: Twenty-eight sepsis survivors underwent CMR at 1.5-Tesla for the assessment of cardiac volumes, systolic function and LGE. Myocardial fibrosis burden was derived quantitatively by LGE, expressed as a percentage of LV mass. Results: Study patients (age 51 ± 16 years; 57% males) had a median LVEF of 59% (IQR: 43–64) of whom 43% had LVSD (LV ejection fraction [LVEF] < 50%). LGE was found in 64% of the study patients by visual assessment, mostly in non-ischaemic patterns. The overall myocardial fibrosis burden was 3.3% (IQR: 0.9–7.1) of LV mass. Myocardial fibrosis burden was inversely correlated to LVEF in sepsis survivors (Rho = -0.385; p = 0.043). Patients with LVSD had greater myocardial fibrosis burden than patients without LVSD (7.3 ± 6.0% vs. 3.1 ± 2.5%; p = 0.041). Myocardial fibrosis burden was not significantly influenced by the presence of major co-morbidities. Conclusions: Myocardial fibrosis burden may play a role in LV dysfunction in sepsis survivors. Further work is needed to better understand its prognostic value. Full article

Small (monomeric) GTP-binding proteins (smgs; Cdc42 and Rac1) play requisite roles in islet beta cell function, including glucose-stimulated insulin secretion. In addition, emerging evidence suggests that sustained (constitutive) activation of smgs (e.g., Rac1) culminates in the genesis of islet beta cell dysfunction under the duress of chronic hyperglycemia. It is noteworthy that functions (i.e., activation–deactivation) of smgs in many cells, including the islet beta cell, have been shown to be under the regulatory control of at least three factors, namely the guanine nucleotide exchange factors (GEFs), the GTPase-activating proteins (GAPs), and the GDP-dissociation inhibitors (GDIs). The overall objective of this review is to highlight our current understanding of the regulatory roles of the RhoGDIβ-Rac1-CARD9 signalome in the pathology of beta cell dysfunction under chronic hyperglycemic stress. For brevity, this review is structured by an overview of smgs and their regulatory proteins/factors in the beta cell, followed by a discussion of potential roles of the RhoGDIβ-Rac1-CARD9 axis in the onset of cellular dysfunction under the duress of metabolic stress. Overall conclusions, potential knowledge gaps, and opportunities for future research in this field of islet biology are highlighted in the last section. Full article

Background/Objectives: Rho-associated coiled-coil-containing protein kinase inhibitors (ROCKis) have now become known as modulators of corneal endothelial wound repair and cell survival. However, evidence remains fragmented across laboratory and clinical reports. We performed a systematic review to synthesize preclinical and clinical data on ROCKis in corneal disease, assess their efficacy and safety, and identify research gaps. Methods: We searched PubMed, Web of Science, Scopus, and Google Scholar (until May 2025) for English-language original studies evaluating ROCKis in corneal models or patients. Inclusion criteria encompassed in vitro, ex vivo, in vivo, and clinical trials reporting functional outcomes (endothelial cell density, wound closure, visual acuity). Results: Thirty-one studies met criteria: 14 preclinical studies and 17 clinical studies. Preclinical models (rabbit, porcine, human explants) uniformly showed ROCKis (Y-27632, Ripasudil, Netarsudil, H-1152) accelerate corneal endothelial cell proliferation, migration, and restoration of a hexagonal monolayer with improved barrier and pump function over days to weeks. In 17 clinical investigations, topical Ripasudil or Netarsudil and cultured cell injections achieved significant corneal thinning, endothelial cell density and central corneal thickness changes, and visual acuity improvements (≥2 lines) with minimal adverse events. Overall bias was moderate in non-randomized studies and low in the RCTs. Conclusions: ROCKis demonstrate consistent pro-regenerative effects on corneal endothelium in multiple models and show promising clinical efficacy in Fuchs endothelial dystrophy and pseudophakic endothelial failure. Future work should explore novel delivery systems and larger controlled trials to optimize dosing, safety, and long-term outcomes. Full article

To support China’s “3060” dual carbon targets, this study quantitatively evaluates the spatial–temporal characteristics and influencing factors of carbon emission performance (CEP) across administrative levels. While prior research has examined CEP patterns, a systematic comparison of factor contributions at different levels—particularly from global and local perspectives—is lacking. This study addresses this gap by analyzing CEP in 31 provinces and 333 prefecture-level cities (2003–2020) using a coupling coordination degree model to measure CEP, spatial autocorrelation indices (Moran’s I) to assess global/local dependence, static/dynamic Spatial Durbin model (SDM/DSDM) with two-way fixed effects to compare global impacts, and geographically and temporally weighted regression (GTWR) to quantify spatiotemporal heterogeneity. The results show the following: (1) CEP showed consistent growth at both levels with positive spatial autocorrelation, revealing significantly richer clustering patterns at the prefectural rather than provincial level. (2) From a global perspective, influencing factors’ contributions to CEP vary significantly between levels. Provincially, dominant factors rank as time-lagged CEP(CEP_lag)> proportion of built-up land(P_built) > spatial lag of CEP(W×CEP) > fractional vegetation coverage (lnFVC); while prefecturally, CEP_lag > spatial error coefficient(rho) > W×CEP > P_built, with the proportion of secondary industry in GDP (GDP2)/proportion of tertiary industry in GDP (GDP3) gaining greater significance. (3) Local regression results reveal significant spatiotemporal heterogeneity in CEP influencing factors. lnFVC and W×CEP show the most distinct differences between levels, while land-use factors like P_built and nighttime light index (NTL) exhibit unstable spatiotemporal effects. The study underscores the need for scale-specific policies addressing spatial spillovers and local heterogeneity, providing actionable insights for China’s carbon mitigation strategies. Full article

Drosophila has provided a highly attractive model system for studying various tissue- and stage-specific processes as well as their pathologies, including a range of human diseases. The existence of a large number of diverse Gal4 drivers to precisely control the expression patterns of UAS transgenes simplifies such studies. However, the choice of driver is always critical, as its possible ectopic expression in non-target cells and tissues can directly impact the results. Therefore, it is very important to thoroughly characterize both the molecular nature and expression pattern of each Gal4 driver line. Here, we aim to fill such gaps regarding the AB1-Gal4 driver, which is typically used to express UAS transgenes in larval salivary glands. In this fly line, the P{GawB} enhancer trap construct encoding the Gal4 protein resides within overlapping evolutionary conserved spastin (spas) and Mitochondrial Rho (Miro) genes. Both these genes are expressed in a number of tissues, including the central nervous system (CNS), and their human orthologs are associated with neurodegenerative diseases. Consistently, we demonstrate that, in third-instar larvae, the expression pattern of AB1-Gal4 is also not restricted to salivary glands. We detect its activity in a subset of Elav-positive neurons in the CNS, including motor neurons, as well as in specific photoreceptor cells in eye discs. Full article

A Rho-GTPases are pivotal regulators of key cellular processes implicated in colorectal cancer (CRC) progression, yet the roles of their regulatory proteins, particularly GTPase-activating proteins (GAPs), remain poorly understood. This study focuses on β2-chimaerin, a Rac1-specific GAP, in Apc-driven tumorigenesis using the ApcMin/+ mouse model. We demonstrate that β2-chimaerin deficiency selectively promotes the growth of colonic polyps without influencing small intestinal polyp formation. Mechanistically, β2-chimaerin loss is associated with enhanced ERK phosphorylation, while canonical Wnt/β-catenin and E-cadherin pathways remain unaffected, suggesting its specific involvement in modulating proliferative signaling in the colon. Consistent with its tumor-suppressive role, bioinformatics analyses reveal that low β2-chimaerin expression correlates with poor prognosis in CRC patients. This study expands the understanding of Rho-GTPase regulatory mechanisms in intestinal tumorigenesis, providing a basis for future therapeutic strategies targeting Rho-GTPase pathways in CRC. Full article

Background and Objectives: Understanding the knowledge and dietary patterns of type 2 diabetes mellitus (T2DM) patients is essential to identify gaps and design tailored health education strategies to improve self-management and clinical outcomes. We assessed the diabetes-related dietary patterns, knowledge, and associated factors of T2DM patients. Methods: The study utilized a cross-sectional design, surveying 363 T2DM patients using a validated and pretested questionnaire. Knowledge levels were categorized as low (<50%), medium (50–75%), and high (>75%), and dietary patterns were classified as unhealthy (<34%), moderately healthy (34–67%), and healthy (>67%). We analyzed the data using the Statistical Package for the Social Sciences (SPSS, version 23.0). The authors tested the relationship between diabetes-related dietary patterns and knowledge with Spearman’s analysis. The multivariate regression approach established the factors associated with these two components. Results: The findings revealed that 36.4% of participants had low knowledge, 34.4% had medium knowledge, and only 29.2% demonstrated high knowledge. Regarding dietary patterns, 34.4% were categorized as unhealthy, 33.3% as moderately healthy, and 32.3% as healthy. The authors found that these two domains were positively correlated (rho = 0.649, p = 0.001). Diabetes-related knowledge was significantly associated with gender (p = 0.018), duration of diabetes (p = 0.001), and patients with a family history of T2DM (p = 0.007). The dietary pattern was significantly associated with age (p = 0.001), duration of diabetes (p = 0.032), and presence of other chronic diseases (p = 0.028). Conclusions: The findings underscore the need for targeted health education strategies that address gaps in dietary knowledge and promote healthier eating behaviors among T2DM patients in Central Saudi Arabia. Full article