Search Results (1,754)

The kallikrein–kinin system and its B1 and B2 receptors are key regulators in metabolic disorders such as obesity, diabetes, and insulin resistance. Obesity, a chronic and multifactorial condition often associated with comorbidities like type 2 diabetes and dyslipidemia, remains poorly understood at the metabolic level. The kinin B2 receptor (B2R) is involved in blood pressure regulation and glucose metabolism, promoting glucose uptake in skeletal muscle via bradykinin. Studies in B2R-KO mice demonstrate that the absence of this receptor predisposes animals to glucose intolerance under a high-fat diet and impairs adaptive thermogenesis, indicating a protective role for B2R in metabolic homeostasis and insulin sensitivity. In contrast, the kinin B1 receptor (B1R) is inducible under pathological conditions and is activated by kinin metabolites. Mouse models lacking B1R exhibit improved metabolic profiles, including protection against high-fat diet-induced obesity and insulin resistance, enhanced energy expenditure, and increased leptin sensitivity. B1R inactivation in adipocytes enhances insulin responsiveness and glucose tolerance, supporting its role in the development of insulin resistance. Moreover, B1R deficiency improves energy metabolism and thermogenic responses to adrenergic and cold stimuli, promoting the activation of brown adipose tissue and the browning of white adipose tissue. Collectively, these findings suggest that B1R and B2R represent promising therapeutic targets for the treatment of metabolic disorders. Full article

Partial cystectomy is a surgical bladder-sparing option for selected patients with muscle-invasive bladder cancer (MIBC), urachal adenocarcinoma and diverticular bladder tumors. Partial cystectomy hold several advantages. It allows for definite pathology and accurate staging while avoiding side effects from radiation therapy and preserves the option for salvage radical therapy (radical cystectomy or radical radiotherapy). Patients should have a CT urogram, prostatic urethral biopsy and mapping biopsies or blue light cystoscopy to rule out multifocal disease or CIS. Small solitary MIBC patients without carcinoma in situ in an area of the bladder where resection can be performed with negative margin would be the ideal candidates for partial cystectomy. Neoadjuvant systemic therapy is recommended for patients undergoing partial cystectomy. Partial cystectomy can be performed either by open or robotic approaches. When compared to radical cystectomy, partial cystectomy affords a lower complication rate and length of stay and better quality of life. Recurrence-free survival, cancer-specific survival and overall survival at 5 years is 39–67%, 62–84% and 45–70%, respectively. Following partial cystectomy, patients should have three monthly cystoscopy and urinary cytology for the first 24 months followed by 6-monthly cystoscopy for year 3 and 4 and then yearly for life. Cross-sectional imaging should be performed every 3–6 months for the first 2–3 years and then annually for 5 years. Full article

Background and Objectives: Acute metastatic cord compression (AMSCC) and femoral impending/pathological fracture negatively impact a patient’s quality of life, morbidity and survival, and are considered significant life events. This study aims to compare AMSCC and FMD as distinct yet overlapping metastatic orthopedic emergencies, addressing whether they represent sequential disease stages or distinct patient subpopulations—an analysis critical for prognosis and treatment planning. Materials and Methods: Records of all patients who underwent surgery for a femoral metastatic disease (FMD) over a decade (2004–2015) and patients who were treated for acute metastatic spinal compression (AMSCC) (2007–2017) were retrieved. There were no patients lost to follow-up. Results: The treatment cohorts were similar in terms of age, gender, tumour origin, and the number of spinal metastases. Fifty-four patients were diagnosed with AMSCC. Following treatment, the Frankel muscle grading improved by 0.5 ± 0.8 grades. Two hundred and eighteen patients underwent surgical intervention for FMD. Seventy percent of femoral metastases were located in the femoral neck and trochanteric area. Impending fractures accounted for 52% of the cohort. The FMD cohort, including impending and pathological fractures, was similar to the AMSCC cohort in terms of age and the time interval between cancer diagnosis and surgery (56.7 ± 74.2 vs. 51.6 ± 69.6, respectively, p = 0.646). The Karnofsky functional score was higher for the FMD cohort (63.3 ± 16.2) than for the AMSCC cohort (48.5 ± 19.5; p < 0.001). The mean survival time for the FMD cohort was double that of the AMSCC, at 18.4 ± 23.5 months versus 9.1 ± 13.6 months, respectively (p = 0.006). Conclusions: In conclusion, this study is novel in proposing that FMD and AMSCC are distinct clinical entities, differing in their impact on patient function and, most importantly, on patient survival. Full article

Background/Objectives: Since breast cancer (BC) survival rates have increased to 91% at 5 years and 80% at 15 years postdiagnosis, there is a growing awareness of the importance of addressing the long-term well-being of patients. Consequently, integrative oncology, which combines standard therapies with complementary approaches (nutrition, mind–body practices, and lifestyle modifications), has emerged as a patient-centred model aimed at improving symptom management, treatment adherence, and overall quality of life (QoL). This study aims to demonstrate how integrative therapies can benefit body composition, phase angle, and fluid and electrolyte balance through bioelectrical impedance analysis (BIA). Methods: This study considers a patient who underwent BC surgery and was enrolled in the AMICO clinic for anamnesis, as well as their oncological pathology data, assessment of QoL, and BIA. The breast surgeon specialising in integrative oncology therapies prescribed the patient curcumin and polydatin, moderate physical activity, a balanced diet, and Qigong sessions. The patient underwent monitoring through haematochemical analysis, BIA, and a QoL questionnaire, with follow-up every four months. Results: Between 4 and 12 months, fat mass (FM) and body mass index (BMI) markedly decreased, whereas fat-free mass (FFM), total body water (TBW), and skeletal muscle mass (SMM) increased progressively. Moreover, the improvements in the Na/K ratio and phase angle (PhA) suggest a shift toward better electrolyte and fluid balance and enhanced cellular integrity and membrane function. Equally outstanding were her psychological benefits in terms of mood, sleep, anxiety, and melancholy. Conclusions: Patient progress in body composition, metabolic function, pain management, and psychological status measured during the 12-month follow-up demonstrates the potential benefits of an integrative approach to supportive cancer care. Full article

Quadricep weakness is frequently observed in patients following anterior cruciate ligament (ACL) injury or in those with knee osteoarthritis, often contributing to functional impairments and persistent symptoms. While high-intensity resistance training has been shown to effectively improve muscle strength, its application may be limited in certain populations due to pain or the risk of surgical complications. In recent years, blood flow restriction (BFR) training has emerged as a promising alternative. Growing evidence indicates that low-load BFR exercise can significantly improve muscle strength, induce hypertrophy, and enhance knee function, with outcomes comparable to those of high-intensity resistance training. When implemented using appropriate protocols, BFR training appears to be a safe and efficacious rehabilitation strategy for individuals with knee pathology. Full article

Prolactin (PRL) is a hormone primarily associated with lactation, but it plays various roles in both men and women. PRL belongs to the family of peptide hormones, including placental lactogen and growth hormone. Interestingly, PRL is a pleiotropic hormone affecting several physiological and pathological conditions, including fertility. Moreover, several pathophysiological roles have been associated with this hormone, including those of the immune system, autoimmune disorders, asthma, and ageing. Additionally, PRL receptors are ubiquitously expressed in tissues, including the mammary gland, gonads, liver, kidney, adrenal gland, brain, heart, lungs, pituitary gland, uterus, skeletal muscle, skin blood cells, and immune system. Therefore, in the present paper, we cover the potential role that PRL may play in asthma by promoting inflammation and modulating immune responses. The detection of its receptor in lung tissue suggests a direct role in airway smooth muscle contractility through activation of signaling pathways such as JAK2-STAT5, MAPK/ERK1/2, and PI3K/Akt, as well as influencing ionic currents that regulate cell contraction, proliferation, and survival. In this sense, this review aims to explore the potential involvement of PRL in asthma pathophysiology by examining its interactions with intracellular signaling pathways and its possible impact on airway smooth muscle contractility and immune modulation. Full article

Plant-derived extracellular vesicles (PDEVs) are nanoscale, phospholipid bilayer-enclosed vesicles secreted by living cells through cytokinesis under physiological and pathological conditions. Owing to their high biocompatibility and stability, PDEVs have attracted considerable interest in regenerative medicine applications. They can exhibit the capacity to enhance cellular proliferation, migration, and multi-lineage differentiation through immunomodulation, anti-inflammation effects, antioxidative protection, and tissue regeneration mechanisms. Given their abundant availability, favorable safety profile, and low immunogenicity risks, PDEVs have been successfully employed in therapeutic interventions for skeletal muscle disorders, cardiovascular diseases, neurodegenerative conditions, and tissue regeneration applications. This review mainly provides a comprehensive overview of PDEVs, systematically examining their biological properties, standardized isolation and characterization methodologies, preservation techniques, and current applications in regenerative medicine. Furthermore, we critically discuss future research directions and clinical translation potential, aiming to facilitate the advancement of PDEV-based therapeutic strategies. Full article

Prolonged high-dose administration of synthetic glucocorticoids (GCs) leads to limb muscle atrophy and weakness, yet its underlying mechanisms remain incompletely understood. Muscle fibers and muscle satellite cells (MSCs) are essential for skeletal muscle development and associated pathologies. This study demonstrates that dexamethasone (Dex) induced MSC-derived extracellular vesicles (EVs) impair myogenesis in muscle fiber-like cells (MFLCs) via inducible nitric oxide synthase (iNOS) suppression. High-throughput sequencing revealed a marked upregulation of miR-335-5p in MSC-derived EVs following Dex treatment. Mechanistically, EV miR-335-5p targeted MAPK11, leading to iNOS downregulation and subsequent UPS activation in MFLCs, which directly promoted muscle protein degradation. Collectively, our findings identify the EV miR-335-5p/MAPK11/iNOS axis as a critical mediator of GC-induced muscle atrophy, offering novel insights into therapeutic strategies targeting EV-mediated signaling in muscle wasting disorders. Full article

Background/Objectives: In non-muscle-invasive bladder cancer (NMIBC), the decision for immediate postoperative single-dose intravesical chemotherapy (SI) is based on clinical and presumed pathological features, as a definitive pathology is unknown at the time of surgery. This study aims to assess how accurately urologists can predict the pathological features of bladder tumors based solely on cystoscopic appearance and evaluate their ability to identify patients eligible for SI. Methods: A total of 104 patients with bladder masses were included. Seven senior urologists and four residents participated. Before transurethral resection, both groups predicted tumor stage, grade, and the presence of carcinoma in situ (CIS). Resident predictions were collected for all 104 patients, while senior predictions were collected for 72 patients. Based on these predictions, patient eligibility for SI was determined according to the EAU NMIBC guidelines. After final pathology reports, risk scores were recalculated and compared with the surgeons’ predictions. Cohen’s Kappa (κ) coefficient was used to assess agreement between predictions and pathology. Positive and negative predictive values were also calculated for both groups. Results: Strong agreement with final pathology could not be demonstrated for stage, grade, or CIS for either group. Urology residents’ predictions were slightly more accurate than those of senior urologists. Overall, 19.4% (14/72) (based on senior urologists’ predictions) and 18.2% (19/104) (based on resident predictions) of patients were misclassified and either overtreated or undertreated. Conclusions: Cystoscopic visual prediction alone is insufficient for determining eligibility for immediate postoperative intravesical chemotherapy, regardless of the urologist’s experience. More objective criteria are needed to improve the selection of appropriate patients for SI. Full article

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that primarily affects motor neurons, leading to loss of muscle control, and, ultimately, respiratory failure and death. Despite some advances in recent years, the underlying genetic and molecular mechanisms of ALS remain largely elusive. In this respect, a better understanding of these mechanisms is needed to identify new and biologically relevant therapeutic targets that could be developed into treatments that are truly disease-modifying, in that they address the underlying causes rather than the symptoms of ALS. In this study, we used two approaches to model multi-omics data in order to map and elucidate the genetic and molecular mechanisms involved in ALS, i.e., the molecular landscape building approach and the Patrimony platform. These two methods are complementary because they rely upon different omics data sets, analytic methods, and scoring systems to identify and rank therapeutic target candidates. The orthogonal combination of the two modeling approaches led to significant convergences, as well as some complementarity, both for validating existing therapeutic targets and identifying novel targets. As for validating existing targets, we found that, out of 217 different targets that have been or are being investigated for drug development, 10 have high scores in both the landscape and Patrimony models, suggesting that they are highly relevant for ALS. Moreover, through both models, we identified or corroborated novel putative drug targets for ALS. A notable example of such a target is MATR3, a protein that has strong genetic, molecular, and functional links with ALS pathology. In conclusion, by using two distinct and highly complementary disease modeling approaches, this study enhances our understanding of ALS pathogenesis and provides a framework for prioritizing new therapeutic targets. Moreover, our findings underscore the potential of leveraging multi-omics analyses to improve target discovery and accelerate the development of effective treatments for ALS, and potentially other related complex human diseases. Full article

Parathyroid hormone (PTH) has been studied to determine its broader role in musculoskeletal health, particularly its effects on skeletal muscle. Bone and muscle are inextricably linked via mechanical loading and biochemical signaling, with both processes playing important roles in muscular metabolism and function. Furthermore, the nervous system must maintain muscle mass and function, as neuromuscular transmission controls muscle contraction, protein synthesis, and energy metabolism. As a systemic endocrine regulator, PTH influences the physiology of skeletal muscle—both directly and through interactions with bone and the nervous system, modulating myokines, osteokines, and neuromuscular activity. The intricate relationships between PTH, muscle, bone, and nerves continue to be investigated due to their implications for aging, metabolic pathologies, and musculoskeletal disorders. Full article

Protein association and aggregation are fundamental processes that play critical roles in a variety of biological phenomena from cell signaling to the development of incurable diseases, including amyloidoses. Understanding the basic biophysical principles governing protein aggregation processes is of crucial importance for developing treatment strategies for diseases associated with protein aggregation, including sarcopenia, as well as for the treatment of pathological processes associated with the disruption of functional protein complexes. This work, using a set of methods such as atomic force microscopy (AFM), transmission electron microscopy (TEM), Fourier transform infrared spectroscopy (FTIR), and X-ray diffraction, as well as bioinformatics analysis, investigated the structures of complexes formed by titin and myosin-binding protein C (MyBP-C). TEM revealed the formation of morphologically ordered aggregates in the form of beads during co-incubation of titin and MyBP-C under close-to-physiological conditions (175 mM KCl, pH 7.0). AFM showed the formation of a relatively homogeneous film with local areas of relief change. Fluorimetry with thioflavin T, as well as FTIR spectroscopy, revealed signs of an amyloid-like structure, including a signal in the cross-β region. X-ray diffraction showed the presence of a cross-β structure characteristic of amyloid aggregates. Such structural features were not observed in the control samples of the investigated proteins separately. In sarcomeres, these proteins are associated with each other, and this interaction plays a partial role in the formation of a strong sarcomeric cytoskeleton. We found that under physiological ionic-strength conditions titin and MyBP-C form complexes in which an amyloid-like structure is present. The possible functional significance of amyloid-like aggregation of these proteins in muscle cells in vivo is discussed. Full article

Echovirus 18, a member of the B group of enteroviruses, is a significant etiological agent of aseptic meningitis and viral encephalitis in children. In this study, we investigated the pathogenicity of E18 by establishing a mouse infection model after comparing various mouse strains and injection methods. Two-day-old IFNAR1 knockout mice infected with clinical isolates of E18 exhibited symptoms such as lethargy, hind limb paralysis, and even mortality. Similarly, some two-day-old C57BL/6J mice displayed comparable symptoms; however, the incidence was lower than that observed in IFNAR1 knockout mice. No similar symptoms were noted in any Balb/c mice. Significant pathological changes were observed in skeletal muscle, brain tissue, and other organs of symptomatic mice; among these tissues, skeletal muscle demonstrated the highest viral load. The established infection model using two-day-old IFNAR1 knockout mice provides valuable insights into further investigations regarding its pathological injury mechanisms as well as the protective effects conferred by antibodies. Full article

Background/Objectives: Given the multifaceted role of estrogen hormones in skeletal muscle pathophysiology and their well-established immunomodulatory properties, this study aimed to characterize the expression of the G-protein-coupled estrogen receptor (GPER) in patients with inflammatory myopathies (IM). Methods: Immunohistochemical analysis was performed on muscle biopsies from 13 patients with IM, 11 with non-inflammatory myopathies (N.IM), and 5control subjects. Intergroup differences in GPER score were statistically evaluated. We performed an analysis based on the Visual Analog Scale (VAS). The scoring system evaluates overall pathology (VAS score) based on four distinct components: inflammation, vascular involvement, myopathic changes, and connective tissue alterations. Results: Immunolocalization analysis demonstrated that GPER is constitutively expressed in human skeletal muscle and is upregulated in IM. Enhanced expression included both sarcolemmal and intracellular membrane localization. Notably, GPER upregulation showed a positive correlation with the severity of tissue inflammation. The IM group had significantly higher VAS scores compared to both the N.IM and control groups. Conclusions: We provide the first histopathological characterization of GPER expression in human skeletal muscle. In IM, GPER upregulation may play a protective role by negatively modulating the release of inflammatory mediators, as suggested by experimental evidence from other models of inflammation. The emerging therapeutic development of GPER agonists may represent a promising avenue for the treatment of inflammatory myopathies. Full article

Atherosclerosis constitutes a pathological process underlying cardiovascular diseases. There is growing evidence that IGFBP5 is a causative factor, although the conclusions of different studies are inconsistent. The present study aims to confirm the role and mechanism of IGFBP5 in atherosclerosis. The expression of IGFBP5 was induced in the skeletal muscle of male ApoE^−/− mice, an atherosclerosis model, using adeno-associated virus, resulting in elevated circulating IGFBP5 levels. Changes in blood lipids were detected, and pathological changes in the aorta were observed. Analysis of IGFBP5 function using RNA sequencing and validation were performed in a mouse aortic smooth muscle cell line. The results demonstrated that IGFBP5 overexpression exacerbated the development of aortic lesions in this murine models without any discernible alterations in lipid profile parameters; the arterial transcriptomic landscape revealed that heightened IGFBP5 levels predominantly influenced pathways governing smooth muscle cell proliferation and motility. In vitro experimentation corroborated these findings, showcasing the stimulatory effect of IGFBP5 on VSMC (vascular smooth muscle cell) proliferation and migration, provoking a transition toward a proliferative phenotype. IGFBP5 promotes atherosclerosis in ApoE^−/− mice through the phenotypic transformation of VSMCs. This finding suggests that IGFBP5 has the potential to serve as an indicator of atherosclerosis diagnosis and a target for therapeutic interventions in the future. Full article