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The Turkish Journal of Pediatrics May 2024Hyaline fibromatosis syndrome is a rare autosomal recessive disorder caused by ANTXR2 pathogenic variants. The disorder is characterized by the deposition of amorphous...
BACKGROUND
Hyaline fibromatosis syndrome is a rare autosomal recessive disorder caused by ANTXR2 pathogenic variants. The disorder is characterized by the deposition of amorphous hyaline material in connective tissues. The hallmarks of the disease are joint contractures, generalized skin stiffness, hyperpigmented papules over extensor surfaces of joints, fleshy perianal masses, severe diarrhea, and gingival hypertrophy. The severity of the disease varies and prognosis is poor. No specific treatment is yet available. Most patients with the severe form of the condition pass away before the second year of age. In this study, we describe the clinical and molecular findings of a cohort of seven hyaline fibromatosis syndrome patients who were diagnosed and followed up at a single tertiary reference center in Turkey.
METHODS
Genomic DNA was extracted by standard salting out method from peripheric blood samples of three patients. In one patient DNA extraction was performed on pathology slides since peripheric blood DNA was not available. All coding exons of the ANTXR2 were amplified and sequenced on ABI Prism 3500 Genetic Analyser.
RESULTS
Sanger sequencing was performed in 3 patients and homozygous c.945T>G p.(Cys315Trp), c.1073dup p.(Ala359CysfsTer13), and c.1074del p.(Ala359HisfsTer50) variants were identified in ANTXR2. All patients passed away before the age of five years.
CONCLUSIONS
HFS is a rare, progressive disorder with a broad phenotypic spectrum. HFS can be recognized easily with distinctive clinical features. Nevertheless, it has poor prognosis with increased mortality due to severe clinical decompensation.
Topics: Humans; Hyaline Fibromatosis Syndrome; Male; Female; Infant; Child, Preschool; Receptors, Peptide; Turkey; Child
PubMed: 38814306
DOI: 10.24953/turkjpediatr.2024.4511 -
Arteriosclerosis, Thrombosis, and... May 2024Pulmonary hypertension (PH) represents an important phenotype in heart failure with preserved ejection fraction (HFpEF). However, management of PH-HFpEF is challenging...
BACKGROUND
Pulmonary hypertension (PH) represents an important phenotype in heart failure with preserved ejection fraction (HFpEF). However, management of PH-HFpEF is challenging because mechanisms involved in the regulation of PH-HFpEF remain unclear.
METHODS
We used a mass spectrometry-based comparative plasma proteomics approach as a sensitive and comprehensive hypothesis-generating discovery technique to profile proteins in patients with PH-HFpEF and control subjects. We then validated and investigated the role of one of the identified proteins using in vitro cell cultures, in vivo animal models, and independent cohort of human samples.
RESULTS
Plasma proteomics identified high protein abundance levels of B2M (β2-microglobulin) in patients with PH-HFpEF. Interestingly, both circulating and skeletal muscle levels of B2M were increased in mice with skeletal muscle SIRT3 (sirtuin-3) deficiency or high-fat diet-induced PH-HFpEF. Plasma and muscle biopsies from a validation cohort of PH-HFpEF patients were found to have increased B2M levels, which positively correlated with disease severity, especially pulmonary capillary wedge pressure and right atrial pressure at rest. Not only did the administration of exogenous B2M promote migration/proliferation in pulmonary arterial vascular endothelial cells but it also increased PCNA (proliferating cell nuclear antigen) expression and cell proliferation in pulmonary arterial vascular smooth muscle cells. Finally, deletion improved glucose intolerance, reduced pulmonary vascular remodeling, lowered PH, and attenuated RV hypertrophy in mice with high-fat diet-induced PH-HFpEF.
CONCLUSIONS
Patients with PH-HFpEF display higher circulating and skeletal muscle expression levels of B2M, the magnitude of which correlates with disease severity. Our findings also reveal a previously unknown pathogenic role of B2M in the regulation of pulmonary vascular proliferative remodeling and PH-HFpEF. These data suggest that circulating and skeletal muscle B2M can be promising targets for the management of PH-HFpEF.
PubMed: 38813697
DOI: 10.1161/ATVBAHA.123.320270 -
Frontiers in Physiology 2024Vasodilatation in response to NO is a fundamental response of the vasculature, and during aging, the vasculature is characterized by an increase in stiffness and...
Vasodilatation in response to NO is a fundamental response of the vasculature, and during aging, the vasculature is characterized by an increase in stiffness and decrease in sensitivity to NO mediated vasodilatation. Vascular tone is regulated by the activation of smooth muscle and nonmuscle (NM) myosin, which are regulated by the activities of myosin light chain kinase (MLCK) and MLC phosphatase. MLC phosphatase is a trimeric enzyme with a catalytic subunit, myosin targeting subunit (MYPT1) and 20 kDa subunit of unknown function. Alternative mRNA splicing produces LZ+/LZ- MYPT1 isoforms and the relative expression of LZ+/LZ- MYPT1 determines the sensitivity to NO mediated vasodilatation. This study tested the hypothesis that aging is associated with changes in LZ+ MYPT1 and NM myosin expression, which alter vascular reactivity. We determined MYPT1 and NM myosin expression, force and the sensitivity of both endothelial dependent and endothelial independent relaxation in tertiary mesenteric arteries of young (6mo) and elderly (24mo) Fischer344 rats. The data demonstrate that aging is associated with a decrease in both the expression of NM myosin and force, but LZ+ MYPT expression and the sensitivity to both endothelial dependent and independent vasodilatation did not change. Further, smooth muscle cell hypertrophy increases the thickness of the medial layer of smooth muscle with aging. The reduction of NM myosin may represent an aging associated compensatory mechanism to normalize the stiffness of resistance vessels in response to the increase in media thickness observed during aging.
PubMed: 38808359
DOI: 10.3389/fphys.2024.1411420 -
BMC Musculoskeletal Disorders May 2024It was reported the paraspinal muscle played an important role in spinal stability. The preoperative paraspinal muscle was related to S1 screw loosening. But the...
BACKGROUND
It was reported the paraspinal muscle played an important role in spinal stability. The preoperative paraspinal muscle was related to S1 screw loosening. But the relationship between preoperative and postoperative change of psoas major muscle (PS) and S1 pedicle screw loosening in degenerative lumbar spinal stenosis (DLSS) patients has not been reported. This study investigated the effects of preoperative and follow-up variations in the psoas major muscle (PS) on the first sacral vertebra (S1) screw loosening in patients with DLSS.
METHODS
212 patients with DLSS who underwent lumbar surgery were included. The patients were divided into the S1 screw loosening group and the S1 screw non-loosening group. Muscle parameters were measured preoperatively and at last follow-up magnetic resonance imaging. A logistic regression analysis was performed to investigate the risk factors for S1 screw loosening.
RESULTS
The S1 screw loosening rate was 36.32% (77/212). The relative total cross-sectional areas and relative functional cross-sectional areas (rfCSAs) of the PS at L2-S1 were significantly higher after surgery. The increased rfCSA values of the PS at L3-S1 in the S1 screw non-loosening group were significantly higher than those in the S1 screw loosening group. The regression analysis showed male, lower CT value of L1 and longer segment fusion were independent risk factors for S1 screw loosening, and postoperative hypertrophy of the PS was a protective factor for S1 screw loosening.
CONCLUSIONS
Compared to the preoperative muscle, the PS size increased and fatty infiltration decreased after surgery from L2-3 to L5-S1 in patients with DLSS after short-segment lumbar fusion surgery. Postoperative hypertrophy of the PS might be considered as a protective factor for S1 screw loosening. MRI morphometric parameters and postoperative selected exercise of PS for DLSS patients after posterior lumbar fusion surgery might contribute to improvement of surgical outcome.
Topics: Humans; Male; Spinal Stenosis; Female; Lumbar Vertebrae; Aged; Psoas Muscles; Middle Aged; Follow-Up Studies; Spinal Fusion; Pedicle Screws; Magnetic Resonance Imaging; Sacrum; Retrospective Studies; Risk Factors; Aged, 80 and over; Preoperative Period
PubMed: 38807200
DOI: 10.1186/s12891-024-07298-0 -
Journal of Functional Morphology and... May 2024Lean body mass (LBM) is correlated with powerlifting performance in athletes competing in different bodyweight classes. However, it remains unknown whether changes in...
Lean body mass (LBM) is correlated with powerlifting performance in athletes competing in different bodyweight classes. However, it remains unknown whether changes in LBM are correlated with performance changes in powerlifters preparing for a competition. The aim of this study was to investigate the changes in LBM and performance in powerlifters preparing for a competition. Eight male powerlifters (age 31.7 ± 9.8 years, height 1.77 ± 0.06 m, weight 99.2 ± 14.6 kg) and three female powerlifters (age 32.7 ± 16.3 years, height 1.54 ± 0.06 m, weight 66.6 ± 20.9 kg) participated in the study. The athletes followed individualized periodized training programs for 12 weeks, aiming to maximize their performance for the national championship. The maximum strength (1-RM) in the squat, bench press, and deadlift, body composition, handgrip strength, anaerobic power, quadriceps' cross-sectional area and vastus lateralis muscle architecture were measured before and after the training period. Significant increases were found after the training period in the squat (5.8 ± 7.0%, < 0.05), bench press (4.9 ± 9.8%, = 0.05) and deadlift (8.3 ± 16.7%, < 0.05). Significant correlations were found between the 1-RM and LBM before and after the training period (r > 0.75, < 0.05). The changes in the 1-RM after the training intervention correlated with the changes in the total LBM ( < 0.05). These results suggest that individual changes in LBM due to systematic resistance training for a competition may dictate increases in the 1-RM strength in powerlifters.
PubMed: 38804455
DOI: 10.3390/jfmk9020089 -
Scientific Reports May 2024Previous investigations have highlighted notable variations in cardiovascular risk indicators associated with various professional categories. However, only a few...
Previous investigations have highlighted notable variations in cardiovascular risk indicators associated with various professional categories. However, only a few studies have examined structural and functional cardiac parameters using echocardiography within distinct occupational groups. Hence, this study endeavored to assess cardiac structural and functional parameters in three additional occupations: firefighters (FFs), police officers (POs), and office workers (OWs). This prospective study encompassed 197 male participants (97 FFs, 54 POs, and 46 OWs) from Germany. All participants underwent 2D and Doppler echocardiography in resting conditions; standard parasternal and apical axis views were employed to evaluate structural (diastolic and systolic) and functional (systolic and diastolic function, and strain) cardiac parameters. All three occupational groups exhibited a tendency towards septal hypertrophy. Notably, OWs exhibited the largest diastolic interventricular septum diameter (IVSd), at 1.33 ± 0.25 cm. IVSd significantly varied between POs and OWs (p = 0.000) and between POs and FFs (p = 0.025). Additionally, during diastole a substantially larger left ventricular posterior wall diameter (LVPWd) was observed in OWs compared to FFs (p = 0.001) and POs (p = 0.013). The left ventricular diastolic cavity diameter (LVIDd) and the left ventricular systolic cavity diameter (LVIDs) were significantly higher in POs than they were in FFs (LVIDd: p = 0.001; LVIDs: p = 0.009), and the LVIDd was notably higher in FFs (p = 0.015) and POs compared to OWs (p = 0.000). FFs exhibited significantly better diastolic function, indicated by higher diastolic peak velocity ratios (MV E/A ratio) and E/E' ratios, compared to POs (E/A ratio: p = 0.025; E/E' ratio: p = 0.014). No significant difference in diastolic performance was found between OWs and FFs. Significantly higher E'(lateral) values were noted in POs compared to FFs (p = 0.003) and OWs (p = 0.004). Ejection fraction did not significantly differ among FFs, POs, and OWs (p > 0.6). The left ventricular mass (LV Mass) was notably higher in POs than it was in FFs (p = 0.039) and OWs (p = 0.033). Strain parameter differences were notably improved in two- (p = 0.006) and four-chamber (p = 0.018) views for FFs compared to POs. Concentric remodeling was the predominant change observed in all three occupational groups. Significant differences in the presence of various forms of hypertrophy were observed in FFs, POs, and OWs (exact Fisher test p-values: FFs vs. OWs = 0.021, POs vs. OWs = 0.002). OWs demonstrated notably higher rates of concentric remodeling than FFs did (71.77% vs. 47.9%). This study underscores disparities in both functional and structural parameters in diverse occupational groups. Larger prospective studies are warranted to investigate and delineate differences in structural and functional cardiac parameters across occupational groups, and to discern their associated effects and risks on the cardiovascular health of these distinct professional cohorts.
Topics: Humans; Male; Cross-Sectional Studies; Adult; Middle Aged; Prospective Studies; Echocardiography; Echocardiography, Doppler; Firefighters; Heart Ventricles; Germany; Occupations; Diastole; Police; Heart; Workplace; Ventricular Function, Left; Working Conditions
PubMed: 38802474
DOI: 10.1038/s41598-024-62190-0 -
Experimental and Therapeutic Medicine Jul 2024Osteoarthritis (OA) is a disease of the joints, characterized by chronic inflammation, cartilage destruction and extracellular matrix (ECM) remodeling. Aberrant...
Osteoarthritis (OA) is a disease of the joints, characterized by chronic inflammation, cartilage destruction and extracellular matrix (ECM) remodeling. Aberrant chondrocyte hypertrophy promotes cartilage destruction and OA development. Collagen X, the biomarker of chondrocyte hypertrophy, is upregulated by runt-related transcription factor 2 (Runx2), which is mediated by the bone morphogenetic protein 4 (BMP4)/Smad1 signaling pathway. BMP binding endothelial regulator (BMPER), a secreted glycoprotein, acts as an agonist of BMP4. 5,7,3',4'-tetramethoxyflavone (TMF) is a natural flavonoid derived from L. Results of our previous study demonstrated that TMF exhibits chondroprotective effects against OA development through the activation of Forkhead box protein O3a (FOXO3a) expression. However, whether TMF suppresses chondrocyte hypertrophy through activation of FOXO3a expression and inhibition of BMPER/BMP4/Smad1 signaling remains unknown. Results of the present study revealed that TMF inhibited collagen X and Runx2 expression, inhibited BMPER/BMP4/Smad1 signaling, and activated FOXO3a expression; thus, protecting against chondrocyte hypertrophy and OA development. However, BMPER overexpression and FOXO3a knockdown impacted the protective effects of TMF. Thus, TMF inhibited chondrocyte hypertrophy in OA cartilage through mediating the FOXO3a/BMPER signaling pathway.
PubMed: 38800044
DOI: 10.3892/etm.2024.12571 -
Iranian Journal of Basic Medical... 2024Right ventricular hypertrophy (RVH) often results in failure of the right ventricle or even the left ventricle. Rosmarinic acid (RA), a natural polyphenol, is commonly...
Rosmarinic acid ameliorates the complications of monocrotaline-induced right ventricular hypertrophy on the left ventricle: Investigating the signaling pathway of Wnt/β-catenin in the heart.
OBJECTIVES
Right ventricular hypertrophy (RVH) often results in failure of the right ventricle or even the left ventricle. Rosmarinic acid (RA), a natural polyphenol, is commonly found in Boraginaceae species and some species of ferns and hornworts. This study looked at how RA affects oxidative stress and left ventricular hemodynamic functions as well as RVH in monocrotaline (MCT) induced RVH model rats.
MATERIALS AND METHODS
To cause RVH, MCT (60 mg/kg) was intraperitoneally (IP) injected. Rats were given saline or RA (10, 15, and 30 mg/kg, gavage, over 21 days). In anesthetized rats, the lead II electrocardiogram was recorded. The hemodynamic functions of the isolated heart were measured using the Langendorff apparatus (at constant pressure). Investigations were made into the right ventricular hypertrophy index (RVHI), the activities of superoxide dismutase, catalase, glutathione, and Wnt and β-catenin gene expressions in the left ventricle. H&E staining was used.
RESULTS
A significant decline in electrocardiogram parameters and anti-oxidant enzyme activities, an increase in QTc (Q-T corrected) intervals, MDA (Malondialdehyde), RVHI, and Wnt/β-catenin gene expression, and also significant changes in the hemodynamic parameters were demonstrated in the MCT group. RA improved the above-mentioned factors.
CONCLUSION
According to the findings, RA may act as a cardioprotective agent against cardiovascular complications brought on by RVH due to its capacity to boost the activity of cardiac anti-oxidant enzymes and decrease the expression of genes involved in vascular calcification.
PubMed: 38800027
DOI: 10.22038/IJBMS.2024.75201.16301 -
Autophagy inhibitor 3-methyladenine attenuates renal injury in streptozotocin-induced diabetic mice.Iranian Journal of Basic Medical... 2024To investigate whether 3-methyladenine (3-MA) can protect the kidney of streptozotocin (STZ) - induced diabetes mice, and explore its possible mechanism.
OBJECTIVES
To investigate whether 3-methyladenine (3-MA) can protect the kidney of streptozotocin (STZ) - induced diabetes mice, and explore its possible mechanism.
MATERIALS AND METHODS
STZ was used to induce diabetes in C57BL/6J mice. The mice were divided into normal control group (NC), diabetes group (DM), and diabetes+3-MA intervention group (DM+3-MA). Blood glucose, water consumption, and body weight were recorded weekly. At the end of the 6th week of drug treatment, 24-hour urine was collected. Blood and kidneys were collected for PAS staining to evaluate the degree of renal injury. Sirius red staining was used to assess collagen deposition. Blood urea nitrogen (BUN), serum creatinine, and 24-hour urine albumin were used to evaluate renal function. Western blot was used to detect fibrosis-related protein, inflammatory mediators, high mobility group box 1 (HMGB1)/NF-κB signal pathway molecule, vascular endothelial growth factor (VEGF), and podocin, and immunohistochemistry (IHC) was used to detect the expression and localization of autophagy-related protein and fibronectin.
RESULTS
Compared with the kidney of normal control mice, the kidney of diabetes control mice was more pale and hypertrophic. Hyperglycemia induces renal autophagy and activates the HMGB1/NF-κB signal pathway, leading to the increase of inflammatory mediators, extracellular matrix (ECM) deposition, and proteinuria in the kidney. In diabetic mice treated with 3-MA, blood glucose decreased, autophagy and HMGB1/NF-κB signaling pathways in the kidneys were inhibited, and proteinuria, renal hypertrophy, inflammation, and fibrosis were improved.
CONCLUSION
3-MA can attenuate renal injury in STZ-induced diabetic mice through inhibition of autophagy and HMGB1/NF-κB signaling pathway.
PubMed: 38800022
DOI: 10.22038/IJBMS.2024.71378.15518 -
IScience Jun 2024Tuning of protein homeostasis through mobilization of the unfolded protein response (UPR) is key to the capacity of pancreatic beta cells to cope with variable demand...
Tuning of protein homeostasis through mobilization of the unfolded protein response (UPR) is key to the capacity of pancreatic beta cells to cope with variable demand for insulin. Here, we asked how insulin-degrading enzyme (IDE) affects beta cell adaptation to metabolic and immune stress. C57BL/6 and autoimmune non-obese diabetic (NOD) mice lacking IDE were exposed to proteotoxic, metabolic, and immune stress. IDE deficiency induced a low-level UPR with islet hypertrophy at the steady state, rapamycin-sensitive beta cell proliferation enhanced by proteotoxic stress, and beta cell decompensation upon high-fat feeding. IDE deficiency also enhanced the UPR triggered by proteotoxic stress in human EndoC-βH1 cells. In NOD mice, islet inflammation specifically induced regenerating islet-derived protein 2, a protein attenuating autoimmune inflammation. These findings establish a role of IDE in islet cell protein homeostasis, demonstrate how its absence induces metabolic decompensation despite beta cell proliferation, and UPR-independent islet regeneration in the presence of inflammation.
PubMed: 38799566
DOI: 10.1016/j.isci.2024.109929