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Cell Communication and Signaling : CCS Oct 2023Familial hyperkalemic hypertension (FHHt), also known as Pseudohypoaldosteronism type II (PHAII) or Gordon syndrome is a rare Mendelian disease classically characterized... (Review)
Review
Familial hyperkalemic hypertension (FHHt), also known as Pseudohypoaldosteronism type II (PHAII) or Gordon syndrome is a rare Mendelian disease classically characterized by hyperkalemia, hyperchloremic metabolic acidosis, and high systolic blood pressure. The most severe form of the disease is caused by autosomal dominant variants in CUL3 (Cullin 3), a critical subunit of the multimeric CUL3-RING ubiquitin ligase complex. The recent identification of a novel FHHt disease variant of CUL3 revealed intricacies within the underlying disease mechanism. When combined with studies on canonical CUL3 variant-induced FHHt, these findings further support CUL3's role in regulating renal electrolyte transport and maintaining systemic vascular tone. However, the pathophysiological effects of CUL3 variants are often accompanied by diverse systemic disturbances in addition to classical FHHt symptoms. Recent global proteomic analyses provide a rationale for these systemic disturbances, paving the way for future mechanistic studies to reveal how CUL3 variants dysregulate processes outside of the renovascular axis. Video Abstract.
Topics: Humans; Pseudohypoaldosteronism; Proteomics; Kidney; Hypertension; Cullin Proteins
PubMed: 37845702
DOI: 10.1186/s12964-023-01269-z -
Proceedings of the National Academy of... Apr 2024The complex interplay between malignant cells and the cellular and molecular components of the tumor stroma is a key aspect of cancer growth and development. These...
The complex interplay between malignant cells and the cellular and molecular components of the tumor stroma is a key aspect of cancer growth and development. These tumor-host interactions are often affected by soluble bioactive molecules such as proteoglycans. Decorin, an archetypical small leucine-rich proteoglycan primarily expressed by stromal cells, affects cancer growth in its soluble form by interacting with several receptor tyrosine kinases (RTK). Overall, decorin leads to a context-dependent and protracted cessation of oncogenic RTK activity by attenuating their ability to drive a prosurvival program and to sustain a proangiogenic network. Through an unbiased transcriptomic analysis using deep RNAseq, we identified that decorin down-regulated a cluster of tumor-associated genes involved in lymphatic vessel (LV) development when systemically delivered to mice harboring breast carcinoma allografts. We found that Lyve1 and Podoplanin, two established markers of LVs, were markedly suppressed at both the mRNA and protein levels, and this suppression correlated with a significant reduction in tumor LVs. We further identified that soluble decorin, but not its homologous proteoglycan biglycan, inhibited LV sprouting in an ex vivo 3D model of lymphangiogenesis. Mechanistically, we found that decorin interacted with vascular endothelial growth factor receptor 3 (VEGFR3), the main lymphatic RTK, and its activity was required for the decorin-mediated block of lymphangiogenesis. Finally, we identified that Lyve1 was in part degraded via decorin-evoked autophagy in a nutrient- and energy-independent manner. These findings implicate decorin as a biological factor with antilymphangiogenic activity and provide a potential therapeutic agent for curtailing breast cancer growth and metastasis.
Topics: Decorin; Lymphangiogenesis; Animals; Mice; Humans; Female; Breast Neoplasms; Lymphatic Vessels; Cell Line, Tumor; Disease Progression; Vesicular Transport Proteins; Membrane Glycoproteins; Gene Expression Regulation, Neoplastic
PubMed: 38652741
DOI: 10.1073/pnas.2317760121 -
International Journal of Molecular... Dec 2023Psoriasis is an inflammatory skin disease mediated by the immune system and characterized by an inflammatory ring, also known as an epithelial immune microenvironment... (Review)
Review
Psoriasis is an inflammatory skin disease mediated by the immune system and characterized by an inflammatory ring, also known as an epithelial immune microenvironment (EIME). The interaction between the epithelial tissue of the skin and the immune system has a crucial role in the immune cycle of psoriasis. Although the formation of new blood vessels in skin lesions provides energy support for the proliferation of epidermal keratinocytes, the role of angiogenesis in psoriasis has not been extensively studied. Vascular endothelial growth factor A (VEGFA) is a key regulator of angiogenesis that has an important role in the development of psoriasis. VEGFA promotes angiogenesis and directly stimulates epidermal keratinocytes and infiltrating immune cells, thus contributing to the progression of psoriasis. Measuring VEGFA levels to identify angiogenic characteristics in psoriasis patients may be a predictive biomarker for disease severity and response to anti-angiogenic therapy. Clinical data have shown that anti-angiogenic therapy can improve skin lesions in psoriasis patients. Therefore, this study aimed to uncover the underestimated role of blood vessels in psoriasis, explore the relationship between VEGFA and keratinocytes in the EIME, and inspire innovative drug therapies for the treatment of psoriasis.
Topics: Humans; Vascular Endothelial Growth Factor A; Psoriasis; Treatment Outcome; Skin; Dermatitis
PubMed: 38203230
DOI: 10.3390/ijms25010059 -
Journal of Cellular and Molecular... Apr 2024The small GTPase RhoA and the downstream Rho kinase (ROCK) regulate several cell functions and pathological processes in the vascular system that contribute to the... (Review)
Review
The small GTPase RhoA and the downstream Rho kinase (ROCK) regulate several cell functions and pathological processes in the vascular system that contribute to the age-dependent risk of cardiovascular disease, including endothelial dysfunction, excessive permeability, inflammation, impaired angiogenesis, abnormal vasoconstriction, decreased nitric oxide production and apoptosis. Frailty is a loss of physiological reserve and adaptive capacity with advanced age and is accompanied by a pro-inflammatory and pro-oxidative state that promotes vascular dysfunction and thrombosis. This review summarises the role of the RhoA/Rho kinase signalling pathway in endothelial dysfunction, the acquisition of the pro-thrombotic state and vascular ageing. We also discuss the possible role of RhoA/Rho kinase signalling as a promising therapeutic target for the prevention and treatment of age-related cardiovascular disease.
Topics: Humans; Cardiovascular Diseases; rho-Associated Kinases; Thrombosis; Vascular Diseases; Endothelial Cells
PubMed: 38568071
DOI: 10.1111/jcmm.18153 -
Experimental Gerontology Nov 2023Severe sarcopenia may result in severe disability. Early diagnosis is currently the key to enhancing the treatment of sarcopenia, and there is an urgent need for a...
An experimental study for quantitative assessment of fatty infiltration and blood flow perfusion in quadriceps muscle of rats using IDEAL-IQ and BOLD-MRI for early diagnosis of sarcopenia.
BACKGROUND
Severe sarcopenia may result in severe disability. Early diagnosis is currently the key to enhancing the treatment of sarcopenia, and there is an urgent need for a highly sensitive and dependable tool to evaluate the course of early sarcopenia in clinical practice. This study aims to investigate longitudinally the early diagnosability of magnetic resonance imaging (MRI)-based fat infiltration and blood flow perfusion technology in sarcopenia progression.
METHODS
48 Sprague-Dawley rats were randomly assigned into six groups that were based on different periods of dexamethasone (DEX) injection (0, 2, 4, 6, 8, 10 days). Multimodal MRI was scanned to assess muscle mass. Grip strength and swimming exhaustion time of rats were measured to assess muscle strength and function. Immunofluorescence staining for CD31 was employed to assess skeletal muscle capillary formation, and western blot was used to detect vascular endothelial growth factor-A (VEGF-A) and muscle ring finger-1 (MuRF-1) protein expression. Subsequently, we analyzed the correlation between imaging and histopathologic parameters. A receiver operating characteristic (ROC) analysis was conducted to assess the effectiveness of quantitative MRI parameters for discriminating diagnosis in both pre- and post-modeling of DEX-induced sarcopenic rats.
RESULTS
Significant differences were found in PDFF, R2* and T2 values on day 2 of DEX-induction compared to the control group, occurring prior to the MRI-CSA values and limb grip strength on day 6 of induction and swimming exhaustion time on day 8 of induction. There is a strong correlation between MRI-CSA with HE-CSA values (r = 0.67; p < 0.001), oil red O (ORO) area with PDFF (r = 0.67; p < 0.001), microvascular density (MVD) (r = -0.79; p < 0.001) and VEGF-A (r = -0.73; p < 0.001) with R2*, MuRF-1 with MRI-CSA (r = -0.82; p < 0.001). The AUC of PDFF, R2*, and T2 values used for modeling evaluation are 0.81, 0.93, and 0.98, respectively.
CONCLUSION
Imaging parameters PDFF, R2*, and T2 can be used to sensitively evaluate early pathological changes in sarcopenia. The successful construction of a sarcopenia rat model can be assessed when PDFF exceeds 1.25, R2* exceeds 53.85, and T2 exceeds 33.88.
Topics: Rats; Animals; Sarcopenia; Vascular Endothelial Growth Factor A; Quadriceps Muscle; Rats, Sprague-Dawley; Magnetic Resonance Imaging; Perfusion; Early Diagnosis
PubMed: 37929293
DOI: 10.1016/j.exger.2023.112322 -
Scientific Reports Sep 2023To evaluate the differential associations of high-risk plaque characteristics (HRPC) with resting or hyperemic physiologic indexes (instantaneous wave-free ratio [iFR]...
To evaluate the differential associations of high-risk plaque characteristics (HRPC) with resting or hyperemic physiologic indexes (instantaneous wave-free ratio [iFR] or fractional flow reserve [FFR]), a total of 214 vessels from 127 patients with stable angina or acute coronary syndrome who underwent coronary computed tomography angiography (CCTA) and invasive physiologic assessment were investigated. HPRC were classified into quantitative (minimal luminal area < 4 mm or plaque burden ≥ 70%) and qualitative features (low attenuation plaque, positive remodeling, napkin ring sign, or spotty calcification). Vessels with FFR ≤ 0.80 or iFR ≤ 0.89 had significantly higher proportions of HRPC than those with FFR > 0.80 or iFR > 0.89, respectively. FFR was independently associated with both quantitative and qualitative HRPC, but iFR was only associated with quantitative HRPC. Both FFR and iFR were significantly associated with the presence of ≥ 3 HRPC, and FFR demonstrated higher discrimination ability than iFR (AUC 0.703 vs. 0.648, P = 0.045), which was predominantly driven by greater discriminating ability of FFR for quantitative HRPC (AUC 0.832 vs. 0.744, P = 0.005). In conclusion, both FFR and iFR were significantly associated with CCTA-derived HRPC. Compared with iFR, however, FFR was independently associated with the presence of qualitative HRPC and showed a higher predictive ability for the presence of ≥ 3 HRPC.
Topics: Humans; Fractional Flow Reserve, Myocardial; Acute Coronary Syndrome; Angina, Stable; Angiography; Calcification, Physiologic; Plaque, Amyloid
PubMed: 37749337
DOI: 10.1038/s41598-023-43352-y -
Journal of the American Heart... Jan 2024Pulse wave velocity (PWV) is a noninvasive measure of arterial stiffness and predictor of cardiovascular disease. However, the association between PWV and vascular...
BACKGROUND
Pulse wave velocity (PWV) is a noninvasive measure of arterial stiffness and predictor of cardiovascular disease. However, the association between PWV and vascular calcification across different vascular beds has not been fully investigated. This study aimed to quantify the association between PWV and multiterritory calcification and to explore whether PWV can identify individuals with vascular calcification beyond traditional risk factors.
METHODS AND RESULTS
Among 1351 older adults (mean age, 79.2 years [SD, 4.1]) from the ARIC (Atherosclerosis Risk in Communities) study, we measured segment-specific PWVs: heart-carotid, heart-femoral, carotid-femoral, heart-ankle, brachial-ankle, and femoral-ankle. Dependent variables were high calcium score (≥75th percentile of Agatston score) across different vascular beds: coronary arteries, aortic valve ring, aortic valve, mitral valve, ascending aorta, and descending aorta. Quartiles of carotid-femoral, heart-femoral, heart-ankle, and brachial-ankle PWV were significantly associated with coronary artery calcium (eg, adjusted odds ratio [OR] for the highest versus lowest quartile of carotid-femoral PWV, 1.84 [95% CI, 1.24-2.74]). Overall, PWVs were most strongly associated with descending aorta calcification, with significant results for carotid-femoral, heart-femoral, heart-ankle, and brachial-ankle PWV (eg, adjusted OR for the highest versus lowest quartile of carotid-femoral PWV, 3.99 [95% CI, 2.61-6.17]). In contrast, femoral-ankle PWV was inversely associated with descending aorta calcification. Some PWVs improved the discrimination of coronary artery calcium and descending aorta calcification beyond traditional risk factors.
CONCLUSIONS
The associations of PWV with vascular calcification varied substantially across segments, with descending aorta calcification most closely linked to PWVs. Our study suggests that some PWVs, especially carotid-femoral PWV, are helpful to identify individuals with coronary artery calcium and descending aorta calcification.
Topics: Humans; Aged; Pulse Wave Analysis; Calcium; Vascular Calcification; Atherosclerosis; Cardiovascular Diseases; Vascular Stiffness
PubMed: 38214278
DOI: 10.1161/JAHA.123.031778 -
SAGE Open Medical Case Reports 2023A female infant, born at 37 week 5 days to a mother via induced vaginal delivery for preeclampsia, was prenatally diagnosed with a right aortic arch with vascular ring....
A female infant, born at 37 week 5 days to a mother via induced vaginal delivery for preeclampsia, was prenatally diagnosed with a right aortic arch with vascular ring. On the third day of life, the infant exhibited a bronze-gray coloration, and a direct bilirubin of 1.7 mg/dL was detected. The abdominal ultrasound did not visualize the gallbladder. Clinically, the infant displayed features consistent with Alagille syndrome, including unusual facial appearance, butterfly vertebrae, cardiovascular defects, and cholestasis. The geneticist noted that the mother of the patient also exhibited similar features. Both the infant and the mother were diagnosed with Alagille syndrome, both having the same heterozygous JAG1 gene (NM_000214.2) variant (c.1890_1893del, p.Ile630Metfs*112). We believe that the vascular ring observed in our patient is the first reported instance of a vascular ring associated with Alagille syndrome.
PubMed: 37667743
DOI: 10.1177/2050313X231197321 -
World Journal of Surgical Oncology Nov 2023To investigate the diagnostic value of conventional white light endoscopy (WLE), narrow band imaging (NBI) endoscopy, and Lugol's iodine staining under WLE (endoscopic...
BACKGROUND
To investigate the diagnostic value of conventional white light endoscopy (WLE), narrow band imaging (NBI) endoscopy, and Lugol's iodine staining under WLE (endoscopic iodine staining) in the screening and early diagnosis of nasopharyngeal carcinoma.
METHODS
Patients with nasopharyngeal lesions requiring biopsy attending the Department of Otolaryngology Head and Neck Surgery in our hospital between January 2021 and April 2023 were included in this study. Before biopsy, all subjects underwent conventional WLE, NBI endoscopy, and endoscopic iodine staining. On WLE, according to nasopharyngeal lesion morphology and color, patients were diagnosed with nasopharyngeal carcinoma ( +) or chronic hyperplastic nasopharyngitis (-). On NBI endoscopy, according to nasopharyngeal lesion vascular morphology, patients with type V manifestations (nasopharyngeal carcinoma) were categorized as NBI ( +) and patients with type I-IV manifestations (chronic hyperplastic nasopharyngitis) were categorized as NBI (-). Endoscopic iodine staining (1.6% Lugol's iodine solution) was positive ( +) if the mucosal surface was brown with no white patches, or negative (-) if there was no or light brown staining of the mucosal surface. Patients were divided into 2 groups based on histopathological diagnosis: nasopharyngeal carcinoma or chronic hyperplastic nasopharyngitis. Endoscopic diagnoses were compared with histopathological findings. The diagnostic performance of WLE, NBI endoscopy and endoscopic iodine staining for nasopharyngeal carcinoma were determined.
RESULTS
This study included 159 patients. On histopathology, 29 patients were diagnosed with nasopharyngeal carcinoma, and 130 patients were diagnosed with chronic hyperplastic nasopharyngitis. There were no significant differences in the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), accuracy, and area under the receiver operating characteristic (ROC) curve (AUC) of conventional WLE, NBI endoscopy or endoscopic iodine staining for differentiating nasopharyngeal carcinoma and chronic hyperplastic nasopharyngitis. The diagnostic performance of the combination of conventional WLE, NBI endoscopy and endoscopic iodine staining was significantly improved compared to any procedure alone.
CONCLUSIONS
Conventional WLE, NBI endoscopy or endoscopic iodine staining had good diagnostic performance for differentiating nasopharyngeal carcinoma and chronic hyperplastic nasopharyngitis. In particular, NBI endoscopy and endoscopic iodine staining alone or combined had clinical utility for identifying patients with nasopharyngeal lesions that are eligible for a watch-and-wait strategy.
Topics: Humans; Nasopharyngeal Carcinoma; Narrow Band Imaging; Nasopharyngitis; Endoscopy, Gastrointestinal; Nasopharyngeal Neoplasms; Staining and Labeling; Iodine
PubMed: 38037075
DOI: 10.1186/s12957-023-03258-5