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Cells May 2024Heart failure is the common concluding pathway for a majority of cardiovascular diseases and is associated with cardiac dysfunction. Since heart failure is invariably... (Review)
Review
Heart failure is the common concluding pathway for a majority of cardiovascular diseases and is associated with cardiac dysfunction. Since heart failure is invariably preceded by adaptive or maladaptive cardiac hypertrophy, several biochemical mechanisms have been proposed to explain the development of cardiac hypertrophy and progression to heart failure. One of these includes the activation of different neuroendocrine systems for elevating the circulating levels of different vasoactive hormones such as catecholamines, angiotensin II, vasopressin, serotonin and endothelins. All these hormones are released in the circulation and stimulate different signal transduction systems by acting on their respective receptors on the cell membrane to promote protein synthesis in cardiomyocytes and induce cardiac hypertrophy. The elevated levels of these vasoactive hormones induce hemodynamic overload, increase ventricular wall tension, increase protein synthesis and the occurrence of cardiac remodeling. In addition, there occurs an increase in proinflammatory cytokines and collagen synthesis for the induction of myocardial fibrosis and the transition of adaptive to maladaptive hypertrophy. The prolonged exposure of the hypertrophied heart to these vasoactive hormones has been reported to result in the oxidation of catecholamines and serotonin via monoamine oxidase as well as the activation of NADPH oxidase via angiotensin II and endothelins to promote oxidative stress. The development of oxidative stress produces subcellular defects, Ca-handling abnormalities, mitochondrial Ca-overload and cardiac dysfunction by activating different proteases and depressing cardiac gene expression, in addition to destabilizing the extracellular matrix upon activating some metalloproteinases. These observations support the view that elevated levels of various vasoactive hormones, by producing hemodynamic overload and activating their respective receptor-mediated signal transduction mechanisms, induce cardiac hypertrophy. Furthermore, the occurrence of oxidative stress due to the prolonged exposure of the hypertrophied heart to these hormones plays a critical role in the progression of heart failure.
Topics: Heart Failure; Humans; Cardiomegaly; Signal Transduction; Animals; Angiotensin II; Oxidative Stress
PubMed: 38786079
DOI: 10.3390/cells13100856 -
Cells May 2024This review addresses the need for innovative co-culture systems integrating the enteric nervous system (ENS) with intestinal organoids. The breakthroughs achieved... (Review)
Review
This review addresses the need for innovative co-culture systems integrating the enteric nervous system (ENS) with intestinal organoids. The breakthroughs achieved through these techniques will pave the way for a transformative era in gastrointestinal (GI) disease modeling and treatment strategies. This review serves as an introduction to the companion protocol paper featured in this journal. The protocol outlines the isolation and co-culture of myenteric and submucosal neurons with small intestinal organoids. This review provides an overview of the intestinal organoid culture field to establish a solid foundation for effective protocol application. Remarkably, the ENS surpasses the number of neurons in the spinal cord. Referred to as the "second brain", the ENS orchestrates pivotal roles in GI functions, including motility, blood flow, and secretion. The ENS is organized into myenteric and submucosal plexuses. These plexuses house diverse subtypes of neurons. Due to its proximity to the gut musculature and its cell type complexity, there are methodological intricacies in studying the ENS. Diverse approaches such as primary cell cultures, three-dimensional (3D) neurospheres, and induced ENS cells offer diverse insights into the multifaceted functionality of the ENS. The ENS exhibits dynamic interactions with the intestinal epithelium, the muscle layer, and the immune system, influencing epithelial physiology, motility, immune responses, and the microbiome. Neurotransmitters, including acetylcholine (ACh), serotonin (5-HT), and vasoactive intestinal peptide (VIP), play pivotal roles in these intricate interactions. Understanding these dynamics is imperative, as the ENS is implicated in various diseases, ranging from neuropathies to GI disorders and neurodegenerative diseases. The emergence of organoid technology presents an unprecedented opportunity to study ENS interactions within the complex milieu of the small and large intestines. This manuscript underscores the urgent need for standardized protocols and advanced techniques to unravel the complexities of the ENS and its dynamic relationship with the gut ecosystem. The insights gleaned from such endeavors hold the potential to revolutionize GI disease modeling and treatment paradigms.
Topics: Enteric Nervous System; Organoids; Humans; Coculture Techniques; Gastrointestinal Diseases; Animals; Models, Biological; Neurons; Intestines
PubMed: 38786042
DOI: 10.3390/cells13100820 -
Current Research in Physiology 2024Chronic kidney disease (CKD) is a progressive and long-term condition marked by a gradual decline in kidney function. CKD is prevalent among those with conditions such... (Review)
Review
Chronic kidney disease (CKD) is a progressive and long-term condition marked by a gradual decline in kidney function. CKD is prevalent among those with conditions such as diabetes mellitus, hypertension, and glomerulonephritis. Affecting over 10% of the global population, CKD stands as a significant cause of morbidity and mortality. Despite substantial advances in understanding CKD pathophysiology and management, there is still a need to explore novel mechanisms and potential therapeutic targets. Urotensin II (UII), a potent vasoactive peptide, has garnered attention for its possible role in the development and progression of CKD. The UII system consists of endogenous ligands UII and UII-related peptide (URP) and their receptor, UT. URP pathophysiology is understudied, but alterations in tissue expression levels of UII and UT and blood or urinary UII concentrations have been linked to cardiovascular and kidney dysfunctions, including systemic hypertension, chronic heart failure, glomerulonephritis, and diabetes. UII gene polymorphisms are associated with increased risk of diabetes. Pharmacological inhibition or genetic ablation of UT mitigated kidney and cardiovascular disease in rodents, making the UII system a potential target for slowing CKD progression. However, a deeper understanding of the UII system's cellular mechanisms in renal and extrarenal organs is essential for comprehending its role in CKD pathophysiology. This review explores the evolving connections between the UII system and CKD, addressing potential mechanisms, therapeutic implications, controversies, and unexplored concepts.
PubMed: 38779598
DOI: 10.1016/j.crphys.2024.100126 -
Chinese Medicine May 2024The restoration of cerebrovascular regulation and improvement of cerebral blood flow in ischaemic regions are crucial for improving the clinical prognosis after stroke....
BACKGROUND
The restoration of cerebrovascular regulation and improvement of cerebral blood flow in ischaemic regions are crucial for improving the clinical prognosis after stroke. An-Gong-Niu-Huang-Wan (AGNHW) is a famous traditional compound Chinese medicine that has been used for over 220 years to treat acute ischaemic stroke; however, its role in the regulation of cerebral blood flow is still unclear. The aim of the present study was to investigate the regulatory effect of AGNHW on cerebral blood flow and microcirculation after ischaemic stroke and to elucidate the underlying mechanisms involved.
METHODS
Male C57BL/6 mice were subjected to distal middle cerebral artery occlusion (dMCAO) and randomly assigned to the sham, MCAO, or AGNHW groups. AGNHW was administered intragastrically 1 h after dMCAO. The rotarod test was utilized to evaluate behavioural function; TTC was used to determine the infarct volume; and ischaemic injury was assessed by detecting brain levels of SOD, MDA and NO. Then, cortical perfusion and acetazolamide-induced cerebrovascular reactivity were assessed using laser speckle contrast imaging, and the velocity and flux of red blood cells in cortical capillaries were detected using two-photon laser scanning microscopy. In addition, we employed RNA-Seq to identify variations in gene expression profiles and assessed endothelium-dependent changes in microcirculatory dysfunction by measuring vasoactive mediator levels.
RESULTS
AGNHW significantly increased cerebral blood flow, reduced the infarct volume, and promoted functional recovery after cerebral ischaemia. AGNHW increased the velocity and flux of red blood cells in capillaries and improved cerebrovascular reactivity in the ischaemic cortex. Furthermore, AGNHW regulated endothelium-dependent microcirculation, as evidenced by decreases in the expression of endothelins (Edn1, Edn3 and Ednrb) and the ratios of brain and serum TXB2/6-keto-PGF1α and ET-1/CGRP.
CONCLUSIONS
AGNHW improved cerebral hypoperfusion, regulated cerebrovascular reactivity and attenuated microcirculatory dysfunction within the ischaemic cortex after stroke. This outstanding effect was achieved by modulating the expression of genes related to vascular endothelial cell function and regulating endothelium-dependent vasoactive mediators.
PubMed: 38778375
DOI: 10.1186/s13020-024-00945-7 -
BMC Nephrology May 2024Pregnancy-related kidney injury contributes to a high burden of acute kidney injury in low-resource settings and causes maternal and perinatal morbidity and mortality....
BACKGROUND
Pregnancy-related kidney injury contributes to a high burden of acute kidney injury in low-resource settings and causes maternal and perinatal morbidity and mortality. Few studies have examined the impact of acute kidney injury in resource-limited countries, with very limited research on pregnancy-specific disorders in Ethiopia. This study aimed to determine the characteristics of pregnancy-related acute kidney injury, outcomes and associated factors.
METHODS
A retrospective study was conducted to evaluate the clinical profile and maternal-fetal outcome of pregnancy-related acute kidney injury at Ayder Comprehensive Specialized Hospital in Tigray, Ethiopia, from January 1, 2017, to December 31, 2021. Maternal and fetal outcomes were analyzed using descriptive statistics. Multivariate logistic regression was used to determine the association between the dependent and independent variables.
RESULTS
Of 27,350 mothers who delivered at Ayder Comprehensive Specialized Hospital between January 1, 2017, and December 31, 2021, a total of 187 women developed pregnancy-related acute kidney injury, a prevalence rate of 68 per 100,000 births. Preeclampsia, sepsis and pre-renal causes due to dehydration and hemorrhage were the most common causes of pregnancy-related acute kidney injury in this study. Hemodialysis was needed in 8.6% (n = 16) of patients. Of the 187 pregnancy-related acute kidney injuries, 143 (76.5%) recovered completely and 30 (16%) partially. The mortality rate was 7.5%. Preexisting chronic kidney disease (AOR = 30.13; 95% CI: 2.92, 310.84), use of vasoactive agents (AOR = 5.77; 95% CI: 1.47, 22.67), increase in creatinine per unit (AOR = 1.65; 95% CI: 1.11, 2.45) and complications related to acute kidney injury (AOR = 5.26; 95% CI: 1.73, 16.00) were determinants of the composite endpoints (partial renal recovery and death).
CONCLUSIONS
This study emphasizes acute kidney injury in resource-limited settings is a significant cause of maternal and fetal morbidity and mortality. The vast majority of patients with pregnancy-related acute kidney injury recovered completely from kidney injury. The main causes of pregnancy-related acute kidney injury were preeclampsia, sepsis and pre-renal associated with hemorrhage and dehydration. Preexisting renal disease, use of vasopressors, increase in creatinine per unit and complications associated with acute kidney injury were determining factors for concomitant fetomaternal mortality. Appropriate preventive strategies during prenatal care and prompt treatment are needed for pregnancy-related acute kidney injury.
Topics: Humans; Pregnancy; Female; Acute Kidney Injury; Retrospective Studies; Adult; Ethiopia; Pregnancy Complications; Young Adult; Pre-Eclampsia; Hospitals, Teaching; Pregnancy Outcome; Sepsis; Renal Dialysis; Dehydration; Infant, Newborn; Prevalence; Developing Countries
PubMed: 38778267
DOI: 10.1186/s12882-024-03616-9 -
Archives of Rheumatology Mar 2024This study aimed to evaluate the diagnostic tests and treatments applied in patients with multisystem inflammatory syndrome in children (MIS-C) and to determine the...
OBJECTIVES
This study aimed to evaluate the diagnostic tests and treatments applied in patients with multisystem inflammatory syndrome in children (MIS-C) and to determine the effect of the disease on health costs.
PATIENTS AND METHODS
This retrospective cohort study included 59 MIS-C patients (40 males, 19 females; mean age: 7.7±4.2 years; range, 4 months to 16.5 years) who were admitted and treated between April 1, 2020, and November 1, 2021. Demographic and clinical features with hospital costs and length of stay were retrospectively reviewed from the medical files and computerized system of the hospital. Direct medical care costs of items were calculated with the hospital perspective using a combination of microcosting technique (resource-based accounting method) and hospital list data. Cases were classified as mild, moderate, or severe, and the patients were divided into two groups: the mild group and the moderate-severe group. Classification was determined by the vasoactive inotropic score (VIS), degree of respiratory support, and evidence of organ damage.
RESULTS
The mean age of the cases in the mild group was 6.5±3.7 years, and the mean age of the cases in the moderate-severe group was 9.2±4.3 years. Of 59 patients, 19 (32.2%) were followed up in the pediatric intensive care unit. The median duration of hospitalization in the hospital was 8 (interquartile range: 7-12) days. The total cost of the patients hospitalized with the diagnosis of MIS-C during the study period was 849,242.93$, and the mean cost per patient was 14,393.94±9,631.92$. In the distribution of the total cost of hospitalization according to expenses, the highest rate was pharmacy and blood products (51.99%) and IVIG costs (43.99%). While the mean total cost per person was 13,682.87±8,799.63$ in mild cases, it was 16,433.82±9,440.02$ in moderate-severe cases, and no statistically significant relationship was found between the two groups (p>0.05). There was no difference in the mean cost per patient between the cases with and without heart, lung, kidney, or neurologic involvement and advanced respiratory support (p>0.05). There was a strong positive correlation between the total costs and age (r=0.883, n=59, p<0.0001), with increased amount of costs with increased age.
CONCLUSION
In the study, no statistically significant correlation was found between the total cost of per person in the mild group and the moderate-severe group (p>0.05). This finding may be due to the wide use of IVIG in MIS-C treatment, in addition to low transfer rates to pediatric intensive care units due to high-flow nasal cannula usage.
PubMed: 38774689
DOI: 10.46497/ArchRheumatol.2023.10147 -
Frontiers in Endocrinology 2024Polycystic ovary syndrome (PCOS) is a common multifactorial and polygenic disorder of the endocrine system, affecting up to 20% of women in reproductive age with a still...
INTRODUCTION
Polycystic ovary syndrome (PCOS) is a common multifactorial and polygenic disorder of the endocrine system, affecting up to 20% of women in reproductive age with a still unknown etiology. Follicular fluid (FF) represents an environment for the normal development of follicles rich in metabolites, hormones and neurotransmitters, but in some instances of PCOS the composition can be different. Vasoactive intestinal peptide (VIP) is an endogenous autonomic neuropeptide involved in follicular atresia, granulosa cell physiology and steroidogenesis.
METHODS
ELISA assays were performed to measure VIP and estradiol levels in human follicular fluids, while AMH, FSH, LH, estradiol and progesterone in the plasma were quantified by chemiluminescence. UHPLC/QTOF was used to perform the untargeted metabolomic analysis.
RESULTS
Our ELISA and metabolomic results show: i) an increased concentration of VIP in follicular fluid of PCOS patients (n=9) of about 30% with respect to control group (n=10) (132 ± 28 pg/ml versus 103 ± 26 pg/ml, p=0,03) in women undergoing fertilization (IVF), ii) a linear positive correlation (p=0.05, r=0.45) between VIP concentration and serum Anti-Müllerian Hormone (AMH) concentration and iii) a linear negative correlation between VIP and noradrenaline metabolism. No correlation between VIP and estradiol (E2) concentration in follicular fluid was found. A negative correlation was found between VIP and noradrenaline metabolite 3,4-dihydroxyphenylglycolaldehyde (DOPGAL) in follicular fluids.
CONCLUSION
VIP concentration in follicular fluids was increased in PCOS patients and a correlation was found with noradrenaline metabolism indicating a possible dysregulation of the sympathetic reflex in the ovarian follicles. The functional role of VIP as noradrenergic modulator in ovarian physiology and PCOS pathophysiology was discussed.
Topics: Humans; Female; Polycystic Ovary Syndrome; Vasoactive Intestinal Peptide; Fertilization in Vitro; Follicular Fluid; Adult; Estradiol; Anti-Mullerian Hormone; Case-Control Studies
PubMed: 38774232
DOI: 10.3389/fendo.2024.1331282 -
Investigative Ophthalmology & Visual... May 2024Earlier reports highlighted the predominant presence of aquaporin 4 (AQP4) in the duct cells of rabbit lacrimal glands (LGs). Whereas significant alterations in AQP4...
PURPOSE
Earlier reports highlighted the predominant presence of aquaporin 4 (AQP4) in the duct cells of rabbit lacrimal glands (LGs). Whereas significant alterations in AQP4 mRNA levels have been observed in experimental dry eye and during pregnancy, the impact of AQP4 in LG ductal fluid production remains unclear. In our recent work, the role of AQP4 in LG ductal fluid secretion was investigated utilizing wild type (WT) and AQP4 knock out (KO) mice.
METHODS
Tear production was assessed in both WT and KO animals. Immunostaining was used to identify AQP4 protein. Duct segments were harvested from LGs of WT and KO mice. Fluid secretion and filtration permeability (Pf) were quantified using video-microscopy. Ductal tear production, elicited by a cell-permeable cAMP analogue (8-bromo cAMP), carbachol, vasoactive intestinal peptide (VIP), and phenylephrine (PHE), were assessed in both WT and KO ducts.
RESULTS
A higher expression of AQP4 protein was noted in the duct cells from WT mice when compared to acinar cells. Pf did not show notable alterations between WT and AQP4 KO ducts. Carbachol elicited comparable secretory responses in ducts from both WT and KO animals. However, 8-bromo cAMP, VIP, and PHE stimulation resulted in decreased secretion in ducts from AQP4 KO LGs.
CONCLUSIONS
Our findings underscore the functional relevance of AQP4 in the fluid production of mouse LG ducts. AQP4 seems to play different roles in fluid secretions elicited by different secretagogues. Specifically, cAMP-mediated, and adrenergic agonist-related secretions were reduced in AQP4 KO ducts.
Topics: Animals; Mice; Lacrimal Apparatus; Tears; Mice, Knockout; Aquaporin 4; Mice, Inbred C57BL; Female
PubMed: 38771571
DOI: 10.1167/iovs.65.5.30 -
Cureus Apr 2024Coma blisters, or coma bullae, are lesions often seen in the setting of impaired consciousness. Most commonly associated with drug-induced comas, coma bullae have been...
Coma blisters, or coma bullae, are lesions often seen in the setting of impaired consciousness. Most commonly associated with drug-induced comas, coma bullae have been repeatedly linked to central nervous system (CNS) depressing agents, such as opiates. These lesions are believed to develop due to a complex multifactorial process involving external pressure on the skin, which leads to hypoxia and eventual death of eccrine sweat glands. In addition, the vasoactive and inflammatory properties of CNS depressing agents may play a role in this process. Come bullae usually develop on pressure points 48-72 hours after the onset of impaired consciousness and are self-limiting. We present the case of a 68-year-old male who was brought to the emergency department after being found unresponsive on the street. The urine drug screen was positive for cocaine and fentanyl. The initial examination showed several large, non-tender bullae on his scalp that continued to expand over two days. He subsequently developed similar lesions on his thighs, right shoulder, and knuckles. Dermatology was consulted and clinically diagnosed the patient with coma bullae, likely attributed to his altered consciousness and opiate use. Notably, more violaceous bullae were found on the bilateral lower extremities, with dermatology suspecting additional vasculitic features related to concurrent opiate and cocaine use. Skin biopsy and aspiration were deferred to avoid the risk of infection, and the patient was discharged per dermatology's recommendations for no immediate intervention. He continued to follow with wound care for the next six months, with most of the bullae healing. However, eschars developed over the scalp and left lower extremity, requiring debridement by general surgery. This case report underscores a unique manifestation of coma bullae. Unlike typical presentations localized to pressure-dependent areas and appearing after two to three days of unconsciousness, our patient exhibited blisters in atypical sites with associated vasculitic features. Moreover, the development of eschars over time may be linked to ongoing vasoactive drug use, reperfusion injury, and social determinants of health. This case highlights the complex and multifactorial nature of coma bullae, emphasizing the challenges in wound care and management despite their expected self-resolution.
PubMed: 38770478
DOI: 10.7759/cureus.58646 -
Journal of Traditional Chinese Medicine... Jun 2024To explore the early hemostatic mechanism of Jianpi Yiqi Shexue decoction (, JYSD) in treating immune thrombocytopathy (ITP), based on the functional homeostasis of... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
To explore the early hemostatic mechanism of Jianpi Yiqi Shexue decoction (, JYSD) in treating immune thrombocytopathy (ITP), based on the functional homeostasis of brain-intestine axis and blood neurotransmitter METHODS: Non-drug treatment cases: Healthy volunteers were selected as normal control group and compared with patients with dysfunctional uterine bleeding, gastrointestinal tumors with bleeding and ITP, to detect the changes of blood 5-hydroxytryptamine (5-HT), β-endorphin (β-EP), vasoactive intestinal peptide (VIP) and compare the changes of blood neuro-transmitters in patients with different disease symptoms. Drug treatment cases: According to the randomized controlled multicenter clinical trial, 272 ITP patients were randomly divided into three groups: treatment group (JYSD) combined group (JYSD + Prednisone) control group (Prednisone). The changes of blood neuro-transmitter (5-HT, β-EP, VIP) before and after treatment were detected on the basis of peripheral blood platelet (PLT) and grade score.
RESULTS
Non-drug treatment cases: compared with the normal control group, the 5-HT level was higher, and the VIP and β-EP levels were both lower in the ITP group ( < 0.001), and the 5-HT, VIP and β-EP levels in the Gastrointestinal tumors with bleeding group were also lower compared with the normal control group ( < 0.05, 0.001). Drug treatment cases: The PLT grading scores of the combination group and the control group after treatment were lower than that before treatment ( < 0.05, 0.001). The PLT grading score of the 3 groups were compared in pairs after treatment: the combination group was the lowest among the 3 groups, which was better than the treatment group, but no better than the control group ( the treatment group, = 0.005, the control group, = 0.709). The statistical results of full analysis set (FAS) and per protocol set (PPS) were consistent. The bleeding symptom scores of the treatment and combination groups began to drop 7 d after treatment, and kept dropping 14 d after treatment until the end of the study ( < 0.05). On the other hand, the control group started to show favorable results 14 d after treatment ( < 0.05). The FAS and PPS analysis results were consistent. In the control group, the 5-HT level was higher and VIP level was lower after treatment, compared with those before treatment ( < 0.05, 0.001). The β-EP levels were both increased in the treatment and combination group after treatment, compared with those before treatment ( < 0.05). After treatment, the β-EP levels in the treatment and control groups were significantly lower compared with the combination groups ( < 0.05). After treatment, compared with the control group, the VIP levels in the treatment and combination groups were up-regulated, and the differences were statistically significant by rank sum test ( < 0.01), and by -test ( = 0.0002, 0.0001).
CONCLUSIONS
The prednisone tablet is better than the JYSD in increasing the level of PLT, while prednisone tablet combined with JYSD has more advantages in improving patients' peripheral blood PLT levels. However, in improving the bleeding time of ITP patients, the combination of the two drugs was significantly delayed compared with the single usage, showing the characteristics and advantages of traditional Chinese medicine. JYSD can regulate the neurotransmitter level of ITP patients through the function of the brain-gut axis, mobilize 5-HT in the blood of ITP patients to promote the contraction of blood vessels and smooth muscles, and activate the coagulation mechanism are the early hemostatic mechanisms of JYSD. Up-regulate the levels of β-EP and balancing VIP levels may be an important part of the immune mechanism of JYSD for regulating ITP patients.
Topics: Humans; Drugs, Chinese Herbal; Female; Middle Aged; Adult; Male; Serotonin; Aged; Young Adult; Vasoactive Intestinal Peptide; Purpura, Thrombocytopenic, Idiopathic; beta-Endorphin; Adolescent; Hemostatics; Hemostasis
PubMed: 38767638
DOI: 10.19852/j.cnki.jtcm.20240423.003