Estradiol mitigates stress-induced cardiac injury and inflammation by downregulating ADAM17 via the GPER-1/PI3K signaling pathway.

Stress-induced cardiovascular diseases characterized by inflammation are among the leading causes of morbidity and mortality in postmenopausal women worldwide. Estradiol (E2) is known to be cardioprotective via the modulation of inflammatory mediators during stress. But the mechanism is unclear. TNFα, a key player in inflammation, is primarily converted to its active form by 'A Disintegrin and Metalloprotease 17' (ADAM17). We investigated if E2 can regulate ADAM17 during stress. Experiments were performed using female FVB wild-type (WT), C57BL/6 WT, and G protein-coupled estrogen receptor 1 knockout (GPER-1 KO) mice and H9c2 cells. The study revealed a significant increase in cardiac injury and inflammation during isoproterenol (ISO)-induced stress in ovariectomized (OVX) mice. Additionally, ADAM17's membrane content (mADAM17) was remarkably increased in OVX and GPER-1 KO mice during stress. However, in vivo supplementation of E2 significantly reduced cardiac injury, mADAM17, and inflammation. Also, administering G1 (GPER-1 agonist) in mice under stress reduced mADAM17. Further experiments demonstrated that E2, via GPER-1/PI3K pathway, localized ADAM17 at the perinuclear region by normalizing ß1AR-Gαs, mediating the switch from ß2AR-Gαi to Gαs, and reducing phosphorylated kinases, including p38 MAPKs and ERKs. Thus, using G15 and LY294002 to inhibit GPER-1 and its down signaling molecule, PI3K, respectively, in the presence of E2 during stress resulted in the disappearance of E2's modulatory effect on mADAM17. In vitro knockdown of ADAM17 during stress significantly reduced cardiac injury and inflammation, confirming its significant inflammatory role. These interesting findings provide novel evidence that E2 and G1 are potential therapeutic agents for ADAM17-induced inflammatory diseases associated with postmenopausal females.

Effects of core muscles strengthening exercises with routine physical therapy on trunk balance in stroke patients: A randomized controlled trial.

OBJECTIVE: To compare the effects of core muscle strengthening exercises with and without routine physical therapy on trunk balance in chronic stroke patients. METHODS: The randomised controlled trial was conducted at Mubarak Medical Complex, Sargodha, Pakistan, from October 28, 2021, to April 28, 2022, and comprised patients of either gender with chronic stroke aged 40-60 years. The subjects were randomised using the lottery method into group A that was managed with routine physical therapy, and group B which was further managed with core strengthening exercises. The intervention comprised 4 sessions per week for 8 weeks. Outcome was measured using Trunk Impairment Scale and Time Up and Go test. Data was collected at baseline, week 4 and post-intervention. Data was analysed using SPSS 23. RESULTS: Of the 80 individuals screened, 74(92.5%) were included. There were 37(50%) patients in group A; 30(81%) males and 7(19%) females with mean age 56.73±2.37 years. The remaining 37(50%) patients were in group B; 27(73%) males and 10(27%) females with mean age 55.65±2.88 years. Trunk balance and functional mobility improved significantly post-intervention in both groups (p<0.05), but group B values were significantly better compared to group A values (p<0.05). CONCLUSIONS: Core muscle strengthening exercises combined with routine physical therapy were found to be more effective compared to routine physical therapy alone in chronic stroke patients for improving trunk balance and functional mobility. Registration Number: IRCT20211116053070N1.

The orphan nuclear receptor Nurr1 agonist amodiaquine mediates neuroprotective effects in 6-OHDA Parkinson's disease animal model by enhancing the phosphorylation of P38 mitogen-activated kinase but not PI3K/AKT signaling pathway.

Recent studies implicate the defects or altered expression of the orphan nuclear receptor Nurr1 gene in the substantia nigra in Parkinson's disease pathogenesis. In an attempt to corroborate the treatment-modifying disease that would replicate the effect of Nurr1, it has been found that amodiaquine and Nurr1 had the same chemical scaffolding, indicating a crucial structure-activity relationship. Interestingly, amodiaquine stimulate the transcriptional function of Nurr1 by physical interaction with its ligand-binding domain (LBD). However, the signaling route by which Nurr1 is activated by amodiaquine to cause the protective effect remains to be elucidated. We first demonstrated that amodiaquine treatment ameliorated behavioural deficits in 6-OHDA Parkinson's disease mouse model, and it promoted dopaminergic neurons protection signified by Tyrosine hydroxylase (TH) and dopamine transporter (DAT) mRNA; Tyrosine hydroxylase (TH) protein expression level and the immunoreactivity in the substantia nigra compacta. Subsequently, we used inhibitors to ascertain the effect of amodiaquine on Akt and P38 Mapk as crucial signaling pathways for neuroprotection. Wortmannin (Akt Inhibitor) induced a significant reduction of Akt mRNA; however, there was no statistical difference between the amodiaquine-treated group and the control group suggesting that amodiaquine may not be the active stimulant of Akt. Western blot analysis confirmed that the phosphorylated Akt decreased significantly in the amodiaquine group compared to the control group. In the same vein, we found that amodiaquine substantially increased the level of phosphorylated P38 Mapk. When P38 Mapk inhibited by SB203580 (P38-Mapk Inhibitor), the total P38 Mapk but not the phosphorylated P38 Mapk decreased significantly, while tyrosine hydroxylase significantly increased. These results collectively suggest that amodiaquine can augment tyrosine hydroxylase expression via phosphorylated P38 Mapk while negatively regulating the phosphorylated Akt in protein expression.

Musculoskeletal discomfort and wrist flexor tendonitis among street sweepers and associated risk factors.

BACKGROUND: Street sweepers are reported to suffer from high rates of work-related musculoskeletal discomfort worldwide, especially in their wrists. OBJECTIVE: The study aimed to 1) determine the prevalence of musculoskeletal disorders and 2) specifically determine the prevalence of wrist flexor tendonitis and its associated risk factors among street sweepers. METHODS: Three hundred and eighty-five sweepers employed by the Faisalabad Waste Management Company (FWMC) participated in this cross-sectional study. A self-structured questionnaire was used to collect data: the first section provided demographic information, the second assessed musculoskeletal disorders, and the third section assessed the wrist flexor tendonitis among street sweepers. RESULTS: The mean age of the sweepers was 38.34 years. Out of 385 street sweepers, the prevalence of musculoskeletal discomfort was reported in 265 (68.83%). The prevalence of musculoskeletal discomfort in sweepers reported during COVID-19 according to the past 12 months, the highest three prevalence rates were 46.5% in the wrists/hands, 37.9% in the shoulders and 35.1% in the lower back. The three highest prevalence rates of musculoskeletal discomfort in sweepers according to the last 7 days were 29.6% in the wrists/hands, 24.4% in the lower back and 24.2% in the shoulders. Out of total 385 participants, prevalence of wrist flexor tendonitis was reported in 103 (26.8%) sweepers. Significant association was found (p < 0.05) between wrist flexor tendonitis and gender (p < 0.003), age (p < 0.05), working experience (p < 0.003), street sweeping distance (p < 0.01), number of brooms used per month (p < 0.002) and getting tired at the end of work (p < 0.001). CONCLUSION: The prevalence of musculoskeletal discomfort and wrist flexor tendonitis seen during COVID-19 is high among sweepers, with wrist/hand being the most commonly reported region for pain. This study emphasizes the importance of providing guidelines about effective precautionary healthcare measures for street sweepers.

Single-nuclei RNA sequencing uncovers heterogenous transcriptional signatures in Parkinson's disease associated with nuclear receptor-related factor 1 defect.

Previous studies have found that deficiency in nuclear receptor-related factor 1 (Nurr1), which participates in the development, differentiation, survival, and degeneration of dopaminergic neurons, is associated with Parkinson's disease, but the mechanism of action is perplexing. Here, we first ascertained the repercussion of knocking down Nurr1 by performing liquid chromatography coupled with tandem mass spectrometry. We found that 231 genes were highly expressed in dopaminergic neurons with Nurr1 deficiency, 14 of which were linked to the Parkinson's disease pathway based on Kyoto Encyclopedia of Genes and Genomes analysis. To better understand how Nurr1 deficiency autonomously invokes the decline of dopaminergic neurons and elicits Parkinson's disease symptoms, we performed single-nuclei RNA sequencing in a Nurr1 LV-shRNA mouse model. The results revealed cellular heterogeneity in the substantia nigra and a number of activated genes, the preponderance of which encode components of the major histocompatibility II complex. Cd74, H2-Ab1, H2-Aa, H2-Eb1, Lyz2, Mrc1, Slc6a3, Slc47a1, Ms4a4b, and Ptprc2 were the top 10 differentially expressed genes. Immunofluorescence staining showed that, after Nurr1 knockdown, the number of CD74-immunoreactive cells in mouse brain tissue was markedly increased. In addition, Cd74 expression was increased in a mouse model of Parkinson's disease induced by treatment with 6-hydroxydopamine. Taken together, our results suggest that Nurr1 deficiency results in an increase in Cd74 expression, thereby leading to the destruction of dopaminergic neurons. These findings provide a potential therapeutic target for the treatment of Parkinson's disease.

Posterior urethral valves in patients with trisomy 21: Similar renal outcomes and rates of volitional voiding.

INTRODUCTION: Posterior urethral valves (PUV) occur in patients with Down Syndrome (DS) at a rate of 3-4%; far higher than the general population. Our understanding of the relationship between PUVs and DS is in its infancy, with the majority of the literature consisting of case reports. In this study, we present the largest known series of DS patients with PUVs. AIM: We hypothesized that patients with DS and PUVs would have worse functional bladder outcomes and renal outcomes when compared to PUV patients without DS. STUDY DESIGN: We queried our prospectively managed multi-institutional database of PUV patients from 1990 to 2021. We identified patients with a concomitant diagnosis of DS and PUV. In addition, we performed a systematic review of the literature describing the presentation of children with PUV and DS. Patient demographics, renal outcomes, voiding habits, surgical interventions, and radiologic images were aggregated and analyzed. RESULTS: Out of the 537 patients in our PUV database, we identified 18 patients with a concomitant diagnosis of PUV and DS, as well as 14 patients with a concomitant diagnosis of PUV and DS from the literature. DS and non-DS patients had a similar age at presentation, 31.5 days (2-731) and 17 (4-846), and length of follow up 6.32 years (2-11.2) and 6.98 (1-13). Both groups had similar nadir creatinines DS 0.43 (0.4-0.8), non-DS 0.31 (0.2-0.5) and similar rates of renal failure (DS 11.1% and non-DS 14.5%). With respect to bladder outcomes, a similar percentage of patients were volitionally voiding at last follow up (DS 72.2% and non-DS 72.3%). Our literature review corroborated these findings. CONCLUSIONS: Patients with DS and PUV have similar renal outcomes to other PUV patients in terms of renal function, progression to renal failure, and probability of volitional voiding with continence. Given the increased rate of PUVs in the DS population, physicians should have a high index of suspicion for PUV when patients with DS present with voiding dysfunction.

Caregiver distress: A mixed methods evaluation of the mental health burden of caring for children with bladder exstrophy.

Introduction: Caring for children with bladder exstrophy-epispadias complex (BEEC) exacts a long-term emotional toll on caregivers. Previous studies leave a gap in understanding the impact that caring for a child with BEEC has on caregivers in low- and middle-income countries (LMIC). We hypothesize that families and caregivers experience psychological distress that has long gone unaddressed. Materials and methods: From 2018 to 2020, researchers conducted a multi-method evaluation of caregiver distress with participants recruited as part of the annual International Bladder Exstrophy Collaboration based in Ahmedabad, Gujarat, India. In 2018, pilot data was collected through cognitive interviews. In 2019, researchers conducted structured interviews predicated on themes from the previous year, which subsequently prompted formal mental health screenings in 2020. Caregivers who reported suicidal thoughts were immediately referred for intervention. Results: In 2018, caregivers described the primary source of stigma arose from their village (n = 9, 26.5%). Caregivers also identified long-term concerns (n = 18, 52.9%), including future fertility and marital prospects, as sources of anxiety. In 2019, caregivers substantiated preliminary findings with the primary source of anticipated (n = 9, 31%) and experienced (n = 19, 65.5%) stigma again stemming from their communities. Both cohorts identified the collaboration as a positive source of support (n = 23, 36.5%). In 2020, caregivers stated decreased emotional wellbeing as number of subsequent repairs increased (n = 54, 75%, p = 0.002). Caregivers of children who underwent initial surgery within 5 years of screening reported higher anxiety (n = 46, 63.8%) and this was exacerbated as the number of subsequent repairs increased (p = 0.043). Conclusion: Complex, long-term course of care, including additional surgeries, significantly impacts caregiver distress in the LMIC setting. Screening for caregivers of children with complex congenital anomalies, like BEEC, should be an essential element of any comprehensive effort to alleviate the global burden of disease.

SOX1 Is a Backup Gene for Brain Neurons and Glioma Stem Cell Protection and Proliferation.

Failed neuroprotection leads to the initiation of several diseases. SOX1 plays many roles in embryogenesis, oncogenesis, and male sex determination, and can promote glioma stem cell proliferation, invasion, and migration due to its high expression in glioblastoma cells. The functional versatility of the SOX1 gene in malignancy, epilepsy, and Parkinson's disease, as well as its adverse effects on dopaminergic neurons, makes it an interesting research focus. Hence, we collate the most important discoveries relating to the neuroprotective effects of SOX1 in brain cancer and propose hypothesis worthy of SOX1's role in the survival of senescent neuronal cells, its roles in fibroblast cell proliferation, and cell fat for neuroprotection, and the discharge of electrical impulses for homeostasis. Increase in electrical impulses transmitted by senescent cells affects the synthesis of neurotransmitters, which will modify the brain cell metabolism and microenvironment.

Failure of Glial Cell-Line Derived Neurotrophic Factor (GDNF) in Clinical Trials Orchestrated By Reduced NR4A2 (NURR1) Transcription Factor in Parkinson's Disease. A Systematic Review.

Parkinson's disease (PD) is one of the most common neurodegenerative maladies with unforeseen complex pathologies. While this neurodegenerative disorder's neuropathology is reasonably well known, its etiology remains a mystery, making it challenging to aim therapy. Glial cell-line derived neurotrophic factor (GDNF) remains an auspicious therapeutic molecule for treating PD. Neurotrophic factor derived from glial cell lines is effective in rodents and nonhuman primates, but clinical findings have been equivocal. Laborious exertions have been made over the past few decades to improve and assess GDNF in treating PD (clinical studies). Definitive clinical trials have, however, failed to demonstrate a survival advantage. Consequently, there seemed to be a doubt as to whether GDNF has merit in the potential treatment of PD. The purpose of this cutting edge review is to speculate as to why the clinical trials have failed to meet the primary endpoint. We introduce a hypothesis, "Failure of GDNF in clinical trials succumbed by nuclear receptor-related factor 1 (Nurr1) shortfall." We demonstrate how Nurr1 binds to GDNF to induce dopaminergic neuron synthesis. Due to its undisputable neuro-protection aptitude, we display Nurr1 (also called Nr4a2) as a promising therapeutic target for PD.

ADAM17, A Key Player of Cardiac Inflammation and Fibrosis in Heart Failure Development During Chronic Catecholamine Stress.

Heart failure development is characterized by persistent inflammation and progressive fibrosis owing to chronic catecholamine stress. In a chronic stress state, elevated catecholamines result in the overstimulation of beta-adrenergic receptors (ßARs), specifically ß2-AR coupling with Gαi protein. Gαi signaling increases the activation of receptor-stimulated p38 mitogen-activated-protein-kinases (p38 MAPKs) and extracellular signal-regulated kinases (ERKs). Phosphorylation by these kinases is a common way to positively regulate the catalytic activity of A Disintegrin and Metalloprotease 17 (ADAM17), a metalloprotease that has grown much attention in recent years and has emerged as a chief regulatory hub in inflammation, fibrosis, and immunity due to its vital proteolytic activity. ADAM17 cleaves and activates proinflammatory cytokines and fibrotic factors that enhance cardiac dysfunction via inflammation and fibrosis. However, there is limited information on the cardiovascular aspect of ADAM17, especially in heart failure. Hence, this concise review provides a comprehensive insight into the structure of ADAM17, how it is activated and regulated during chronic catecholamine stress in heart failure development. This review highlights the inflammatory and fibrotic roles of ADAM17's substrates; Tumor Necrosis Factor α (TNFα), soluble interleukin-6 receptor (sIL-6R), and amphiregulin (AREG). Finally, how ADAM17-induced chronic inflammation and progressive fibrosis aggravate cardiac dysfunction is discussed.