Progress on growth promoting therapies other than growth hormone.

Recombinant human growth hormone is a classical therapeutic drug for children with short stature. In recent years, as the mechanism of growth in children has been further explored, growth-promoting therapies other than growth hormone have made great progress. Recombinant human insulin-like growth factor (IGF)-1 is the main treatment for primary IGF-1 deficiency, and C-type natriuretic peptide (CNP) offers a therapeutic option for children with short stature due to chondrodysplasia. Growth hormone-releasing peptide analogues stimulate growth hormone release and may be used for growth-promoting therapy. In addition, gonadotropin-releasing hormone analogue (GnRHa) and aromatase inhibitors may delay the bone age in children and may be beneficial in improving final height. In this article, the research progress of growth-promoting therapies other than growth hormones is reviewed to provide more options for the clinical treatment of children with short stature.

Alternate-day fasting delays pubertal development in normal-weight mice but prevents high-fat diet-induced obesity and precocious puberty.

BACKGROUND/OBJECTIVES: Childhood obesity, particularly in girls, is linked to early puberty onset, heightening risks for adult-onset diseases. Addressing childhood obesity and precocious puberty is vital to mitigate societal burdens. Despite existing costly and invasive medical interventions, introducing lifestyle-based alternatives is essential. Our study investigates alternate-day fasting's (ADF) impact on pubertal development in normal-weight and high-fat diet (HFD)-induced obese female mice. METHODS: Four groups of female mice were utilized, with dams initially fed control chow during and before pregnancy. Post-parturition, two groups continued on control chow, while two switched to an HFD. Offspring diets mirrored maternal exposure. One control and one HFD group were subjected to ADF. Morphometry and hormone analyses at various time points were performed. RESULTS: Our findings demonstrate that ADF in normal-weight mice led to reduced body length, weight, uterine, and ovarian weights, accompanied by delayed puberty and lower levels of sex hormones and growth hormone (GH). Remarkably, GH treatment effectively prevented ADF-induced growth reduction but did not prevent delayed puberty. Conversely, an HFD increased body length, induced obesity and precocious puberty, and altered sex hormones and leptin levels, which were counteracted by ADF regimen. Our data indicate ADF's potential in managing childhood obesity and precocious puberty. CONCLUSIONS: ADF reduced GH and sex hormone levels, contributing to reduced growth and delayed puberty, respectively. Therefore, parents of normal-weight children should be cautious about prolonged overnight fasting. ADF prevented HFD-induced obesity and precocious puberty, offering an alternative to medical approaches; nevertheless, further studies are needed for translation into clinical practice.

Investigation on the hesitancy of COVID-19 vaccination among liver transplant recipients: A cross-sectional study in China.

Objectives: The hospitalization and mortality rate from COVID-19 appears to be higher in liver transplant recipients when compared with general populations. Vaccination is an effective strategy to reduce the risk during the COVID-19 pandemic. We aimed to evaluate COVID-19 vaccine hesitancy in liver transplant recipients. Methods: In April 2022, we conducted an online-based survey through WeChat platform to investigate the vaccination hesitancy among liver transplant recipients followed at Shanghai Renji Hospital and further explore possible influencing factors. Survey items included multiple choice, Likert-type rating scale and open-ended answers. Participants were classified as no hesitancy group and hesitancy group. Using univariate analysis, ROC curve analysis and multiple logistic regression to evaluate associations between baseline characteristics and COVID-19 vaccine hesitancy. Results: 449 liver transplant recipients participated in the survey with 299 (66.6%) of them being categorized as vaccine hesitancy. In no hesitancy group, 73 (48.7%) recipients had completed vaccination, while 77 (51.3%) were not yet but intended to be vaccinated. In contrast, 195 (65.2%) recipients in hesitancy group were hesitant to get vaccinated, while the remaining 104 (34.8%) refused. The most common side effect was injection arm pain (n = 9, 12.3%). The common reasons for vaccine willingness was trusted in the effectiveness of the vaccine and fear of contracting COVID-19. The most common reason for vaccination hesitancy is fear of side effects, and the most effective improvement was the support from the attending physician. Factors associated with vaccine hesitancy include female sex, influenza vaccination status, awareness of the importance and safety of vaccine, attitudes of doctors and others toward vaccine, medical worker source information of vaccine, relative/friend with medical background, total score of VHS (Vaccine Hesitancy Scale), accessibility of vaccine. Conclusion: For liver transplant recipients, COVID-19 vaccine is an important preventive measure. Identifying the factors influencing COVID-19 vaccine hesitancy is therefore critical to developing a promotion plan. Our study shows that more comprehensive vaccine knowledge popularization and relevant medical workers' training can effectively improve the acceptance of COVID-19 vaccine in this population.

Profiling of miR-205/P4HA3 Following Angiotensin II-Induced Atrial Fibrosis: Implications for Atrial Fibrillation.

Objective: Atrial fibroblasts are the main component of atrial fibrosis. Data in previous studies proved the implication of miRNAs in AF progression and the association of miR-205 with cancer associated-fibroblasts, while no evidence supported the implication of miR-205 in atrial fibrosis. Therefore, this study aims to explore the effect and mechanism of miR-205/P4HA3 axis on atrial fibrosis. Methods: Angiotensin II (Ang II) was used to induce atrial fibrosis model in rats, which was verified by H&E staining and Masson staining. qRT-PCR and Western blot were applied to measure the expressions of miR-205, P4HA3, collagen I, and α-SMA. The rat atrial fibroblasts were isolated and then subjected to Ang II treatment or cell transfection for determination of cell biological functions using CCK-8, BrdU assay, TUNEL staining, and cell scratch assay. qRT-PCR and Western blot was applied to analyze the expressions of miR-205, P4HA3, collagen I, α-SMA, JNK, and p-JNK in atrial fibroblasts. Dual-luciferase reporter gene assay and RNA immune-precipitation experiment was employed to verify the binding relationship between miR-205 and P4HA3. Results: Ang II induced rats had disordered arrangement of atrial muscles with uneven nuclear sizes and necrotic atrial myocytes, and increased collagen deposition, in which elevated expressions of P4HA3, collagen I, and α-SMA as well as suppressed expression level of miR-205 were found. In vitro, Ang II treatment in atrial fibroblasts with overexpression of P4HA3 facilitated cellular migration and proliferation, with the induction of JNK signaling pathway. However, these trends were reversed after transfection with miR-205 mimic. P4HA3 is a target gene of miR-205. Conclusion: The miR-205/P4HA3 axis is implicated in atrial fibrosis by inhibition of rat fibroblast proliferation and migration and the inactivation of JNK signaling pathway.

A Novel Rat Model of Cardiac Donation After Circulatory Death Combined With Normothermic ex situ Heart Perfusion.

Background: In heart transplantation, the adoption of hearts from donation after circulatory death (DCD) is considered to be a promising approach to expanding the donor pool. Normothermic ex situ heart perfusion (ESHP) is emerging as a novel preservation strategy for DCD hearts. Therefore, pre-clinical animal models of ESHP are essential to address some key issues before efficient clinical translation. We aim to develop a novel, reproducible, and economical rat model of DCD protocol combined with normothermic ESHP. Methods: Circulatory death of the anesthetized rats in the DCD group was declared when systolic blood pressure below 30 mmHg or asystole was observed after asphyxiation. Additional 15 min of standoff period was allowed to elapse. After perfusion of cold cardioplegia, the DCD hearts were excised and perfused with allogenic blood-based perfusate at constant flow for 90 min in the normothermic ESHP system. Functional assessment and blood gas analysis were performed every 30 min during ESHP. The alteration of DCD hearts submitted to different durations of ESHP (30, 60, and 90 min) in oxidative stress, apoptosis, tissue energy state, inflammatory response, histopathology, cell swelling, and myocardial infarction during ESHP was evaluated. Rats in the non-DCD group were treated similarly but not exposed to warm ischemia and preserved by the normothermic ESHP system for 90 min. Results: The DCD hearts showed compromised function at the beginning of ESHP and recovered over time, while non-DCD hearts presented better cardiac function during ESHP. The alteration of DCD hearts in oxidative stress, apoptosis, tissue energy state, histopathological changes, cell swelling, and inflammatory response didn't differ among different durations of ESHP. At the end of 90-min ESHP, DCD, and non-DCD hearts presented similarly in apoptosis, oxidative stress, inflammatory response, myocardial infarction, and histopathological changes. Moreover, the DCD hearts had lower energy storage and more evident cell swelling compared to the non-DCD hearts. Conclusion: We established a reproducible, clinically relevant, and economical rat model of DCD protocol combined with normothermic ESHP, where the DCD hearts can maintain a stable state during 90-min ESHP.

Normothermic ex vivo Heart Perfusion Combined With Melatonin Enhances Myocardial Protection in Rat Donation After Circulatory Death Hearts via Inhibiting NLRP3 Inflammasome-Mediated Pyroptosis.

OBJECTIVE: The adoption of hearts from donation after circulatory death (DCD) is a promising approach for the shortage of suitable organs in heart transplantation. However, DCD hearts suffer from serious ischemia/reperfusion injury (IRI). Recent studies demonstrate that nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome-mediated pyroptosis is a novel target to ameliorate myocardial IRI. Melatonin is shown to inhibit NLRP3 inflammasome-mediated pyroptosis. Therefore, this study is designed to verify the hypothesis that melatonin can protect the heart graft preserved with ex vivo heart perfusion (EVHP) against myocardial IRI via inhibiting NLRP3 inflammasome-mediated pyroptosis in a rat model of DCD. METHODS: Donor-heart rats were randomly divided into three groups: (1) Control group: non-DCD hearts were harvested from heart-beating rats and immediately preserved with allogenic blood-based perfusate at constant flow for 105 min in the normothermic EVHP system; (2) DCD-vehicle group; and (3) DCD-melatonin group: rats were subjected to the DCD procedure with 25 min of warm ischemia injury and preserved by the normothermic EVHP system for 105 min. Melatonin (200 µmol/L) or vehicle was perfused in the cardioplegia and throughout the whole EVHP period. Cardiac functional assessment was performed every 30 min during EVHP. The level of oxidative stress, inflammatory response, apoptosis, and NLRP3 inflammasome-mediated pyroptosis of heart grafts submitted to EVHP were evaluated. RESULTS: Twenty five-minute warm ischemia injury resulted in a significant decrease in the developed pressure (DP), dP/dt max , and dP/dt min of left ventricular of the DCD hearts, while the treatment with melatonin significantly increased the DP, dP/dt max of the left ventricular of DCD hearts compared with DCD-vehicle group. Furthermore, warm ischemia injury led to a significant increase in the level of oxidative stress, inflammatory response, apoptosis, and NLRP3 inflammasome-mediated pyroptosis in the hearts preserved with EVHP. However, melatonin added in the cardioplegia and throughout the EVHP period significantly attenuated the level of oxidative stress, inflammatory response, apoptosis, and NLRP3 inflammasome-mediated pyroptosis compared with DCD-vehicle group. CONCLUSION: EVHP combined with melatonin post-conditioning attenuates myocardial IRI in DCD hearts by inhibiting NLRP3 inflammasome-mediated pyroptosis, which might expand the donor pool by the adoption of transplantable DCD hearts.