Mitochondrial quality control in human health and disease.

Mitochondria, the most crucial energy-generating organelles in eukaryotic cells, play a pivotal role in regulating energy metabolism. However, their significance extends beyond this, as they are also indispensable in vital life processes such as cell proliferation, differentiation, immune responses, and redox balance. In response to various physiological signals or external stimuli, a sophisticated mitochondrial quality control (MQC) mechanism has evolved, encompassing key processes like mitochondrial biogenesis, mitochondrial dynamics, and mitophagy, which have garnered increasing attention from researchers to unveil their specific molecular mechanisms. In this review, we present a comprehensive summary of the primary mechanisms and functions of key regulators involved in major components of MQC. Furthermore, the critical physiological functions regulated by MQC and its diverse roles in the progression of various systemic diseases have been described in detail. We also discuss agonists or antagonists targeting MQC, aiming to explore potential therapeutic and research prospects by enhancing MQC to stabilize mitochondrial function.

Mangiferin alleviates diabetic pulmonary fibrosis in mice via inhibiting endothelial-mesenchymal transition through AMPK/FoxO3/SIRT3 axis.

Diabetes mellitus results in numerous complications. Diabetic pulmonary fibrosis (DPF), a late pulmonary complication of diabetes, has not attracted as much attention as diabetic nephropathy and cardiomyopathy. Mangiferin (MF) is a natural small molecular compound that exhibits a variety of pharmacological effects including anti-inflammatory, anti-cancer, anti-diabetes, and anti-fibrosis effects. In this study, we investigated whether long-term diabetes shock induces DPF, and explored whether MF had a protective effect against DPF. We first examined the lung tissues and sections of 20 diabetic patients obtained from discarded lung surgical resection specimens and found that pulmonary fibrosis mainly accumulated around the pulmonary vessels, accompanied by significantly enhanced endothelial-mesenchymal transition (EndMT). We established a mouse model of DPF by STZ injections. Ten days after the final STZ injection, the mice were administered MF (20, 60 mg/kg, i.g.) every 3 days for 4 weeks, and kept feeding until 16 weeks and euthanized. We showed that pulmonary fibrotic lesions were developed in the diabetic mice, which began around the pulmonary vessels, while MF administration did not affect long-term blood glucose levels, but dose-dependently alleviated diabetes-induced pulmonary fibrosis. In human umbilical vein endothelial cells (HUVECs), exposure to high glucose (33.3 mM) induced EndMT, which was dose-dependently inhibited by treatment with MF (10, 50 µM). Furthermore, MF treatment promoted SIRT3 expression in high glucose-exposed HUVECs by directly binding to AMPK to enhance the activity of FoxO3, which finally reversed diabetes-induced EndMT. We conclude that MF attenuates DPF by inhibiting EndMT through the AMPK/FoxO3/SIRT3 axis. MF could be a potential candidate for the early prevention and treatment of DPF.

Recapitulation of SARS-CoV-2 Infection and Cholangiocyte Damage with Human Liver Organoids

The newly emerged pandemic coronavirus, SARS-CoV-2, has posed a significant public health threat worldwide. However, the mode of virus transmission and tissue tropism is not well established yet. Recent findings of substantial liver damage in patients and ACE2+ cholangiocytes in healthy liver tissues prompted us to hypothesize that human liver ductal organoids could serve as a model to determine the susceptibility and mechanisms underlining the liver damage upon SARS-CoV-2 infection. By single-cell RNA sequencing, we found that long-term liver ductal organoid culture preserved the human specific ACE2+ population of cholangiocytes. Moreover, human liver ductal organoids were permissive to SARS-CoV-2 infection and support robust replication. Notably, virus infection impaired the barrier and bile acid transporting functions of cholangiocytes through dysregulation of genes involved in tight junction formation and bile acid transportation, which could explain the bile acid accumulation and consequent liver damage in patients. These results indicate that control of liver damage caused directly by viral infection should be valued in treating COVID-19 patients. Our findings also provide an application of human organoids in investigating the tropism and pathogenesis of SARS-CoV-2, which would facilitate novel drug discovery.

Efficacy of electroacupuncture nerve stimulation therapy for interstitial cystitis/bladder pain syndrome / 中国针灸

OBJECTIVE@#To explore the clinical efficacy of electroacupuncture nerve stimulation therapy (ENST) for interstitial cystitis/painful bladder syndrome (IC/PBS).@*METHODS@#A total of 68 patients with IC/PBS were randomly divided into an observation group and a control group, 34 cases in each one. The patients in the observation group were treated with ENST; abdominal four acupoints and sacral four acupoints were connected with a pair of electrodes and treated alternately every other day. The ENST was given 50 min per times, three times a week for 3 months. The patients in the control group were treated with perfusion therapy of four-medication combination (heparin sodinm, lidocaine, sodium bicarbonate, gentamicin sulfate), twice a week for the first 6-8 weeks, followed by twice per month for 3 months. The infusion fluid remained for 1 h before discharging. The O' Leary-Sant score, including interstitial cystitis symptom index (ICSI) and interstitial cystitis problem index (ICPI), 24 h urination frequency, visual analogue scale (VAS) and maximum bladder volume were observed before treatment and treatment of 1 month, 3 months and 6 months after treatment respectively; the adverse events during the treatment were also recorded.@*RESULTS@#Compared before treatment, the O'Leary-Sant score (ICSI, ICPI), 24 h urination frequency, VAS and maximum bladder volume in the two groups were improved after 1, 3 months treatment and 6 months after treatment (all <0.05). The scores of ICSI, ICPI, VAS and 24 h urination frequency in the observation group were significantly lower than those in the control group (<0.05). The maximum bladder volume in the observation group was significantly higher than that in the control group (<0.05). Six months after treatment, the total effective rate in the observation group was 87.5% (28/32), which was higher than 69.7% (23/33) in the control group (<0.01). No significant adverse events occurred during the treatment.@*CONCLUSION@#ENST could effectively relieve the clinical symptoms of IC/PBS, but its long-term efficacy needs further observation.

Changes of Leukemia Stem Cells in Acute Myeloid Leukemia before and after Treatment / 中国实验血液学杂志

<p><b>OBJECTIVE</b>To investigate the presence of leukemia stem cells (LSC) in acute myeloid leukemia (AML) and find out the relative position of leukemia cells in the figures of flow cytometry, and to analyze the relationship between minimal residual diseases (MRD) and the level of LSC, so as to explore the correlation of LSC changes with the curative effect and the prognosis during chemical therapy.</p><p><b>METHODS</b>A total of 85 samples were collected from 50 AML (except M3) patients, including 50 samples from the newly diagnosed patients, 7 samples of AML patients with non-remission and 28 samples of AML patients with complete remission. All samples were used for detection of LSC from immune phenotype of CD34/CD38/CD123 by flow cytometry. The detection of immune phenotypic of leukemia cells was performed in the newly diagnosed patients. The detection of leukemia- associated immune phenotypes (LAIP) was implemented in the non-newly diagnosed patients.</p><p><b>RESULTS</b>The LSC was identified in the CD34/ CD38/ CD123 in AML and consistent with the relative position of the leukemia cell in flow cytometry figures. Statistical analysis showed significant difference in LSC content between the newly diagnosed AML group and the post-chemotherapy complete remission group(P<0.01),but did not between the newly diagnosed AML group and the post-chemotherapy non-remission group(P>0.05).There was significant positive correlation between the LSC content and MRD level in 28 AML patients with complete remission (r=0.680,P<0.01).</p><p><b>CONCLUSION</b>LSC exist in AML and the relative position are consistent with the leukemia cells in flow cytometry figures, the size characteristics and weak expression of CD45 are also similar to leukemia cells. The proportion of LSC decreases after chemotherapy. Detecting and tracking the LSC changes in bone marrow and combination with detecting minimal resident disease(MRD) may contribute to evaluate the theraputic efficacy and prognosis of leukemia patients.</p>

Inhibition of microRNA-214 promotes epithelial–mesenchymal transition process and induces interstitial cystitis in postmenopausal women by upregulating Mfn2

Our study aims to investigate the roles that microRNA-214 (miR-214) plays in the epithelial mesenchymal transition (EMT) process and the development of interstitial cystitis (IC) in postmenopausal women by targeting Mitofusin 2 (Mfn2). IC bladder tissues and adjacent normal bladder tissues were collected from postmenopausal women. Immunohistochemistry (IHC) staining was conducted. The target relationship between miR-214 and Mfn2 was determined by a dual luciferase reporter gene assay. Adipose-derived mesenchymal stem cells (ADMSCs) were extracted from postmenopausal rats and assigned to the blank, mimics, miR-214 inhibitors, mimics negative control (NC), inhibitors NC, Mfn2 siRNA, miR-214 inhibitors and Mfn2 siRNA groups. Exosomes secreted by transfected ADMSCs were instilled into the bladders of postmenopausal rats. The expression of miR-214 and Mfn2 mRNA and EMT markers was assessed by qRT-PCR and western blotting. It was confirmed that Mfn2 was the target gene of miR-214 in IC. Compared with the normal bladder tissues, miR-214 decreased, but Mfn2 increased in IC bladder tissues. Compared with the blank group, the expression of miR-214 and the expression levels of N-cadherin, Fibronectin, Twist1, Snail and Vimentin mRNA and protein increased, whereas the expression levels of Mfn2, E-cadherin and ZO-1 mRNA and protein decreased in the miR-214 mimics and Mfn2 groups. The expression of MiR-214 and the expression levels of N-cadherin, Fibronectin, Twist1, Snail and Vimentin mRNA and protein decreased, whereas the expression levels of Mfn2, E-cadherin and ZO-1 mRNA and protein increased in the miR-214 inhibitors group. Our findings indicate that the inhibition of miR-214 promotes the EMT process and contributes to bladder wall fibrosis by up-regulating Mfn2, thus leading to the occurrence of IC in postmenopausal women.

Presence of autoantibodies against β1-adrenoceptor aggravates the kidney injury in rats / 生理学报

Since the autoantibodies against the second extracellular loop of β(1)-adrenoceptor (β(1)-AABs) have been found in the sera of patients with idiopathic dilated cardiomyopathy (IDCM), the involvement of autoimmune mechanisms in the pathogenesis of many cardiovascular diseases has extensively been investigated. Our previous study found that urinary occult blood and protein excretion were frequently found in the rats with positive β(1)-AABs, but the mechanisms are unclear. Therefore, we infused the β(1)-AABs into the vein periodically in an attempt to investigate whether β(1)-AABs could induce morphological and functional changes in the kidneys of adult and aged rats and explore the possible mechanisms. The synthetic peptide according to the sequences of the second extracellular loop of β(1)-adrenoceptor (β(1)-AR-ECII) was used to immunize the adult rats to acquire enough β(1)-AABs for use. Neonatal rat ventricular myocytes (NRVMs) culture was used to observe the biological effects of β(1)-AABs on the beating rate. The purified β(1)-AABs were transfused into the vein of rats. The sera level of blood urea nitrogen (BUN), creatinine (CR), uric acid (UA), urinary specific gravity, protein excretion, occult blood and urinary glucose were detected at the different time points by biochemistry and urine analyzers. HE and Masson's trichrome staining were used to detect the changes in kidney structure of passively immunized rats. Enhanced green fluorescent protein (EGFP) and β(1)-AR-EGFP plasmids were transfected into the human embryonic kidney 293 (HEK293) cells in order to observe the changes in cell injury with the treatment of β(1)-AABs. It was found that the sera level of BUN, CR and UA increased gradually and the ratio of BUN to CR decreased progressively with the administration of β(1)-AABs. The increasing of proteinuria, urinary occult blood and urinary glucose was detected by urine analyzer in β(1)-AABs group. By HE and Masson's coloration, lots of mononuclear cell infiltration and collagen fibers deposition could be observed at the 24th week of immunization. After the treatment of β(1)-AABs, the caspase-3 activity increased significantly in the HEK293 cells transfected with β(1)-AR-EGFP plasmids, while no significant changes were observed for lactate dehydrogenase (LDH) activity. The results indicate that long-term presence of β(1)-AABs can induce the morphological and functional damage of the kidneys in adult and aged rats.

Modulation and function of calcium signaling in retinal horizontal cells / 生理学报

Calcium is one of the most versatile intracellular second messengers, which plays crucial roles in many intracellular signaling pathways. Researches on intracellular calcium distribution, regulation and function are important for our understanding of cellular physiology. In this mini-review, the regulation of intracellular calcium signal in retinal horizontal cells and the relevant physiological functions were introduced based on the experiments carried out in our laboratory. Intracellular calcium dynamics following the activation of AMPA and NMDA receptors were introduced based on our experiments performed on carp retinal horizontal cells using calcium imaging technique and computational methods. An initial peak response was observed in both cases, which indicated an active participation of intracellular calcium store during the calcium dynamics initiated by AMPA/NMDA receptor activation. Intracellular recording experiments indicated that calcium signaling was crucial for the gradual enhancement of the retinal horizontal cell's responsiveness in exposure to repetitive red flashes. Possible roles of intracellular calcium signaling in the regulation of GABA transporter activity were also introduced based on our whole-cell recording experiments performed on isolated carp retinal horizontal cells.

Analysis of normal eye anterior segments in different ages / 上海第二医科大学学报

Objective To measure and conduct statistic analysis of normal eyes by Pentacam. Methods Two hundred and twenty-one healthy people (442 eyes) underwent examinations of Pentacam, and they were divided into 5 groups by age: <40 years old group (50 people, 100 eyes), 40-49 years old group (50 people, 100 eyes), 50-59 years old group (50 people, 100 eyes), 60-69 years old group (50 people, 100 eyes) and >70 years old group (21 people, 42 eyes). Results With the increase of age, there were significant differences in chamber volume, chamber angle and anterior chamber depth among age groups (P<0.05). In elder age groups, there were significant differences in these parameters between males and females (P<0.01). Conclusion Anterior segment parameters are significantly correlated with age. After 60 years old, the anterior segment parameters become significantly different with gender.

Ethical Issues in the Emergency Nursing of Upper Gastrointestinal Hemorrhage / 中国医学伦理学

To strengthen nursing ethics education and nursing construction are the solid foundation for successful emergency nursing.This paper analyzes the demand for building a reasonable nursing echelon,explores problems in current condition,and comes up with feasible countermeasures,thus providing reference for strengthening nursing echelon construction.