Currently, the incidence of Parkinson's disease (PD) is on the rise. More and more evidences suggest that mitochondrial dysfunction plays a crucial role in the etiology of PD, and dysfunction of mitochondrial complex I (MCI) is one of the most critical factors leading to mitochondrial dysfunction. On one hand, MCI dysfunction stimulates dopaminergic neurons to produce reactive oxygen species (ROS). On the other hand, MCI dysfunction decreases dopaminergic neuron viability and reduces ATP production. All these outcomes promote the pathological progression of PD. This review summarizes research progress on the role of MCI in the pathogenesis of PD, as well as PD treatment strategies based on MCI.
Parkinson Disease/metabolism* ; Humans ; Electron Transport Complex I/metabolism* ; Mitochondria/physiology* ; Reactive Oxygen Species/metabolism* ; Dopaminergic Neurons/metabolism* ; Animals ; Adenosine Triphosphate/metabolism*

OBJECTIVE: To explore the clinical phenotype and genetic characteristics of a Chinese Han pedigree with Darier's disease (DD). METHODS: A DD pedigree, who visited Tongji Hospital of Tongji University on October 22, 2023, was selected as the study subject. Clinical data of the pedigree were collected, and whole exome sequencing was performed on the proband. Suspected variant loci were screened, and Sanger sequencing was used to validate the variant in pedigree members. Bioinformatics analysis was performed on the variant loci. This study was approved by the Medical Ethics Committee of Tongji Hospital of Tongji University Ethics No.K-W-2024-004). RESULTS: The proband is a 67-year-old female with clinical features of DD, such as keratotic papules in sebaceous areas. whole exome sequencing revealed a missense variant, c.68G>A (p.Gly23Glu), in the exon 1 of ATP2A2 gene of the proband. Sanger sequencing showed that the proband's eldest daughter also carried this variant. This variant was not detected in other pedigree members, indicating a co-segregation of the variant with the disease phenotype in the pedigree. According to the interpretation principles of gene variants by the American College of Medical Genetics and Genomics (ACMG), this variant was classified as pathogenic (PS1+PM1+PM2_Supporting+PP1+PP3+PP4). CONCLUSION The c.68G>A (p.Gly23Glu) variant in the ATP2A2 gene may be the genetic cause of the disease in this pedigree. This finding further enriches the genetic variant spectrum in DD patients and provides a basis for clinical diagnosis and genetic counseling for patients.
Aged ; Female ; Humans ; Male ; China ; Darier Disease/genetics* ; Exome Sequencing ; Mutation, Missense ; Pedigree ; Phenotype ; East Asian People ; Sarcoplasmic Reticulum Calcium-Transporting ATPases

OBJECTIVES: Application of ultrashort wave (USW) to rats with cerebral ischemia and reperfusion injury could inhibit the decrease of expression of secretory pathway Ca²⁺-ATPase 1 (SPCA1), an important participant in Golgi stress, reduce the damage of Golgi apparatus and the apoptosis of neuronal cells, thereby alleviating cerebral ischemia-reperfusion injury. This study aims to investigate the effect of USW on oxygen-glucose deprivation/reperfusion (OGD/R) injury and the expression of SPCA1 at the cellular level. METHODS: N2a cells were randomly divided into a control (Con) group, an OGD/R group, and an USW group. The cells in the Con group were cultured without exposure to OGD. The cells in the OGD/R group were treated with OGD/R. The cells in the USW group were treated with USW after OGD/R. Cell morphology was observed under the inverted phase-contrast optical microscope, cell activity was detected by cell counting kit-8 (CCK-8), apoptosis was detected by flow cytometry, and SPCA1 expression was detected by Western blotting. RESULTS: Most of the cells in the Con group showed spindle shape with a clear outline and good adhesion. In the OGD/R group, cells were wrinkled, with blurred outline, poor adhesion, and lots of suspended dead cells appeared; compared with the OGD/R group, the cell morphology and adherence were improved, with clearer outlines and fewer dead cells in the USW group. Compared with the Con group, the OGD/R group showed decreased cell activity, increased apoptotic rate, and down-regulating SPCA1 expression with significant differences (all <i>Pi><0.001); compared with the OGD/R group, the USW group showed increased cell activity, decreased apoptotic rate, and up-regulating SPCA1 expression with significant differences (<i>Pi><0.01 or <i>Pi><0.001). CONCLUSIONS USW alleviates the injury of cellular OGD/R, and its protective effect may be related to its up-regulation of SPCA1 expression.
Animals ; Rats ; Apoptosis ; Brain Ischemia ; Glucose/metabolism* ; Oxygen/metabolism* ; Reperfusion Injury/metabolism* ; Transcriptional Activation ; Up-Regulation ; Calcium-Transporting ATPases/metabolism*

BACKGROUND: Sarcoplasmic reticulum calcium ATPase 2a (SERCA2a) is a key protein that maintains myocardial Ca 2+ homeostasis. The present study aimed to investigate the mechanism underlying the SERCA2a-SUMOylation (small ubiquitin-like modifier) process after ischemia/reperfusion injury (I/RI) in vitro and in vivo . METHODS: Calcium transient and systolic/diastolic function of cardiomyocytes isolated from Serca2a knockout (KO) and wild-type mice with I/RI were compared. SUMO-relevant protein expression and localization were detected by quantitative real-time PCR (RT-qPCR), Western blotting, and immunofluorescence in vitro and in vivo . Serca2a-SUMOylation, infarct size, and cardiac function of Senp1 or Senp2 overexpressed/suppressed adenovirus infected cardiomyocytes, were detected by immunoprecipitation, triphenyltetrazolium chloride (TTC)-Evans blue staining, and echocardiography respectively. RESULTS: The results showed that the changes of Fura-2 fluorescence intensity and contraction amplitude of cardiomyocytes decreased in the I/RI groups and were further reduced in the Serca2a KO + I/RI groups. Senp1 and Senp2 messenger ribose nucleic acid (mRNA) and protein expression levels in vivo and in cardiomyocytes were highest at 6 h and declined at 12 h after I/RI. However, the highest levels in HL-1 cells were recorded at 12 h. Senp2 expression increased in the cytoplasm, unlike that of Senp1. Inhibition of Senp2 protein reversed the I/RI-induced Serca2a-SUMOylation decline, reduced the infarction area, and improved cardiac function, while inhibition of Senp1 protein could not restore the above indicators. CONCLUSION I/RI activated Senp1 and Senp2 protein expression, which promoted Serca2a-deSUMOylation, while inhibition of Senp2 expression reversed Serca2a-SUMOylation and improved cardiac function.
Animals ; Mice ; Calcium/metabolism* ; Cysteine Endopeptidases/metabolism* ; Myocardial Reperfusion Injury/metabolism* ; Myocardium/metabolism* ; Myocytes, Cardiac/metabolism* ; Proteins/metabolism* ; Sarcoplasmic Reticulum Calcium-Transporting ATPases/genetics*

Objective: To investigate the expression of cation chloride cotransporter (NKCC1/KCC2) in the neurons from cerebral lesions of children with focal cortical dysplasia (FCD) type Ⅱ, to provide a morphological basis for revealing the possible mechanism of epilepsy. Methods: Eight cases of FCD type Ⅱ diagnosed at Beijing Haidian Hospital, Beijing, China and 12 cases diagnosed at Xuanwu Hospital, Capital Medical University, Beijing, China from February 2017 to December 2019 were included. The expression of NKCC1 and KCC2 in FCD type Ⅱa and FCD type Ⅱb was detected using immunohistochemistry and double immunohistochemical stains. The average optical density of NKCC1 in dysmorphic neurons and normal neurons was also determined using immunohistochemical staining in FCD type Ⅱa (10 cases). Results: The patients were all younger than 14 years of age. Ten cases were classified as FCD type IIa, and 10 cases as FCD type Ⅱb. NKCC1 was expressed in the cytoplasm of normal cerebral cortex neurons and KCC2 expressed on cell membranes. In dysmorphic neurons of FCD type Ⅱa, expression of NKCC1 increased, which was statistically higher than that of normal neurons (<i>P<i>0.01). Aberrant expression of KCC2 in dysmorphic neurons was also noted in the cytoplasm. In the FCD Ⅱb type, the expression pattern of NKCC1/KCC2 in dysmorphic neurons was the same as that of FCD type Ⅱa. The aberrant expression of NKCC1 in balloon cells was negative or weakly positive on the cell membrane, while the aberrant expression of KCC2 was absent. Conclusions: The expression pattern of NKCC1/KCC2 in dysmorphic neurons and balloon cells is completely different from that of normal neurons. The NKCC1/KCC2 protein-expression changes may affect the transmembrane chloride flow of neurons, modify the effect of inhibitory neurotransmitters γ-aminobutyric acid and increase neuronal excitability. These effects may be related to the occurrence of clinical epileptic symptoms.
Child ; Humans ; Brain/pathology* ; Cations/metabolism* ; Chlorides/metabolism* ; Epilepsy/metabolism* ; Malformations of Cortical Development, Group I/metabolism* ; Solute Carrier Family 12, Member 2/metabolism* ; Symporters/metabolism*

Cardiovascular Diseases ; Heart Failure ; Humans ; Protein Processing, Post-Translational ; Sarcoplasmic Reticulum Calcium-Transporting ATPases

OBJECTIVE: To explore the molecular basis for a pedigree affected with Darier-White disease. METHODS: Genomic DNA was isolated from 3 patients and 1 unaffected member from the pedigree, as well as 80 healthy controls. Targeted sequence capture and next-generation sequencing were used to screen mutations of skin disease-related genes. Candidate mutations were verified by Sanger sequencing, and co-segregation analysis was carried out to confirm the pathogenicity of mutation. Conservation analysis and protein structure and function were also predicted with Bioinformatic tools. RESULTS: A heterozygous mutation c.2246G>T (p.G749V) was identified in exon 15 of ATP2A2 gene in all 3 patients from the pedigree, but not in the unaffected member or 80 healthy controls. The corresponding amino acid was highly conserved, and mutation of which can lead to structural and functional changes of the protein. CONCLUSION The c.2246G>T missense mutation of the ATP2A2 gene probably underlies the Darier-White disease in this pedigree by causing damages to the structure and function of sarcoplasmic/endoplasmic reticulum calcium ATPase 2 (SERCA2).
Darier Disease ; genetics ; Heterozygote ; Humans ; Mutation, Missense ; Pedigree ; Sarcoplasmic Reticulum Calcium-Transporting ATPases ; genetics

PURPOSE: We evaluated the relationship between fluorine-18 fluoro-2-deoxy-glucose (¹⁸F-FDG) uptake and mitochondrial activity in cancer cells and investigated the prognostic implications of this relationship in patients with invasive ductal carcinoma of the breast (IDCB).METHODS: One hundred forty-six patients with primary IDCB who underwent preoperative ¹⁸F-FDG PET/CT followed by curative surgical resection were enrolled in the current study. Mitochondrial activity of cancer cells was assessed based on translocase of outer mitochondrial membrane 20 (TOMM20) expression and cytochrome C oxidase (COX) activity. A Pearson's correlation analysis was used to assess the relationship between the maximum standardized uptake value of the primary tumour (pSUVmax) and mitochondrial activity. Clinicopathological factors, including pSUVmax, histological grade, oestrogen receptor (ER), progesterone receptor (PR), and TOMM20 expression; and COX activity, were assessed for the prediction of disease-free survival (DFS) using the Kaplan–Meier method and Cox proportional hazards model.RESULTS: Fourteen of the 146 subjects (9.6%) showed tumour recurrence. There was a significant positive correlation between ¹⁸F-FDG uptake and the mitochondrial activity of cancer cells in patients with IDCB, and increased ¹⁸F-FDG uptake and mitochondrial activity were significantly associated with a shorter DFS. Additionally, results from the receiver-operating curve analysis demonstrated that the cut-off values of pSUVmax, TOMM20 expression, and COX activity for the prediction of DFS were 7.76, 4, and 5, respectively. Further, results from the univariate analysis revealed that pSUVmax, TOMM20 expression, PR status, and histologic grade were significantly associated with DFS; however, the multivariate analysis revealed that only pSUVmax was associated with DFS (HR, 6.51; 95% CI, 1.91, 22.20; P = 0.003).CONCLUSIONS: The assessment of preoperative ¹⁸F-FDG uptake and post-surgical mitochondrial activity may be used for the prediction of DFS in patients with IDCB.
Breast ; Breast Neoplasms ; Carcinoma, Ductal ; Disease-Free Survival ; Electron Transport Complex IV ; Humans ; Methods ; Mitochondrial Membranes ; Multivariate Analysis ; Positron-Emission Tomography and Computed Tomography ; Proportional Hazards Models ; Receptors, Progesterone ; Recurrence

In the present study, a Spirometra species of Tanzania origin obtained from an African leopard (Panthera pardus) and spotted hyena (Crocuta crocuta) was identified based on molecular analysis of cytochrome c oxidase I (cox1) and NADH dehydrogenase subunit I (nad1) as well as by morphological observations of an adult tapeworm. One strobila and several segments of a Spirometra species were obtained from the intestine of an African male leopard (Panthera pardus) and spotted hyena (Crocuta crocuta) in the Maswa Game Reserve of Tanzania. The morphological characteristics of S. theileri observed comprised 3 uterine loops on one side and 4 on the other side of the mid-line, a uterine pore situated posterior to the vagina and alternating irregularly either to the right or left of the latter, and vesicular seminis that were much smaller than other Spirometra species. Sequence differences in the cox1 and nad1 genes between S. theileri (Tanzania origin) and S. erinaceieuropaei were 10.1% (cox1) and 12.0% (nad1), while those of S. decipiens and S. ranarum were 9.6%, 9.8% (cox1) and 13.0%, 12.6% (nad1), respectively. The morphological features of the Tanzania-origin Spirometra specimens coincided with those of S. theileri, and the molecular data was also consistent with that of S. theileri, thereby demonstrating the distribution of S. theileri in Tanzania. This places the leopard (Panthera pardus) and spotted hyena (Crocuta crocuta) as new definitive hosts of this spirometrid tapeworm.
Adult ; Animals ; Cestoda ; Electron Transport Complex IV ; Humans ; Hyaenidae ; Intestines ; Male ; NADH Dehydrogenase ; Panthera ; Spirometra ; Tanzania ; Vagina

Gastroesophageal reflux disease (GERD) is diagnosed according to the medical history or in response to proton pump inhibitor therapy. However, the need for further testing is always appropriate. The decisive evidence for the current diagnosis of GERD is severe erosive esophagitis of Los Angeles grade C or D, long-segment Barrett's mucosa or peptic strictures seen on endoscopy or an acid exposure time >6% on ambulatory pH or pH impedance monitoring. If ambulatory reflux monitoring correlates between reflux and the symptoms, then the diagnosis and treatment are certain. If it is difficult to clearly diagnose this malady as seen upon endoscopy and ph/pH impedance monitoring, then this review recommends the biopsy findings, motor evaluation and novel impedance metrics. Novel impedance metrics include the baseline impedance and the post reflux swallow-induced peristaltic wave index. Therefore, making a future GERD diagnosis should focus on defining the patient's phenotype. The phenotype is determined by the level of reflux exposure, clearance efficacy, anatomy of the esophageal gastric junction, and the psychological state of the patient. The purpose of this review is to clarify the diagnostic guideline for GERD according to several test methods.
Biopsy ; Consensus ; Constriction, Pathologic ; Diagnosis ; Electric Impedance ; Endoscopy ; Esophageal pH Monitoring ; Esophagitis ; Gastroesophageal Reflux ; Humans ; Hydrogen-Ion Concentration ; Manometry ; Mucous Membrane ; Phenotype ; Proton Pumps