Zinc Deficiency Causes Glomerulosclerosis and Renal Interstitial Fibrosis Through Oxidative Stress and Increased Lactate Metabolism in Rats.

Chronic kidney disease (CKD) is a highly prevalent condition characterized by renal fibrosis as its ultimate manifestation. Zinc deficiency is closely associated with CKD, evidenced by its link to renal fibrosis. Recently, local lactic acidosis has been demonstrated to promote renal fibrosis. Under zinc-deficient conditions, mitochondrial function is compromised and abnormal lactate metabolism might be induced potentially. However, it remains unclear whether zinc deficiency leads to renal fibrosis through local lactic acidosis. Zinc deficiency rat models were successfully established by feeding zinc-deficient diet. Western blot, qPCR, IHC, and other experiments were employed to investigate the key markers and molecular mechanisms of glomerulosclerosis and renal interstitial fibrosis. Our results indicate that zinc deficiency reduces specific markers of podocytes (podocalyxin, WT1, and nephrin) and activates the Wnt3a/ß-catenin pathway, a key pathway in podocyte injury. Concurrently, glomerulosclerosis is indicated by increased urinary microalbumin and serum creatinine levels along with histological alteration observed through PAS and Masson staining in zinc-deficient rats. Furthermore, various degrees of upregulation for several markers of interstitial fibrosis including α-SMA, FN1 and collagen III are also revealed. These findings were further confirmed by Masson staining and IHC. Additionally, alterations in four markers in the EMT process, N-cadherin, E-cadherin, Vimentin, and snail, were consistent with expectations. We then confirmed the activation of the non-canonical TGF-ß1 pathway known as the PI3K/AKT/mTOR pathway. An elevation in renal ROS levels accompanied by increased mitochondrial marker cytochrome C expression as well as an elevated NADH/NAD + ratio is also observed within the kidneys. Furthermore, the activity of both MMP/TIMP system and fibrinolytic system was abnormally enhanced under zinc deficiency conditions. Finally, we find zinc supplementation could significantly ameliorate relevant pathological alterations induced by zinc deficiency. These results collectively point that zinc deficiency causes podocyte damage ultimately resulting in glomerulosclerosis via accumulation of ROS and induces interstitial fibrosis via lactic acidosis.

Alterations in electroencephalographic functional connectivity in individuals with major depressive disorder: a resting-state electroencephalogram study.

Background: Major depressive disorder (MDD) is the leading cause of disability among all mental illnesses with increasing prevalence. The diagnosis of MDD is susceptible to interference by several factors, which has led to a trend of exploring objective biomarkers. Electroencephalography (EEG) is a non-invasive procedure that is being gradually applied to detect and diagnose MDD through some features such as functional connectivity (FC). Methods: In this research, we analyzed the resting-state EEG of patients with MDD and healthy controls (HCs) in both eyes-open (EO) and eyes-closed (EC) conditions. The phase locking value (PLV) method was utilized to explore the connection and synchronization of neuronal activities spatiotemporally between different brain regions. We compared the PLV between participants with MDD and HCs in five frequency bands (theta, 4-8 Hz; alpha, 8-12 Hz; beta1, 12-16 Hz; beta2, 16-24 Hz; and beta3, 24-40 Hz) and further analyzed the correlation between the PLV of connections with significant differences and the severity of depression (via the scores of 17-item Hamilton Depression Rating Scale, HDRS-17). Results: During the EO period, lower PLVs were found in the right temporal-left midline occipital cortex (RT-LMOC; theta, alpha, beta1, and beta2) and posterior parietal-right temporal cortex (PP-RT; beta1 and beta2) in the MDD group compared with the HC group, while PLVs were higher in the MDD group in LT-LMOC (beta2). During the EC period, for the MDD group, lower theta and beta (beta1, beta2, and beta3) PLVs were found in PP-RT, as well as lower theta, alpha, and beta (beta1, beta2, and beta3) PLVs in RT-LMOC. Additionally, in the left midline frontal cortex-right temporal cortex (LMFC-RT) and posterior parietal cortex-right temporal cortex (PP-RMOC), higher PLVs were observed in beta2. There were no significant correlations between PLVs and HDRS-17 scores when connections with significantly different PLVs (all p > 0.05) were checked. Conclusion: Our study confirmed the presence of differences in FC between patients with MDD and healthy individuals. Lower PLVs in the connection of the right temporal-left occipital cortex were mostly observed, whereas an increase in PLVs was observed in patients with MDD in the connections of the left temporal with occipital lobe (EO), the circuits of the frontal-temporal lobe, and the parietal-occipital lobe. The trends in FC involved in this study were not correlated with the level of depression. Limitations: The study was limited due to the lack of further analysis of confounding factors and follow-up data. Future studies with large-sampled and long-term designs are needed to further explore the distinguishable features of EEG FC in individuals with MDD.

Bowel wall thickness measured by MRI is useful for early diagnosis of bowel endometriosis.

OBJECTIVE: To evaluate MRI features of bowel endometriosis (BE) and verify its clinical significance compared with pathological diagnosis. MATERIALS AND METHODS: Since 2018, patients clinically diagnosed with deep endometriosis (DE) and planned to undergo surgery were enrolled prospectively. MRI parameters including traction, thickening sign of the rectum, obliteration of the Douglas Pouch, sign of adenomyosis, and pelvic adhesion were extracted. Uni- and multi-variate analyses were performed to explore their association with pathological diagnosis of BE. ROC curve was utilized to ascertain the appropriate cutoff value for predicting the presence and assessing the severity of BE. RESULTS: A total of 226 patients with DE were recruited, and 154 BE cases were pathologically confirmed. Logistic regression analysis revealed that thickness of the rectal wall, traction sign of the rectum, and obliteration of the Douglas Pouch were independent factors to predict the presence of BE with the OR 1.59 (95% CI: 1.29-1.96), 0.24 (95% CI: 0.09-0.67), and 0.17 (95% CI: 0.07-0.40), respectively (p all < 0.01). A cutoff value of 6.0 mm for the thickness of rectal wall resulted in the highest predictive value of BE (specificity: 90.3%; sensitivity: 78.6%). For patients with measured thickness of the rectal wall over 6.0 mm, 72.1% (93/129) was confirmed BE with lesions infiltrated more than muscular layer. CONCLUSION: This prospective study indicates that based on precise definition of visualized features on MRI images, BE could be recognized pre-operatively. DE patients with thickness of rectal wall exceeding 6.0 mm have a greater probability of BE. CLINICAL RELEVANCE STATEMENT: Based on precise definition of visualized features and accurate measurement on MRI images, bowel infiltrating among deep endometriosis patients could be recognized pre-operatively. KEY POINTS: • Precise definition of measurable MRI parameters made it possible for early detection of bowel endometriosis. • Thickening sign, traction sign of the rectum, and obliteration of the Douglas Pouch were typical radiological indicators for bowel endometriosis. • Bowel involvement is more sensitive to be detected among pelvic deep endometriosis patients with the thickness of the rectal wall over 6.0 mm.

The efficacy of GnRH-a followed by SanJieZhenTong capsules in long-term management of endometriosis: Study protocol for a multicenter, double-blinded, double-dummy randomized clinical trial.

Background: Endometriosis is a common benign gynecological disorder with high risk of recurrence and adverse impact on fertility-sparing. This study aims to evaluate the effectiveness and safety of SanJieZhenTong Capsules, a traditional Chinese medicine, in the long-term management of endometriosis postoperatively. Methods: and analysis: A prospective, double-blinded, double-dummy parallel-group randomized controlled trial will be conducted at three university-based medical centers in China. A total of 600 patients with rAFS III-IV endometriosis diagnosed by laparoscopy will be enrolled. After fundamental treatment (gonadotropin-releasing hormone agonists injection starts on the first day of menstruation postoperatively, and repeats 3 times every 28 days), participants will be randomly allocated to the oral contraceptive group (oral contraceptive + dummy A) or SanJieZhenTong Capsules group (SanJieZhenTong Capsules + dummy B) in a 1:1 ratio. All participants will be treated and followed up for 52 weeks. The primary outcome is a recurrence rate based on endometriosis-related symptoms, physical examination, and/or ultrasound/MRI findings. The secondary outcome includes changes in quality of life and organic function outcome via the 36-item Short-Form scores and gastrointestinal function score. Conclusion: The current trial could provide rigorous evidence on SanJieZhenTong Capsules application in the long-term management of advanced-stage endometriosis.

Single-Cell RNA Sequencing: Technological Progress and Biomedical Application in Cancer Research.

Single-cell RNA-seq (scRNA-seq) is a revolutionary technology that allows for the genomic investigation of individual cells in a population, allowing for the discovery of unusual cells associated with cancer and metastasis. ScRNA-seq has been used to discover different types of cancers with poor prognosis and medication resistance such as lung cancer, breast cancer, ovarian cancer, and gastric cancer. Besides, scRNA-seq is a promising method that helps us comprehend the biological features and dynamics of cell development, as well as other disorders. This review gives a concise summary of current scRNA-seq technology. We also explain the main technological steps involved in implementing the technology. We highlight the present applications of scRNA-seq in cancer research, including tumor heterogeneity analysis in lung cancer, breast cancer, and ovarian cancer. In addition, this review elucidates potential applications of scRNA-seq in lineage tracing, personalized medicine, illness prediction, and disease diagnosis, which reveals that scRNA-seq facilitates these events by producing genetic variations on the single-cell level.

Targeted DNA demethylation of the Arabidopsis genome using the SunTag-dCpf1-TET1cd system.

DNA methylation is a stable and heritable epigenetic mark, and it plays an important role in regulation of gene expression and transposon silencing. Here we developed a CRISPR/dCpf1-based targeted demethylation system using the catalytic domain of the human demethylase TEN-ELEVEN TRANSLOCATION1 (TET1cd) and a SunTag system. The SunTag-dCpf1-TET1cd system is able to achieve targeted DNA demethylation and up-regulate gene expression when guided to the FWA or CACTA1 loci in Arabidopsis thaliana . Our study provides tools for targeted removal of DNA cytosine methylation, and activation of protein-coding genes or transposons expression.

The application of antidepressant drugs in cancer treatment.

Antidepressants refer to psychotropic drugs which are used to treat mental illness with prominent emotional depression symptoms. It was reported that antidepressants had associated with anti-carcinogenic function which was associated with various signaling pathways and changing of microenvironment. Its mechanism includes cell apoptosis, antiproliferative effects, mitochondria-mediated oxidative stress, DNA damaging, changing of immune response and inflammatory conditions, and acting by inhibiting multidrug resistance of cancer cells. Accumulated studies showed that antidepressants influenced the metabolic pathway of tumor cells. This review summarized recent developments with the impacts and mechanisms of 10 kinds of antidepressants in carcinostasis. Antidepressants are also used in combination therapy with typical anti-tumor drugs which shows a synergic effect in anti-tumor. By contrast, the promotion roles of antidepressants in increasing cancer recurrence risk, mortality, and morbidity are also included. Further clinical experiments and mechanism analyses needed to be achieved. A full understanding of the underlying mechanisms of antidepressants-mediated anticarcinogenic effects may provide new clues for cancer prevention and clinical treatment.

Combination Therapies against COVID-19.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of Coronavirus disease 2019 (COVID-19), which was announced as a pandemic leading to devastating economic and medical burden worldwide. The virus attacks the organ system across the body by binding to its receptor (for example, angiotensin converting enzyme 2) on the surface of the host cell of various organs. The patients present with a variety of pathological symptoms ranging from fever, cough and cytokine storm to acute respiratory distress syndrome (ARDS). Many combination therapies have been developed to combat the disease, via blocking one or more processes of the viral life cycle and/or relieving host complications simultaneously. In this review, the progress of those combination therapies containing at least one small molecule is updated. We believe it'll provide significant inspiration for further development of treatment strategy against SARS-CoV-2, especially its mutant variants.

Reproductive and postsurgical outcomes of infertile women with deep infiltrating endometriosis.

BACKGROUND: This study aimed to summarize and analyze clinical characteristics and reproductive outcomes in postoperative deep infiltrating endometriosis (DIE). METHODS: This retrospective cohort study included 55 reproductive-aged patients who were diagnosed with DIE, wished to conceive and underwent resection surgery at the Obstetrics and Gynecology Hospital, Fudan University, from January 2009-June 2017. Those with any plausible infertility factor or abnormalities in the partner's semen analysis were excluded. Patient characteristics, preoperative symptoms, infertility history, intraoperative findings and reproductive outcomes were followed up and recorded. Risk factors for reproductive outcomes were identified for women who became pregnant versus those who did not by univariate logistic regression. Additionally, pre- and postoperative endometriosis health profile questionnaire-30 (EHP-30), Knowles-Eccersley-Scott Symptom questionnaire (KESS), Cox Menstrual Symptom Scale (CMSS) and Female Sexual Function Index (FSFI) scores were used to evaluate the effect of DIE surgery on quality of life. RESULTS: The average age was 30.22 ± 3.62 years, with no difference between the pregnancy and nonpregnancy groups. The average follow-up time was 26.57 ± 14.51 months. There were 34 pregnancies (61.82%): 24 (70.59%) conceived spontaneously and 10 (29.41%) by in vitro fertilization (IVF). Twenty-eight patients (82.35%) had term deliveries. The interval between operation and pregnancy was 10.33 ± 5.6 (1-26) months. Univariate analysis showed that a lower endometriosis fertility index (EFI) score (EFI < 8) was a risk factor for infertility (OR: 3.17 (1.15-10.14), p = .044). For patients with incomplete surgery, postoperative gonadotropin-releasing hormone agonist (GnRHa) administration improved the pregnancy rate (p < 0.05). Regarding quality of life, there was significant improvement (p < 0.05) in the postoperative EHP-30, KESS and CMSS scores compared with preoperative scores in both groups. Although there was no obvious difference in FSFI scores, significant improvement in dyspareunia was observed (p < 0.05). CONCLUSIONS: Overall, the postoperative pregnancy rate of DIE patients was 61.82%. Surgical management of DIE for patients with complaints of pain and with pregnancy intentions was feasible and effective. Long-term expectant treatment should not be advised for patients with lower EFI scores (EFI < 8), and postoperative IVF-ET may be a good choice. More cases should be enrolled for further study, and randomized studies are required.

Laparoscopic blockage of uterine artery in the management of large cornual pregnancy.

OBJECTIVE: To present a technique of temporary uterine artery clamping before laparoscopic surgery for prevention of blood loss in cornual ectopic pregnancy. DESIGN: Step-by-step explanation of the entire surgical procedure using video and still images (Canadian Task Force classification III). SETTING: Tertiary university-based hospital. PATIENT(S): A 37-year-old woman who presented with amenorrhea of 55 days and extremely high ß-hCG level of 281,400 mIU/mL. Transvaginal ultrasound examination revealed a 7 cm mass with ample blood supply invading the muscularis layer around the right uterine cornua. INTERVENTION(S): Institutional Review Board and Ethics Committee approval was obtained. After pelvic adhesiolysis, retroperitoneum was dissected and the bilateral uterine arteries were exposed. To reduce the possibility of massive hemorrhage, titanium clips were used to temporarily block the bilateral uterine arteries. Laparoscopic inspection showed the mass as dark and blue, consistent with the diagnosis of cornual pregnancy. After removal of the cornual lesion, 2-0 Vicryl was used to reconstruct the uterine cornua. At the end of the surgery, the titanium clips were removed to reverse the uterine blood supply. MAIN OUTCOME MEASUREMENT(S): The surgery lasted for about 2 hours, with estimated blood loss of only 50 mL. The patient recovered completely and was discharged 2 days postoperatively, without any further bleeding or postoperative complications. The pathological examination confirmed the diagnosis of cornual pregnancy. RESULT(S): One month later, the ß-hCG levels decreased to within normal range. At 6-month postoperative follow-up, ultrasound examination showed a normal size uterus. CONCLUSION(S): Temporary blockage of the uterine artery during surgery could prevent heavy blood loss, especially in difficult surgeries such as myomectomy for complex uterus fibromas or adenomyomectomy. Moreover, this technique would be feasible for emergent cases, including conservative surgery for cesarean scar pregnancy, and could also replace traditional uterine artery embolization for treating cornual pregnancy.