Aucubin alleviates doxorubicin-induced cardiotoxicity through crosstalk between NRF2 and HIPK2 mediating autophagy and apoptosis.

BACKGROUND: Doxorubicin (DOX) is widely used for the treatment of a variety of cancers. However, its clinical application is limited by dose-dependent cardiotoxicity. Recent findings demonstrated that autophagy inhibition and apoptosis of cardiomyocytes induced by oxidative stress dominate the pathophysiology of DOX-induced cardiotoxicity (DIC), however, there are no potential molecules targeting on these. PURPOSE: This study aimed to explore whether aucubin (AU) acting on inimitable crosstalk between NRF2 and HIPK2 mediated the autophagy, oxidative stress, and apoptosis in DIC, and provide a new and alternative strategy for the treatment of DIC. METHODS AND RESULTS: We first demonstrated the protection of AU on cardiac structure and function in DIC mice manifested by increased EF and FS values, decreased serum CK-MB and LDH contents and well-aligned cardiac tissue in HE staining. Furthermore, AU alleviated DOX-induced myocardial oxidative stress, mitochondrial damage, apoptosis, and autophagy flux dysregulation in mice, as measured by decreased ROS, 8-OHdG, and TUNEL-positive cells in myocardial tissue, increased SOD and decreased MDA in serum, aligned mitochondria with reduced vacuoles, and increased autophagosomes. In vitro, AU alleviated DOX-induced oxidative stress, autophagy inhibition, and apoptosis by promoting NRF2 and HIPK2 expression. We also identified crosstalk between NRF2 and HIPK2 in DIC as documented by overexpression of NRF2 or HIPK2 reversed cellular oxidative stress, autophagy blocking, and apoptosis aggravated by HIPK2 or NRF2 siRNA, respectively. Simultaneously, AU promoted the expression and nuclear localization of NRF2 protein, which was reversed by HIPK2 siRNA, and AU raised the expression of HIPK2 protein as well, which was reversed by NRF2 siRNA. Crucially, AU did not affect the antitumor activity of DOX against MCF-7 and HepG2 cells, which made up for the shortcomings of previous anti-DIC drugs. CONCLUSION: These collective results innovatively documented that AU regulated the unique crosstalk between NRF2 and HIPK2 to coordinate oxidative stress, autophagy, and apoptosis against DIC without compromising the anti-tumor effect of DOX in vitro.

Laparoscopic versus open radical hysterectomy in FIGO 2018 early-stage cervical adenocarcinoma: Long-term survival outcomes after propensity score matching.

OBJECTIVE: To compare the long-term survival outcomes of laparoscopic radical hysterectomy (LRH) and open radical hysterectomy (ORH) in International Federation of Gynecology and Obstetrics (FIGO) 2018 early-stage cervical adenocarcinoma. METHODS: Based on the clinical diagnosis and treatment for cervical cancer in mainland China (Four C) database, the medical records of 1098 patients with FIGO 2018 early-stage cervical adenocarcinoma were retrospectively reviewed. Long-term and short-term survival outcomes of the two groups were compared using a multivariate Cox regression model and the log-rank method in the whole study population and after propensity score matching. RESULTS: There was no difference in disease-free survival (hazard ratio [HR] 0.921, 95% confidence interval [CI]: 0.532-1.595, p = 0.770) and overall survival (HR 1.168, 95% CI: 0.526-2.592, p = 0.702) between LRH (n = 468) and ORH (n = 468) in the risk-adjusted analysis. LRH resulted in significantly lower estimated blood loss (342.7 vs. 157.5 mL, p < 0.001) and shorter postoperative anal exhaust time (2.8 vs. 2.5 days, p < 0.001) in risk-adjusted analysis. The overall rates of intraoperative complications (2.4% vs. 4.3%, p = 0.100) and postoperative complications (7.5% vs. 6.2%, p = 0.437) showed no significant difference between the two groups. However, the LRH group had a significantly higher incidence of ureter injury (0.4% vs. 2.4%, p = 0.012) and great vessel injury (0.0% vs. 0.9%, p = 0.045) compared to the other group. No statistical variation in the site of recurrence was observed between the two groups (p = 0.613). CONCLUSIONS: LRH has comparable survival outcomes with ORH and was associated with earlier recovery in FIGO 2018 early-stage adenocarcinoma of the uterine cervix. However, the LRH group had higher risk of ureter injury and great vessel injury.

A Novel Pathway of Functional microRNA Uptake and Mitochondria Delivery.

Extracellular microRNAs (miRNAs) play a critical role in horizontal gene regulation. Uptake of extracellular miRNAs by recipient cells and their intracellular transport, however, remains elusive. Here RNA phase separation is shown as a novel pathway of miRNA uptake. In the presence of serum, synthetic miRNAs rapidly self-assembly into ≈110 nm discrete nanoparticles, which enable miRNAs' entry into different cells. Depleting serum cationic proteins prevents the formation of such nanoparticles and thus blocks miRNA uptake. Different from lipofectamine-mediated miRNA transfection in which majority of miRNAs are accumulated in lysosomes of transfected cells, nanoparticles-mediated miRNA uptake predominantly delivers miRNAs into mitochondria in a polyribonucleotide nucleotidyltransferase 1(PNPT1)-dependent manner. Functional assays further show that the internalized miR-21 via miRNA phase separation enhances mitochondrial translation of cytochrome b (CYB), leading to increase in adenosine triphosphate (ATP) and reactive oxygen species (ROS) reduction in HEK293T cells. The findings thus reveal a previously unrecognized mechanism for uptake and delivery functional extracellular miRNAs into mitochondria.

Abdominal type B vs. type C radical hysterectomy in early-stage cervical cancer: A matched single center cohort report.

Objective: To compare survival outcomes of type B radical hysterectomy (RH) and type C RH in patients with early-stage cervical cancer. Methods: We retrospectively identified continuous cervical cancer patients with FIGO stage IA2-IB2 and IIA1 who underwent either type B RH (n = 278) or type C RH (n = 148) performed by the same group of surgeons between 2009 and 2018. Propensity score matching was carried out to minimize selection biases. Intraoperative photographs, immediate postoperative questionnaire and specimen measurements were used to accurately determine the extensive of surgery. We further narrowed the study population to patients with specific histological subtypes and patients with deep stromal invasion. Results: The median follow-up period was 42.41 ± 24.60 months. After adjusting, no differences in the 5-year overall survival (OS) and disease-free survival (DFS) were found between the type B group and the type C group (OS: 87.8% vs. 89.4%, P = 0.814; DFS: 84.9% vs. 85.6%, P = 0.898). In further analysis of patients with squamous-cell carcinoma, adenocarcinoma, adenosquamous carcinoma, similar 5-year OS and DFS rates were found between two groups (OS: 88.7% vs. 97.1%, P = 0.250; DFS: 84.7% vs. 92.3%, P = 0.541). Consistent results were found in patients with deep stromal invasion (OS: 81.8% vs. 100%, P = 0.144; DFS: 82.8% vs. 100%, P = 0.128). Conclusions: Type B RH could be used to treat FIGO stage IA2-IB2 and IIA1 cervical cancer to get equivalent 5-year OS and DFS. Further randomized controlled trials are warranted.

Evaluation of individualized para-tumor resection of cervical cancer patients based on three-dimensional reconstruction.

Objective: To discuss the possibility of individualizing the para-tumor resection range (PRR) in cervical cancer patients based on three-dimensional (3D) reconstruction. Methods: We retrospectively included 374 cervical cancer patients who underwent abdominal radical hysterectomy. Preoperative computerized tomography (CT) or magnetic resonance imaging (MRI) data sets were collected to get 3D models. Postoperative specimens were measured to evaluate surgical scope. Oncological outcomes of patients with different depths of stromal invasion and PRR were compared. Results: A PRR of 32.35 mm was found to be the cut-off point. For the 171 patients with stromal invasion <1/2 depth, patients with a PRR over 32.35 mm had a lower risk of death and higher 5-year overall survival (OS) than that in the ≤32.35 mm group (HR = 0.110, 95% CI: 0.012-0.988, P = 0.046; OS: 98.8% vs. 86.8%, P = 0.012). No significant differences were found in 5-year disease-free survival (DFS) between the two groups (92.2% vs. 84.4%, P = 0.115). For the 178 cases with stromal invasion ≥1/2 depth, no significant differences were found in 5-year OS and DFS between groups (≤32.35 mm group vs. >32.35 mm group, OS: 71.0% vs. 83.0%, P = 0.504; DFS: 65.7% vs. 80.4%, P = 0.305). Conclusion: In patients with stromal invasion <1/2 depth, the PRR should reach 32.35 mm to get more survival benefit and in patients with stromal invasion ≥1/2 depth, the PRR should reach 32.35 mm at least to avoid worse prognosis. Cervical cancer patients with different depths of stromal invasion may receive tailoring resection of the cardinal ligament.

Effects of Chilled Saline Irrigation on SMILE Surgery.

PURPOSE: To investigate the effect of ultra-early visual correction and prognosis of myopic astigmatism after irrigation with the chilled balanced salt solution (BSS) during small incision lenticule extraction (SMILE) surgery. METHODS: A prospective case-control study was enrolled from 202 patients (404 eyes) who had SMILE, and randomly divided into an intervention group and a control group (each group was 101 cases [202 eyes]). After lenticule extraction on SMILE, the corneal cap and the corneal incision were flushed with chilled saline in the intervention group, whereas the control group was flushed with room temperature saline. All patients in the two groups were examined for early complications before and 2 hours, 24 hours, and 7 days after surgery and the results were compared, and statistically analyzed, including the recovery degree of naked eye vision, ocular irritation symptoms, opaque bubble layer, diffuse lamellar keratitis (DLK), uncorrected distance visual acuity (UDVA), and corrected distance visual acuity. RESULTS: The ocular irritation symptoms in the intervention group were milder than those in the control group at 2 hours after surgery, and the recovery of visual acuity at 2 and 24 hours after surgery was significantly faster than that in the control group, but there was no statistical difference in UDVA between the two groups at 7 days after surgery (P > .05). The incidence of DLK in the intervention group was lower than that in the control group, and the difference was significant (P = .041). CONCLUSIONS: Chilled BSS irrigation can reduce the emergency response of corneal tissue after SMILE, relieve ocular irritation, promote vision recovery, and relatively reduce incidence of early complications. [J Refract Surg. 2023;39(4):282-287.].

Impact of different postoperative adjuvant therapies on the survival of early-stage cervical cancer patients with one intermediate-risk factor: A multicenter study of 14 years.

OBJECTIVE: To compare survival outcomes of different postoperative adjuvant therapies (PATs) for early-stage cervical cancer (ECC) patients with one intermediate-risk pathological factor (IPF). METHODS: A total of 2889 patients with stage IA1 to IIA2 cervical cancer were included in this study. Three PAT groups were identified, namely a no adjuvant therapy (NAT) group (n = 773), an adjuvant radiotherapy/chemoradiotherapy (ART) group (n = 1648) and an adjuvant chemotherapy (ACT) group (n = 468). Kaplan-Meier analysis and COX regression analysis were used to compare the overall survival (OS) and disease-free survival (DFS) among the three groups, before and after propensity score matching (PSM). RESULTS: The recurrence and mortality rate rates in the NAT, ART and ACT groups were 9.2%, 8.6%, and 7.9%, respectively (p = 0.737). Kaplan-Meier analysis demonstrated no significant differences in the NAT, ART, and ACT groups in 5-year OS rates (92.8% vs. 93.6% vs. 94.7%, p = 0.594) and DFS rates (88.7% vs. 89.6% vs. 90.5%, p = 0.772). Post-hoc tests yielded similar results, with no differences in 5-year OS and DFS (NAT vs. ART, before and after matching, p > 0.05); (NAT vs. ACT, before and after matching, p > 0.05); and (ACT vs. ART, before and after matching, p > 0.05). CONCLUSION: Postoperative adjuvant radiotherapy, chemoradiotherapy, and chemotherapy are not associated with survival outcomes of ECC patients with one IPF. Considering the side effects and impact on patients' quality of life, the PATs should be carefully considered.

Comparison between laparoscopic and abdominal radical hysterectomy for cervical adenosquamous carcinoma at stage IA2 to IIA2: A multicenter retrospective study.

OBJECTIVE: We aimed to compare the 5-year oncological outcomes of laparoscopic/abdominal radical hysterectomy (LRH/ARH) in patients with cervical adenosquamous carcinoma at stage IA2 to IIA2 based on the 2009 or 2018 International Federation of Gynecology and Obstetrics (FIGO) staging criteria. METHODS: Based on the clinical diagnosis and treatment of cervical cancer in China (Four C) database, Cox risk regression models were applied to analyze tumor prognosis treated with ARH/LRH in FIGO 2009 and 2018 IA2-IIA2 patients and stratified findings according to tumor diameter (≤4 and >4 cm subgroups). And to avoid bias, propensity score matching (PSM) was also used for the cohort study. RESULTS: Based on FIGO 2009 staging criteria (n = 474), there was no significant difference between the ARH and LRH groups in 5-year disease-free survival (DFS) or overall survival (OS). Lymph node metastasis was a risk factor for 5-year DFS in this stage. After PSM, lymphovascular space invasion (LVSI) was an independent risk factor for 5-year OS in the tumors ≤4 cm subgroup. Based on FIGO2018 staging criteria (n = 322), cervical interstitial infiltration depth was an independent risk factor for 5-year OS in the total population and the tumor diameter ≤4 cm subgroup. CONCLUSIONS: Laparoscopic surgery was not a risk factor affecting the oncologic prognosis of adenosquamous carcinoma of the cervix based on either FIGO 2009 or 2018 staging of stage IA2-IIA2. In addition, LRH may be considered for patients with early-stage cervical adenosquamous carcinoma.

Effect of annualized surgeon volume on major surgical complications for abdominal and laparoscopic radical hysterectomy for cervical cancer in China, 2004-2016: a retrospective cohort study.

BACKGROUND: Previous studies have suggested that higher surgeon volume leads to improved perioperative outcomes for oncologic surgery; however, the effect of surgeon volumes on surgical outcomes might differ according to the surgical approach used. This paper attempts to evaluate the effect of surgeon volume on complications or cervical cancer in an abdominal radical hysterectomy (ARH) cohort and laparoscopic radical hysterectomy (LRH) cohort. METHODS: We conducted a population-based retrospective study using the Major Surgical Complications of Cervical Cancer in China (MSCCCC) database to analyse patients who underwent radical hysterectomy (RH) from 2004 to 2016 at 42 hospitals. We estimated the annualized surgeon volumes in the ARH cohort and in the LRH cohort separately. The effect of the surgeon volume of ARH or LRH on surgical complications was examined using multivariable logistic regression models. RESULTS: In total, 22,684 patients who underwent RH for cervical cancer were identified. In the abdominal surgery cohort, the mean surgeon case volume increased from 2004 to 2013 (3.5 to 8.7 cases) and then decreased from 2013 to 2016 (8.7 to 4.9 cases). The mean surgeon case volume number of surgeons performing LRH increased from 1 to 12.1 cases between 2004 and 2016 (P < 0.01). In the abdominal surgery cohort, patients treated by intermediate-volume surgeons were more likely to experience postoperative complications (OR = 1.55, 95% CI = 1.11-2.15) than those treated by high-volume surgeons. In the laparoscopic surgery cohort, surgeon volume did not appear to influence the incidence of intraoperative or postoperative complications (P = 0.46; P = 0.13). CONCLUSIONS: The performance of ARH by intermediate-volume surgeons is associated with an increased risk of postoperative complications. However, surgeon volume may have no effect on intraoperative or postoperative complications after LRH.

Early versus delayed treatment of lateral condylar fracture of the humerus with > 2 mm displacement in children: a retrospective study.

BACKGROUND: The purpose of this study was to investigate the clinical and functional outcomes of early versus delayed treatment of pediatric lateral condylar fractures of the humerus with a displacement greater than 2 mm. METHODS: Sixty-seven children treated surgically at our hospital from March 2016 to September 2021 for lateral condylar fracture of the humerus with displacement > 2 mm were retrospectively analyzed. The children were divided into two groups where early surgery consisted of patients being operated on within 24-h post-injury (n = 36) and delayed surgery consisted of children operated after 24-h post-injury (n = 31). Clinical and functional results were compared between the two groups. RESULTS: There were no significant differences between the two groups in terms of operation time, blood loss and incidences of perioperative complications. However, mean length of incision was significantly greater (P < 0.0001) in the delayed treatment group (5.68 ± 1.08 cm) compared to the early treatment group (3.89 ± 0.82 cm). No differences were found in functional outcomes, consisting of the Baumann angle of the affected limb, the carrying angle, Mayo Elbow Performance Score, and Flynn's criteria at final follow-up. CONCLUSIONS: Delay in surgery for more than 24 h after injury does not influence the clinical and functional results for lateral condylar fracture of the humerus with displacement > 2 mm in children. However, delayed open reduction and pinning may increase the incision length possibly due to increased edema.

Risk factors for and delayed recognition of genitourinary fistula following radical hysterectomy for cervical cancer: a population-based analysis.

OBJECTIVE: This study aimed to identify the risk factors for genitourinary fistulas and delayed fistula recognition after radical hysterectomy for cervical cancer. METHODS: This study was a retrospective analysis of data collected in the Major Surgical complications of Cervical Cancer in China (MSCCCC) database from 2004-2016. Data on sociodemographic characteristics, clinical characteristics, and hospital characteristics were extracted. Differences in the odds of genitourinary fistula development were investigated with multivariate logistic regression analyses, and differences in the time to recognition of genitourinary fistula were assessed by Kruskal-Wallis test. RESULTS: In this study, 23,404 patients met the inclusion criteria. Surgery in a cancer center, a women's and children's hospital, a facility in a first-tier city, or southwest region, stage IIA, type C1 hysterectomy, laparoscopic surgery and ureteral injury were associated with a higher risk of ureterovaginal fistula (UVF) (p<0.050). Surgery in southwest region, bladder injury and laparoscopic surgery were associated with greater odds of vesicovaginal fistula (VVF) (p<0.050). Surgery at cancer centers and high-volume hospitals was associated with an increase in the median time to UVF recognition (p=0.016; p=0.005). International Federation of Gynecology and Obstetrics (FIGO) stage IIA1-IIB was associated with delayed recognition of VVF (p=0.040). CONCLUSION: Intraoperative urinary tract injury and surgical approach were associated with differences in the development of UVFs and VVFs. Patients who underwent surgery in cancer centers and high-volume hospitals were more likely to experience delayed recognition of UVF. Patients with FIGO stage IIA1-IIB disease were more likely to experience delayed recognition of VVF.

The long-term outcomes of clinical responders to neoadjuvant chemotherapy followed by radical surgery in locally advanced cervical cancer.

OBJECTIVE: To compare the long-term oncological outcome of neoadjuvant chemotherapy before radical surgery (NCRS) and definitive chemoradiotherapy (DR) for stage IB2 and IIA2 cervical squamous cell carcinoma. METHODS: The clinical outcome of 480 patients with stage IB2 and IIA2 cervical cancer (308 clinical responders, 111 clinical non-responders, 61 unclear) who underwent NCRS (and subgroup assessments) were compared with those of 233 patients who underwent DR. RESULTS: The clinical response rate was 73.5% in the NCRS group. Multivariate COX regression analyses revealed that NCRS was not correlated with the 5-year overall survival (OS) rate (p = 0.067) or disease-free survival (DFS) rate (p = 0.249). In a subgroup of NCRS, the clinical response group was also shown to be a protective independent factor of 5 year OS rate compared to the DR group (aHR, 0.403; 95% CI, 0.209-0.777), but had no correlation with the 5 year DFS rate (p = 0.089). On the other hand, the clinical non-response group had no correlation with the 5 year OS rate (p = 0.780) or DFS rate (p = 0.669). CONCLUSION: Clinical responders who underwent NCRS exhibited a better oncological outcome compared to those who underwent DR. International Clinical Trials Registry Platform Search Port, http://apps.who.int/trialsearch/ ; CHiCTR1800017778.

Tumor lesion detection in patients with cervical cancer by indocyanine green near-infrared imaging.

PURPOSE: To investigate the feasibility and accuracy of near-infrared fluorescence (NIRF) imaging for detecting the extent of tumor invasion in cervical cancer using indocyanine green (ICG). METHODS: We enrolled 51 patients who were diagnosed with cervical cancer with FIGO stage IB1-IIA2 disease. Patients were administered indocyanine green (ICG) at a dose of 5 mg/kg 24 h prior to surgery. A customized near-infrared fluorescence (NIRF) imaging system was used to identify the extent of tumor invasion when radical hysterectomy specimens were harvested. The relationship between tumor fluorescence intensity and clinicopathological characteristics was analyzed. RESULTS: Of the 51 enrolled patients, 3 patients did not have residual tumors after cervical conization, and tumor lesions were identified by NIRF imaging in all the remaining 48 patients. The results of NIRF imaging were in agreement with the postoperative pathological findings in 95.8% of the patients with stromal invasion, 100% of those with surgical margin invasion, 100% of those with parametrial tumor involvement, and 100% of patients with uterine corpus invasion. The mean signal-to-background ratio (SBR) of the cervical tumors was 2.91 ± 1.64, and the SBR was independent of clinicopathological characteristics. Fluorescence microscopy confirmed that ICG fluorescence was present in the tumor nests. CONCLUSIONS: NIRF imaging enables objective, accurate, and safe identification of tumor invasion during cervical cancer surgery. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT04224467.

The pathological risk score: A new deep learning-based signature for predicting survival in cervical cancer.

PURPOSE: To develop and validate a deep learning-based pathological risk score (RS) with an aim of predicting patients' prognosis to investigate the potential association between the information within the whole slide image (WSI) and cervical cancer prognosis. METHODS: A total of 251 patients with the International Federation of Gynecology and Obstetrics (FIGO) Stage IA1-IIA2 cervical cancer who underwent surgery without any preoperative treatment were enrolled in this study. Both the clinical characteristics and WSI of each patient were collected. To construct a prognosis-associate RS, high-dimensional pathological features were extracted using a convolutional neural network with an autoencoder. With the score threshold selected by X-tile, Kaplan-Meier survival analysis was applied to verify the prediction performance of RS in overall survival (OS) and disease-free survival (DFS) in both the training and testing datasets, as well as different clinical subgroups. RESULTS: For the OS and DFS prediction in the testing cohort, RS showed a Harrell's concordance index of higher than 0.700, while the areas under the curve (AUC) achieved up to 0.800 in the same cohort. Furthermore, Kaplan-Meier survival analysis demonstrated that RS was a potential prognostic factor, even in different datasets or subgroups. It could further distinguish the survival differences after clinicopathological risk stratification. CONCLUSION: In the present study, we developed an effective signature in cervical cancer for prognosis prediction and patients' stratification in OS and DFS.

Associations between insomnia and large vessel occlusion acute ischemic stroke: An observational study

Abstract Objectives: This study explored the association between insomnia and the clinical outcome of large vessel occlusion Acute Ischemic Stroke (AIS) and attempted to explore its potential mechanisms from the perspectives of inflammation and oxidative stress. Methods: AIS patients who underwent endovascular treatment for large vessel occlusion at Binzhou Central Hospital from 2018 to 2022 (n = 508) were included. Patients were divided into an insomnia group and a non-insomnia group. Insomnia was judged by self-reported Athens Insomnia Scale score. Regression analysis was used to compare the differences in the 24-hour and 7-day National Institutes of Health Stroke Scale (NIHSS) score, Early Neurological Deterioration (END), early adverse event incidence, 90-day prognosis and mortality, and serum bio-markers levels. Results: The incidence of insomnia in the study population was 39.6% (n = 144, insomnia group; n = 364, non-insomnia group). Compared with the non-insomnia group, a worse prognosis outcome (63% vs. 49%, adjusted rate ratio: 1.8, 95% Confidence Interval: 1.2-3.7; p = 0.016), higher 24-h and 7-day NIHSS score (17 [9-36] vs. 13 [5-20]; p = 0.024, and 11 [4‒24) vs. 8 [2‒14]; p = 0.031, respectively), higher END (24% vs. 15%, p = 0.022), and higher incidence of adverse events were observed in the insomnia group (79% vs. 59%, p = 0.010). The 90-day mortality was higher in the insomnia group than that in the non-insomnia group (22% vs. 17%), however, such a difference was not statistically significant. Conclusion: Insomnia is closely related to the clinical outcome of AIS with large vessel occlusion, and inflammation and oxidative stress mechanisms may be involved.

Mechanisms and Drug Intervention for Doxorubicin-Induced Cardiotoxicity Based on Mitochondrial Bioenergetics.

Doxorubicin (DOX) is an anthracycline chemotherapy drug, which is indispensable in antitumor therapy. However, its subsequent induction of cardiovascular disease (CVD) has become the primary cause of mortality in cancer survivors. Accumulating evidence has demonstrated that cardiac mitochondrial bioenergetics changes have become a significant marker for doxorubicin-induced cardiotoxicity (DIC). Here, we mainly summarize the related mechanisms of DOX-induced cardiac mitochondrial bioenergetics disorders reported in recent years, including mitochondrial substrate metabolism, the mitochondrial respiratory chain, myocardial ATP storage and utilization, and other mechanisms affecting mitochondrial bioenergetics. In addition, intervention for DOX-induced cardiac mitochondrial bioenergetics disorders using chemical drugs and traditional herbal medicine is also summarized, which will provide a comprehensive process to study and develop more appropriate therapeutic strategies for DIC.

Pallister-Hall syndrome, GLI3, and kidney malformation.

Pallister-Hall syndrome (PHS) is a rare autosomal dominant disease diagnosed by the presence of hypothalamic hamartoma, mesoaxial polydactyly and a truncating variant in the middle third of the GLI-Kruppel family member 3 (GLI3) gene. PHS may also include a wide range of clinical phenotypes affecting multiple organ systems including congenital anomalies of the kidney and urinary tract (CAKUT). The observed clinical phenotypes are consistent with the essential role of GLI3, a transcriptional effector in the hedgehog (Hh) signaling pathway, in organogenesis. However, the mechanisms by which truncation of GLI3 in PHS results in such a variety of clinical phenotypes with variable severity, even within the same organ, remain unclear. In this study we focus on presentation of CAKUT in PHS. A systematic analysis of reported PHS patients (n = 78) revealed a prevalence of 26.9% (21/78) of CAKUT. Hypoplasia (± dysplasia) and agenesis were the two main types of CAKUT; bilateral and unilateral CAKUT were reported with equal frequency. Examination of clinical phenotypes with CAKUT revealed a significant association between CAKUT and craniofacial defects, bifid epiglottis and a Disorder of Sex Development, specifically affecting external genitalia. Lastly, we determined that PHS patients with CAKUT predominately had substitution type variants (as opposed to deletion type variants in non-CAKUT PHS patients) in the middle third of the GLI3 gene. These results provide a foundation for future work aimed at uncovering the molecular mechanisms by which variant GLI3 result in the wide range and severity of clinical features observed in PHS.

Qishen Granule Protects against Doxorubicin-Induced Cardiotoxicity by Coordinating MDM2-p53-Mediated Mitophagy and Mitochondrial Biogenesis.

Doxorubicin (DOX), the anthracycline chemotherapeutic agent, is widely used for the treatment of various cancers. However, its clinical application is compromised by dose-dependent and fatal cardiotoxicity. This study is aimed at investigating the cardioprotective effects of Qishen granule (QSG) and the specific mechanism by which QSG alleviates DOX-induced cardiotoxicity (DIC) and providing an alternative for the treatment of DIC. We first evaluated the cardioprotective effects of QSG in a DIC mouse model, and the obtained results showed that QSG significantly protected against DOX-induced myocardial structural and functional damage, mitochondrial oxidative damage, and apoptosis. Subsequently, after a comprehensive understanding of the specific roles and recent developments of p53-mediated mitochondrial quality control mechanisms in DIC, we investigated whether QSG acted on MDM2 to regulate the activity of p53 and downstream mitophagy and mitochondrial biogenesis. The in vivo results showed that DOX inhibited mitochondrial biogenesis and blocked mitophagy in the mouse myocardium, while QSG reversed these effects. Mechanistically, we combined nutlin-3, which inhibits the binding of p53 and MDM2, with DOX and QSG and evaluated their influence on mitophagy and mitochondrial biogenesis in H9C2 cardiomyocytes. The obtained results showed that both DOX and nutlin-3 substantially inhibited mitophagy and mitochondrial biogenesis and induced mitochondrial oxidative damage and apoptosis, which could be partially recovered by QSG. Importantly, the immunoprecipitation results showed that QSG promoted the binding of MDM2 to p53, thus decreasing the level of p53 protein and the binding of p53 to Parkin. Collectively, QSG could promote the degradation of p53 by enhancing the binding of MDM2 to the p53 protein, resulting in the reduced binding of p53 to the Parkin protein, thus improving Parkin-mediated mitophagy. Increased degradation of p53 protein by QSG simultaneously enhanced mitochondrial biogenesis mediated by PGC-1α. Ultimately, QSG relieved DOX-induced mitochondrial oxidative damage and apoptosis by coordinating mitophagy and mitochondrial biogenesis.

The multi-faced role of FUNDC1 in mitochondrial events and human diseases.

Mitophagy plays a vital role in the selective elimination of dysfunctional and unwanted mitochondria. As a receptor of mitophagy, FUN14 domain containing 1 (FUNDC1) is attracting considerably critical attention. FUNDC1 is involved in the mitochondria fission, the clearance of unfolded protein, iron metabolism in mitochondria, and the crosstalk between mitochondria and endoplasmic reticulum besides mitophagy. Studies have demonstrated that FUNDC1 is associated with the progression of ischemic disease, cancer, and metabolic disease. In this review, we systematically examine the recent advancements in FUNDC1 and the implications of this protein in health and disease.