Anthracyclines are broad-spectrum anticancer drugs, but their clinical use is limited due to their severe cardiotoxicity. Anthracycline-induced cardiotoxicity (AIC) remains a significant cause of heart disease-related mortality in many cancer survivors. The underlying mechanisms of AIC have been explored over the past few decades. Reactive oxygen species and drug-induced inhibition of topoisomerase II beta are well-studied mechanisms, with mitochondria being a prominently investigated organelle. Emerging mechanisms such as ferroptosis, Ca 

Anthracycline-induced cardiotoxicity: An overview from cellular structural perspective

Mitochondria contain connexins, a family of proteins that is known to form gap junction channels. Connexins are synthesized in the endoplasmic reticulum and oligomerized in the Golgi to form hemichannels. Hemichannels from adjacent cells dock with one another to form gap junction channels that aggregate into plaques and allow cell–cell communication. Cell–cell communication was once thought to be the only function of connexins and their gap junction channels. In the mitochondria, however, connexins have been identified as monomers and assembled into hemichannels, thus questioning their role solely as cell–cell communication channels. Accordingly, mitochondrial connexins have been suggested to play critical roles in the regulation of mitochondrial functions, including potassium fluxes and respiration. However, while much is known about plasma membrane gap junction channel connexins, the presence and function of mitochondrial connexins remain poorly understood. In this review, the presence and role of mitochondrial connexins and mitochondrial/connexin-containing structure contact sites will be discussed. An understanding of the significance of mitochondrial connexins and their connexin contact sites is essential to our knowledge of connexins’ functions in normal and pathological conditions, and this information may aid in the development of therapeutic interventions in diseases linked to mitochondria.

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Mitochondrial Connexins and Mitochondrial Contact Sites with Gap Junction Structure

Doxorubicin (DOX) is the most commonly used anthracycline anticancer agent, while its clinical utility is limited by harmful side effects like cardiotoxicity. Numerous studies have elucidated that the programmed cell death plays a significant role in doxorubicin induced cardiotoxicity (DIC). This review summarizes several kinds of programmed cell death, including apoptosis, pyroptosis, necroptosis, autophagy and ferroptosis. Furthermore, oxidative stress, inflammation and mitochondial dysfunction, are also important factors in the molecular mechanisms of DIC. Besides, a comprehensive understanding of specific signal pathway of DIC can be helpful to its treatment. Therefore, the related signal pathways are elucidated in this review, including SIRT1/Nrf2, SIRT1/Klotho, SIRT1/SESN2, AMPK, AKT and PPAR. Heat Shock Proteins function as chaperones, which play important role in various stressful situations, especially in the heart. Thus, some of Heat Shock Proteins involved in DIC are also included. Hence, the last part of this review focuses on the therapeutic research based on the mechanisms above. 

The mechanism and therapeutic strategies in Doxorubicin induced cardiotoxicity: Role of programmed cell death

Abstract Background Current treatment of acute leukemia is based on anthracycline chemotherapy. Anthracyclines, despite improving patient survival, have serious cardiotoxicity and therefore cardiac monitoring should be a priority. The purpose of this study is to explore the possible early predictors of anthracycline-induced subclinical cardiotoxicity(AISC)in acute leukemia patients. Methods We conducted a prospective observational study involving 51 patients with acute leukemia treated with anthracycline. Demographic data, clinical variables, echocardiography variables and biochemical variables were collected at baseline and after 3 cycles of chemotherapy. Patients were divided into the AISC and No-AISC groups according to changes of global longitudinal peak systolic strain. Regression models and receiver operating characteristic curve analysis were used to explore the relationship between the variables and AISC. Result 17 of the patients suffered subclinical cardiotoxicity after 3 cycles of anthracycline treatment. Multiple logistic regression analysis showed a significant association of DBil (OR 0.612, 95% CI 0.409–0.916, p = 0.017), TBil (OR 0.841, 95% CI 0.717–0.986, p = 0.033), PLT (OR 1.012, 95% CI 1.002–1.021, p = 0.016) and Glu (OR 1.873, 95% CI 1.009–3.475, p = 0.047) with the development of AISC. After 3 cycles of chemotherapy, there was a significant difference in PLT between the AISC and NO-AISC groups. Moreover, the dynamic changes in PLT from baseline to after 3 cycles of chemotherapy were each statistically significant in the AISC and NO-AISC groups. The combination of PLT and N-terminal pro–B-type natriuretic peptide (NT-proBNP) had the highest area under curves (AUC) for the diagnosis of AISC than PLT and NT-proBNP alone (AUC = 0.713, 95%CI: 0.56–0.87, P = 0.017). Conclusion Total bilirubin (TBil), direct bilirubin (DBil), platelets (PLT) and blood glucose (Glu) are independent influencing factors for AISC in acute leukemia patients receiving anthracycline therapy. Bilirubin may be a protective factor and PLT may be a contributing factor for AISC. The combination of baseline PLT and baseline NT-proBNP shows satisfactory predictive ability for AISC in acute leukemia cases treated with 3 cycles of chemotherapy. 

Influencing factors of anthracycline-induced subclinical cardiotoxicity in acute leukemia patients

Hyperuricemia and its development to gout have reached epidemic proportions. Systemic hyperuricemia is facilitated by elevated activity of xanthine oxidase, the sole source of uric acid in mammals. Here, we aim to investigate the role of bilirubin in maintaining circulating uric acid homeostasis. We observed serum bilirubin concentrations were inversely correlated with uric acid levels in humans with new-onset hyperuricemia and advanced gout in a clinical cohort consisting of 891 participants. We confirmed that bilirubin biosynthesis impairment recapitulated traits of hyperuricemia symptoms, exemplified by raised circulating uric acid levels and accumulated hepatic xanthine oxidase, and exacerbated mouse hyperuricemia development. Bilirubin administration significantly decreased circulating uric acid levels in hyperuricemia-inducing (HUA) mice receiving potassium oxonate (a uricase inhibitor) or fed with a high fructose diet. Finally, we proved that bilirubin ameliorated mouse hyperuricemia by increasing hepatic xanthine oxidase autophagic degradation, restoring antioxidant defense and normalizing mitochondrial function in a manner dependent on AMPK pathway. Hepatocyte-specific AMPKα knockdown via adeno-associated virus (AAV) 8-TBG-mediated gene delivery compromised the efficacy of bilirubin in HUA mice. Our study demonstrates the deficiency of bilirubin in hyperuricemia progression, and the protective effects exerted by bilirubin against mouse hyperuricemia development, which may potentiate clinical management of hyperuricemia. 

Unconjugated bilirubin promotes uric acid restoration by activating hepatic AMPK pathway

Doxorubicin induces severe cardiotoxicity, accompanied by the high level of bilirubin in the blood. The conventional wisdom is that bilirubin is considered as a marker of liver damage. By contrast, here we aim to explore the potential protective effect of bilirubin on doxorubicin-induced cardiotoxicity, and investigate the mechanism for drug development. Doxorubicin was used to establish cardiotoxicity model in vitro and in vivo. The electrocardiogram (ECG), echocardiography and molecular biological methods were used to detect the effects of bilirubin on doxorubicin-induced cardiotoxicity. Consecutive intraperitoneal injection of bilirubin for 7 days significantly attenuated doxorubicin-induced arrhythmia, prolonged survival time and reduced the levels of aspartate aminotransferase (AST), lactate dehydrogenase (LDH), creatine kinase MB (CK-MB) and α-hydroxybutyrate dehydrogenase (α-HBDH) in mice. Bilirubin also markedly inhibited doxorubicin-induced phosphorylation of c-Jun N-terminal kinase (JNK) and connexin 43 (Cx43), and improved gap junction function in vitro and in vivo. In addition, bilirubin activated adenosine 5′-monophosphate (AMP)-activated protein kinase (AMPK) and induced suppressor of cytokine signaling 3 (SOCS3) expression, which was abolished by Axl inhibition. Moreover, pretreatment with AMPK agonist or AMPK inhibitor could mimic or abolish the cardioprotective effect of bilirubin on H9C2 cells in vitro, respectively. Altogether, bilirubin upregulates gap junctions’ function to protect against doxorubicin-induced cardiotoxicity by activating AMPK-Axl-SOCS3 signaling axis. We enrich the physiological function of bilirubin, and provide theoretical support for drug development.

/pdf/bilirubin-improves-gap-junction-to-alleviate-doxorubicin-782jnwn3.pdf

Bilirubin Improves Gap Junction to Alleviate Doxorubicin-Induced Cardiotoxicity by Regulating AMPK-Axl-SOCS3-Cx43 Axis

Introduction Cystitis glandularis (CG) is a rare chronic bladder hyperplastic disease that mainly manifests by recurrent frequent urination, dysuria and gross hematuria. The current lack of unified diagnosis and treatment criteria makes it essential to comprehensively describe the inflammatory immune environment in CG research. Methods Here, we performed scRNA-sequencing in CG patients for the first time, in which four inflamed tissues as well as three surrounding normal bladder mucosa tissues were included. Specifically, we isolated 18,869 cells to conduct bioinformatic analysis and performed immunofluorescence experiments. Results Our genetic results demonstrate that CG does not have the classic chromosomal variation observed in bladder tumors, reveal the specific effects of TNF in KRT15 epithelial cells, and identify a new population of PIGR epithelial cells with high immunogenicity. In addition, we confirmed the activation difference of various kinds of T cells during chronic bladder inflammation and discovered a new group of CD27-Switch memory B cells expressing a variety of immunoglobulins. Discussion CG was regarded as a rare disease and its basic study is still weak.Our study reveals, for the first time, the different kinds of cell subgroups in CG and provides the necessary basis for the clinical treatment of cystitis glandularis. Besides, our study significantly advances the research on cystitis glandularis at the cellular level and provides a theoretical basis for the future treatment of cystitis glandularis.

/pdf/single-cell-rna-sequencing-reveals-the-immune-luz9f90b.pdf

Single-cell RNA sequencing reveals the immune microenvironment and signaling networks in cystitis glandularis

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Bilirubin Improves Gap Junction to Alleviate Doxorubicin-Induced Cardiotoxicity by Regulating AMPK-Axl-SOCS3-Cx43 Axis

Single-cell RNA sequencing reveals the immune microenvironment and signaling networks in cystitis glandularis