Discovery of an Ortho-Substituted N-Cyclopropylmethyl-7α-phenyl-6,14-endoethano-tetrahydronorthebaine Derivative as a Selective and Potent Kappa Opioid Receptor Agonist with Subsided Sedative Effect.

Research into kappa opioid receptor (KOR) agonists with attenuated central-nervous-system side effects is a critical focus for developing productive and safe analgesics. Herein, a series of ortho-substituted N-cyclopropylmethyl-7α-phenyl-6,14-endoethano-tetrahydronorthebaines were designed, synthesized, and subjected to bioassays. Compound 7a exhibited high subtype selectivity and potent agonistic activity toward KOR (KOR, Ki = 3.9 nM, MOR/KOR = 270, DOR/KOR = 1075; [35S]GTPγS binding, EC50 = 3.4 nM). Additionally, this compound exhibited robust and persistent antinociceptive effects in rodent models with different animal strains (hot plate test, ED50 = 0.20-0.30 mg/kg, i.p.; abdominal constriction test, ED50 = 0.20-0.60 mg/kg, i.p.), with its KOR-mediated mechanism for antinociception firmly established. Notably, compound 7a, unlike conventional KOR agonists, displayed minimal sedation and aversion at the antinociceptive ED50 dose. This feature addresses a crucial limitation in existing KOR agonists, positioning compound 7a as a promising novel therapeutic agent.

Iatrogenic aortic dissection in patients undergoing coronary artery bypass grafting surgery: A systemic review of published literatures.

BACKGROUND: Iatrogenic aortic dissection (IAD) is a rare but highly lethal complication that may occur following coronary artery bypass grafting (CABG) surgery. Aortic dissection (AD) is often asymptomatic, making early detection difficult. We aimed to optimize preoperative evaluation strategies of CABG surgery for minimizing the incidence of IAD and assess early recognition and management of IAD for improving outcomes. METHODS: Electronic databases were searched to identify all case reports of patients undergoing CABG surgery who developed IAD. Clinical characteristics, operative information, perioperative management, and patient outcomes were compiled and analyzed. RESULTS: Nineteen case reports involving 27 patients aged 50 to 81 were included. Patients were from Europe (n = 23) and Asia (n = 4), mostly men (n = 25). The aorta was described as normal, abnormal, and unmentioned (n = 8, 5, and 14, respectively). Sixteen patients had a bypass with more than 3 grafts. Most patients (n = 25) experienced type A dissection. There were intraoperative (n = 12) and postoperative (n = 15) cases. Surgery (n = 19) was the most common treatment, with 9 patients selecting deep hypothermic circulatory arrest. Eighteen patients were restored to health, while 9 patients died (3 died before treatment). CONCLUSIONS: Our study focused on patients with IAD and developed a recommended management protocol for patients undergoing CABG surgery.

The Antidepressant Effect of Magnolol on Depression-Like Behavior of CORT-Treated Mice.

Although the antidepressant-like effect of magnolol has been revealed in previous reports, the mechanism remains unclear. In this study, the antidepressant-like effect of magnolol on corticosterone-induced (CORT-induced) mice was investigated in vivo. After 21 days of CORT induction, the mice showed marked depressive-like behaviors, with a decrease in sucrose preference score and an increase in immobility time in the tail suspension test (TST) and forced swimming test (FST). Pretreatment with either magnolol (50 mg/kg, i.p.) or the kappa opioid receptor (KOR) antagonist nor-BNI (10 mg/kg, i.p.) prevented CORT-induced depression-like behavior and reduced CORT-induced dynorphin (DYN A) elevation in the hippocampal ventral DG. However, no depression-like behavior was observed in mice with KOR downregulation in the ventral DG. We further found that upregulation of DYN A in the DG caused depression-like behavior, which was blocked by intraperitoneal injection of nor-BNI and modulated by magnolol. The present study demonstrated that magnolol could ameliorate CORT-induced depression-like behaviors, by modulating the DYN A/KOR system in the ventral DG of the hippocampus.

The association of vasoactive-inotropic score and surgical patients' outcomes: a systematic review and meta-analysis.

BACKGROUND: The objective of this study is to conduct a systematic review and meta-analysis examining the relationship between the vasoactive-inotropic score (VIS) and patient outcomes in surgical settings. METHODS: Two independent reviewers searched PubMed, Web of Science, EMBASE, Scopus, Cochrane Library, Google Scholar, and CNKI databases from November 2010, when the VIS was first published, to December 2022. Additional studies were identified through hand-searching the reference lists of included studies. Eligible studies were those published in English that evaluated the association between the VIS and short- or long-term patient outcomes in both pediatric and adult surgical patients. Meta-analysis was performed using RevMan Manager version 5.3, and quality assessment followed the Joanna Briggs Institute (JBI) Critical Appraisal Checklists. RESULTS: A total of 58 studies comprising 29,920 patients were included in the systematic review, 34 of which were eligible for meta-analysis. Early postoperative VIS was found to be associated with prolonged mechanical ventilation (OR 5.20, 95% CI 3.78-7.16), mortality (OR 1.08, 95% CI 1.05-1.12), acute kidney injury (AKI) (OR 1.26, 95% CI 1.13-1.41), poor outcomes (OR 1.02, 95% CI 1.01-1.04), and length of stay (LOS) in the ICU (OR 3.50, 95% CI 2.25-5.44). The optimal cutoff value for the VIS as an outcome predictor varied between studies, ranging from 10 to 30. CONCLUSION: Elevated early postoperative VIS is associated with various adverse outcomes, including acute kidney injury (AKI), mechanical ventilation duration, mortality, poor outcomes, and length of stay (LOS) in the ICU. Monitoring the VIS upon return to the Intensive Care Unit (ICU) could assist medical teams in risk stratification, targeted interventions, and parent counseling. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42022359100.

Cardiovascular anesthesia training: A single center survey among fellow doctors.

Despite the proliferation of research on anesthesiology training at all stages of medical education, there is relatively little published literature surveying the perspectives and concerns of anesthesiologists regarding cardiovascular anesthesia training. Therefore, we conducted a survey to investigate the attitudes, barriers, expectations, stress experiences, satisfaction, and future aspirations of anesthesiologists trained at a tertiary cardiovascular specialty hospital in China. A questionnaire survey was conducted among 260 anesthesiologists who received cardiovascular anesthesia training at departments of anesthesiology in a tertiary cardiovascular specialty hospital in China. After the study protocol was approved, electronic questionnaires were distributed to the target group through the online survey software "Wen Juan Xing." Respondents were asked to complete an anonymous questionnaire on their smartphones through WeChat, with the restriction of one response per device enabled. Of the 260 trainees, 240 (98%) completed the questionnaire. The majority of the trainees were 31 years of age or above. A large majority had approximately 10 years of clinical anesthesia practice, and nearly one-third had never undertaken cardiovascular specialty anesthesia practice before. The most common reasons for attending the refresher training were the need to learn basic specialty theory and improve clinical skills. The barriers were mainly time constraints or staff shortages in the department. Sixty-one (93.8%) trainees described the experience as "stressful or highly stressful" and identified poor teacher interaction as the highest-ranking stressor. Anesthesiologists were most dissatisfied with job rewards, with a satisfaction rate of only 15%. Anesthesiologists are highly stressed during the refresher training. Poor teacher interaction and low job rewards were identified as the highest-ranking stressors during cardiovascular anesthesia training. Training providers need to pay more attention to these stressors to enhance the quality of cardiovascular anesthesia training.

Hypoxia improves self-renew and migration of urine-derived stem cells by upregulating autophagy and mitochondrial function through ERK signal pathway.

Urine-derived stem cells (USCs) are autologous stem cells with self-renewal ability and multi-lineage differentiation potential. Our previous studies have shown that hypoxia preconditioning can improve self-renewal and migration abilities of USCs by up-regulating autophagy. The purpose of this study was to investigate the specific mechanism by which hypoxia treatment promotes the biological function of USCs. We found that hypoxia treatment upregulated the expression of phosphralated ERK protein without affecting the expression of total ERK protein. Inhibiting ERK signaling with the PD98059 inhibitor decreased cell proliferation, migration and colony formation during hypoxia treatment. Hypoxia increased ATP production, mitochondrial membrane potential and mt-DNA copy number, which were reversed by inhibiting the ERK signal. Additionally, the number of autophagosomes and autophagic lysosomes was significantly lower in PD98059 group than in the hypoxia group. PD98059 treatment inhibited the up-regulation of autophagy related proteins induced by hypoxia. Therefore, this study suggests that hypoxia improves the self-renewal and migration abilities of USCs by upregulating autophagy and mitochondrial function through ERK signaling pathway. This finding may provide a new therapeutic mechanism for hypoxia pretreated USCs as a source of stem cell transplantation.

Inhibition of pyruvate dehydrogenase kinase 4 attenuates myocardial and mitochondrial injury in sepsis-induced cardiomyopathy.

BACKGROUND: Sepsis-induced cardiomyopathy (SIC) is a cardiac dysfunction caused by sepsis, with mitochondrial dysfunction being a critical contributor. Pyruvate dehydrogenase kinase 4 (PDK4) is a kinase of pyruvate dehydrogenase (PDH) with multifaceted actions in mitochondrial metabolism. However, its role in SIC remains unknown. METHODS: Serum PDK4 levels were measured and analyzed in 27 SIC children, 30 septic children, and 29 healthy children. In addition, the effects of PDK4 knockdown or inhibition on the function and structure of the myocardium and mitochondria of mice exhibiting SIC were assessed. RESULTS: The findings from the analysis of children with SIC revealed that PDK4 was significantly elevated and correlated with disease severity and organ injury. SIC nonsurvivors displayed higher serum PDK4 levels than survivors. Furthermore, mice with SIC benefited from PDK4 knockdown or inhibition, showing improved myocardial contractile function, reduced myocardial injury, and decreased mitochondrial structural injury and dysfunction. In addition, inhibition of PDK4 decreased the inhibitory phosphorylation of pyruvate dehydrogenase complex E1 subunit alpha (PDHE1α), improved abnormal pyruvate metabolism and mitochondrial dysfunction. CONCLUSIONS: PDK4 is a potential biomarker for the diagnosis and prognosis of SIC. In experimental SIC, PDK4 promotes mitochondrial dysfunction with increased phosphorylation of PDHE1α and abnormal pyruvate metabolism.

Anesthesia management of patients undergoing thoracic endovascular aortic repair: A retrospective analysis of single center.

Thoracic endovascular aortic repair (TEVAR) is a new alternative surgical treatment for aortic pathologies, which is more minimally invasive. The aim of current study was to summarize the single-center experience of general anesthesia for patients undergoing TEVAR. In adult patients undergoing surgery for congenital heart disease, the strategy of "fast-track" anesthesia with early extubation in theater is associated with a shorter intensive care unit (ICU) stay, and lower health-care-related costs. Fast-track anesthesia has not been assessed in patients under TEVAR. Adult patients who received general anesthesia for TEVAR in our center from January 2020 to December 2020 were included. Baseline characteristics, airway management, anesthetic techniques and major complications were collected. A total of 204 (171 male, mean age 58.1 ± 11.5 years) patients met inclusion criteria for this study. The distribution of pathologies included 29 descending thoracic aneurysms, 87 type B dissections, and 88 intramural hematoma/perforating aortic ulcer. Etomidate was the induction agent in 190 (93.1%) patients, compared with propofol in 16 (7.8%). Cisatracurium was the muscle relaxant in 201 (98.5%), compared with rocuronium in 3 (1.5%). Midazolam (benzodiazepines) was given to 124 (60.8%) patients during anesthesia induction. General anesthesia was maintained with sevoflurane in 85.3% (174) patients, dexmedetomidine in 201 (98.5%) and propofol in 204 (100%). Postoperative length of stay (LOS) in the hospital was 6.0 (5.0-7.8) days. LOS in the ICU was 23.0 (20.0-27.8) hours. Overall neurologic event rate was 2.0% (n = 4) (spinal cord ischemia 1.5% [n = 3]; stroke 0.5% [n = 1]). After matching, patients who received "fast-track" anesthesia had a shorter LOS in ICUs (21.0 [18.0-24.0] vs 24.0 [20.0-44.0] hours; P = .005), and a shorter postoperative LOS in hospital (5.0 [4.0-7.0] vs 6.0 [5.0-8.0] days; P = .001). There were no in-hospital deaths. Fast-track anesthesia is feasible and safe in patients underwent TEVAR. This management strategy is associated with shorter LOS of ICU and total postoperative hospital stays. An early extubation strategy should be implemented for hemodynamically stable patients.

A Dual Stimuli-Responsive Nanoplatform Loaded PtIV -Triptolide Prodrug for Achieving Synergistic Therapy toward Breast Cancer.

To strengthen the antitumor efficacy and avoid toxicity to normal cells of cisplatin and triptolide, herein, an acid and glutathione (GSH) dual-controlled nanoplatform for enhanced cancer treatment through the synergy of both "1+1" apoptosis and "1+1" ferroptosis is designed. Remarkably, ZIF8 in response to tumor microenvironment enhances drug targeting and protects drugs from premature degradation. Meanwhile, the PtIV  center can be easily reduced to cisplatin because of the large amount of GSH, thus liberating the triptolide as the coordinated ligand. The released cisplatin and hemin in turn boost the tumor cell "1+1" apoptosis through chemotherapy and photodynamic therapy, respectively. Furthermore, GSH reduction through PtIV  weakens the activation of glutathione peroxidase 4 (GPX4) effectively. The released triptolide can inhibit the expressions of GSH by regulating nuclear factor E2 related factor 2 (Nrf2), further promoting membrane lipid peroxidation, thus "1+1" ferroptosis can be achieved. Both in vitro and in vivo results demonstrate that the nanosystem can not only perform superior specificity and therapeutic outcomes but also reduce the toxicity to normal cells/tissues of cisplatin and triptolide effectively. Overall, the prodrug-based smart system provides an efficient therapeutic strategy for cancer treatment by virtue of the effect of enhanced "1+1" apoptosis and "1+1" ferroptosis therapies.

PTEN-induced putative kinase 1 regulates mitochondrial quality control and is essential for the maturation of human induced pluripotent stem cell-derived cardiomyocytes.

Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have attracted attention in the field of regenerative medicine due to their potential ability to repair damaged hearts. However, the immature phenotype of these cells limits their clinical application. Cardiomyocyte maturation is accompanied by changes in mitochondrial quality. PTEN-induced putative kinase 1 (PINK1) has been linked to mitochondrial quality control. However, whether the changes in mitochondrial quality in hiPSC-CMs are associated with PINK1, and the impact of PINK1 on hiPSC-CMs development are not clear. In this study, we found that knockdown of PINK1 in hiPSC-CMs resulted in mitochondrial fragmentation and impaired mitochondrial functions such as mitophagy and mitochondrial biogenesis. PINK1 deletion also inhibited the maturation of hiPSC-CMs, reverting them to a naive structural and functional state. We found that restoring the mitochondrial structure did not completely rescue the mitochondrial dysfunction caused by PINK1 deletion, while activation of PINK1 kinase activity using kinetin promoted mitochondrial fusion, increased the mitochondrial membrane potential and ATP production, and maintained the development and maturation of hiPSC-CMs. In conclusion, PINK1 regulates the mitochondrial structure and function of hiPSC-CMs, and is essential for the maturation of hiPSC-CMs.

Longitudinal Changes in Milk Microorganisms in the First Two Months of Lactation of Primiparous and Multiparous Cows.

The present experiment was carried out to analyze the longitudinal changes in milk microorganisms. For this purpose, milk samples were collected from 12 healthy cows (n = 96; six primiparous cows and six multiparous cows) at eight different time points. The characteristics and variations in microbial composition were analyzed by 16S rRNA gene high-throughput sequencing. In the primiparous group, higher and more stable alpha diversity was observed in transitional and mature milk compared with the colostrum, with no significant difference in alpha diversity at each time point in the multiparous group. Proteobacteria, Firmicutes, Bacteroidota, and Actinobacteriota were the most dominant phyla, and Pseudomonas, UCG-005, Acinetobacter, Vibrio, Lactobacillus, Bacteroides, Serratia, Staphylococcus, and Glutamicibacter were the most dominant genera in both primiparous and multiparous cow milk. Some typically gut-associated microbes, such as Bacteroides, UCG-005, and Rikenellaceae_RC9_gut_group, etc., were enriched in the two groups. Biomarker taxa with the day in time (DIM) were identified by a random forest algorithm, with Staphylococcus showing the highest degree of interpretation, and the difference in milk microbiota between the two groups was mainly reflected in 0 d-15 d. Additionally, network analysis suggested that there were bacteria associated with the total protein content in milk. Collectively, our results disclosed the longitudinal changes in the milk microbiota of primiparous and multiparous cows, providing further evidence in dairy microbiology.

Case Report: Multiple Organ Failure Caused by Hemorrhagic Fever with Renal Syndrome.

Hemorrhagic fever with renal syndrome (HFRS), a natural epidemic disease caused by hantavirus (HV), is one of the viral diseases that pose a major threat to our health. Considering the increasing number of atypical-onset cases reported in some countries, it is important to be familiar with the symptoms of HFRS and the signs of HV infection. This report describes the case of a 55-year-old man with complaints of fever, vomiting, and diarrhea. His symptoms showed no significant improvement after routine anti-infective, antipyretic, and other symptomatic supportive treatments administered at a local clinic. During these treatments, the patient had progressive oliguria; after 3 days, he also developed multiple organ failures, such as the liver and kidney, and was examined for positive serum IgM antibodies to hemorrhagic fever during treatment at our hospital. The patient was finally diagnosed with HFRS followed by multiple organ failure. After antiviral therapy, including ribavirin, piperacillin, and tazobactam, continuous renal replacement therapy, fluid metabolism adjustment, and related supportive therapy were administered, which improved his liver and kidney function. He was discharged on the 25th day after hospitalization. It is difficult to manage patients who develop multiple organ failure after HFRS. Moreover, this condition is rare in clinical settings, with fever being the initial indication. For diseases with unknown origin such as refractory fever and diarrhea, it is crucial to differentiate them from common pathogenic infection and HV infections to provide timely treatment that improves the prognosis of patients.

A Systematic Review and Meta-Analysis of Comparing Drainage Alone versus Drainage with Primary Fistula Treatment for the Perianal Abscess in Children.

This systematic review and meta-analysis of nonrandomized studies (NRSs) aimed to evaluate the clinical efficacy and safety of two types of surgical interventions (respectively drainage alone and drainage with primary fistula treatment) for perianal abscesses (PAs) in children. Studies from 1992 to July 2022 were searched in 10 electronic databases. All relevant NRSs with available data which compared surgical drainage with or without primary fistula treatment were included. Patients with underlying diseases which led to abscess formation were excluded. The Newcastle-Ottawa Scale was used to assess the risk of bias and quality of the included studies. The outcomes were the healing rate, fistula formation rate, fecal incontinence, and wound healing duration. A total of 16 articles with 1,262 patients were considered suitable for the final meta-analysis. Primary fistula treatment was associated with a significantly higher healing rate when compared with incision and drainage alone (odds ratio [OR]: 5.76, 95% confidence interval [CI]: 4.04-8.22). This aggressive procedure for PA resulted in an 86% reduction in the fistula formation rate (OR: 0.14, 95% CI: 0.06-0.32). Limited data showed patients who underwent primary fistula treatment have a minor effect on postoperative fecal incontinence. Primary fistula treatment demonstrates a better clinical efficacy in promoting the healing rate and decreasing the formation of fistulas in PAs in children. The available evidence for a minor impact on anal function after this intervention is less strong.

High bitrate data transmission in the 8-14 µm atmospheric window using an external Stark-effect modulator with digital equalization.

High bitrate mid-infrared links using simple (NRZ) and multi-level (PAM-4) data coding schemes have been realized in the 8 µm to 14 µm atmospheric transparency window. The free space optics system is composed of unipolar quantum optoelectronic devices, namely a continuous wave quantum cascade laser, an external Stark-effect modulator and a quantum cascade detector, all operating at room-temperature. Pre- and post-processing are implemented to get enhanced bitrates, especially for PAM-4 where inter-symbol interference and noise are particularly detrimental to symbol demodulation. By exploiting these equalization procedures, our system, with a full frequency cutoff of 2 GHz, has reached transmission bitrates of 12 Gbit/s NRZ and 11 Gbit/s PAM-4 fulfilling the 6.25 % overhead hard-decision forward error correction threshold, limited only by the low signal-to-noise ratio of our detector.

Nrf2/PINK1-mediated mitophagy induction alleviates sodium fluoride-induced hepatic injury by improving mitochondrial function, oxidative stress, and inflammation.

Mitophagy has distinct functions, which can lead to either protection or damage of tissues. Though current evidence indicated that NaF triggers mitophagy, the role and regulation of mitophagy in sodium fluoride (NaF)-induced liver injury still remain unclear. Therefore, we exployed the cell and mouse models and confirmed that NaF treatment activates mitophagy. Knocking down PTEN-induced putative kinase protein 1 (PINK1) expression attenuated mitophagy and increased the degree of mitochondrial impairment, oxidative stress, and apoptosis in NaF-treated HepG2 cells. In vivo experiments indicated that PINK1 deficiency weakened NaF-induced mitophagy. Moreover, PINK1-deficient mices aggravated NaF-induced hepatic mitochondrial injury, oxidative stress, and inflammation in livers, evidenced by the increased number of abnormal mitochondria, decreased adenosine triphosphate (ATP) and glutathione (GSH) levels, elevated reactive oxygen species (ROS) and malondialdehyde (MDA) content, enhanced hepatic macrophage infiltration and inflammatory cytokine levels. Notably, NaF exposure activated Nrf2 signaling both in vitro and in vivo. Nrf2 siRNA transfection blocked the upregulation of PINK1 expression and the induction of mitophagy in NaF-treated HepG2 cells. Also, ML385 (Nrf2 inhibitor) partially blocked the upregulation of PINK1 expression caused by NaF in mice livers. To sum up, the present study provided the demonstration that Nrf2/PINK1-mediated mitophagy activation offers a hepatoprotective effect by inhibiting NaF-induced mitochondrial dysfunction, oxidative stress, and inflammation.

HnRNP K reduces viral gene expression by targeting cytosine-rich sequences in porcine reproductive and respiratory syndrome virus-2 genome to dampen the viral growth.

HnRNP K is a well-known member of HnRNP family proteins that has been implicated in the regulation of protein expression. Currently, the impact of HnRNP K on the reproduction cycle of a broad range of virus were reported, while the precise function for PRRSV was lacking. In this study, we determined that both PRRSV infection and ectopic expression of N protein induced an enrichment of HnRNP K in the cytoplasm. Using RNA pulldown and RNA immunoprecipitation, we described the interactions between the KH2 domain of HnRNP K and cytosine-rich sequences (CRS) in PRRSV genomic RNA corresponding to Nsp7α coding region. Meanwhile, overexpression of HnRNP K inhibited viral gene expression and PRRSV replication, while silencing of HnRNP K resulted in an increased in virus yield. Taken together, this study assists in the understanding of PRRSV-host interactions, and the development of vaccines based on viral genome engineering.

Altered serum lipid levels are associated with prognosis of diffuse large B cell lymphoma and influenced by utility of rituximab.

Diffuse large B cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma, and the prognosis of the disease varied. This research aims to investigate the impact of serum lipid level on the outcome of DLBCL patients and their interaction with rituximab (RTX). Data of newly diagnosed DLBCL in the third affiliated hospital of Soochow University were retrospectively collected. Baseline serum lipid levels, clinical data, and survival information were simultaneously recorded. Data of healthy controls were collected with age matching. Serum lipid levels significantly differed for the patients. All were transformed into categorical variables for the analysis of survival. During a median follow-up of 58 months, 32.8% patients died. Univariate analysis revealed all serum lipid indicators were associated with overall survival (OS); all except for total cholesterol (TC) and apolipoprotein B (apoB) showed significant impact on progression-free survival (PFS). Multivariable analysis confirmed the adverse effect of triglyceride (TG) on PFS (P = 0.013) and favorable impact of high-density lipoprotein (HDL) on OS (P = 0.003). For cases treated without RTX, apolipoprotein A (apoA) had independent favorable effect on both PFS (P = 0.004) and OS (P = 0.001). Comparably, for patients who received RTX, HDL showed remarkably predictive value of PFS (P = 0.011) and OS (P = 0.019). In conclusion, the abnormal serum lipids occurred throughout the course of DLBCL, and the associations of serum lipids and the prognosis of the disease were interfered by RTX. Trial registration: 2022()CL033; June 26, 2022, retrospectively registered.

A positive self-amplified H2O2 and acidity circulation for boosting CDT-PTT-starvation therapy.

The therapeutic application of chemodynamic therapy (CDT) is severely limited by the insufficient intracellular H2O2 and acidity in tumor. Herein, an acid-sensitive nanoplatform (ZIF67-ICG/TAM@GOx) to promote H2O2 and acidity enhancement through intracellular cyclic amplification for enhanced CDT is rationally designed. Notably, the acidic conditions of the tumor microenvironment (TME) can turn on the switch of the nanoplatform, setting free the loaded tamoxifen (TAM) and indocyanine green (ICG). The mitochondrial respiration inhibitor TAM and the superoxide dismutase-mimicking ZIF67 synergistically lead to an increase in the content of O2 and H2O2, accelerating the depletion of ß-d-glucose by GOx to generate gluconate and H2O2. The gluconate in turn boosts the acidity to facilitate the collapse of nanoparticles, further significantly promoting the accumulation of intracellular H2O2 through a positive circulation. Consequently, the amplificated endogenous H2O2 is catalyzed by Co2+ to liberate hydroxyl radicals (•OH). Besides, ICG-mediated photothermal therapy (PTT) and GOx-induced starvation therapy along with CDT realize the synergistic cancer treatment. Importantly, in vitro and in vivo experiments verified that the nanoplatform performed superior specificity and excellent therapeutic responses. The smart nanoplatform overcomes H2O2 and acidity deficiency simultaneously for intensive CDT, providing new prospects for the development of biocompatible cancer synergistic therapy strategies.

Andrographolide-treated bone marrow mesenchymal stem cells-derived conditioned medium protects cardiomyocytes from injury by metabolic remodeling.

BACKGROUND: Bone marrow mesenchymal stem cells (BMSCs) transplantation therapy providing a great hope for the recovery of myocardial ischemic hypoxic injury. However, the microenvironment after myocardial injury is not conducive to the survival of BMSCs, which limits the therapeutic application of BMSCs. Our previous study has confirmed that the survival of BMSCs cells in the glucose and serum deprivation under hypoxia (GSDH) is increased after Andrographolide (AG) pretreatment, but whether this treatment could improve the effect of BMSCs in repairing of myocardial injury has not been verified. METHODS AND RESULT: We first treated H9C2 with GSDH to simulate the microenvironment of myocardial injury in vitro, then we pretreated rat primary BMSCs with AG, and collected conditioned medium derived from BMSCs (BMSCs-CM) and conditioned medium derived from AG-pretreated BMSCs (AG-BMSCs-CM) after GSDH treatment. And they were used to treat H9C2 cells under GSDH to further detect oxidative stress and metabolic changes. The results showed that AG-BMSCs-CM could be more advantageous for cardiomyocyte injury repair than BMSCs-CM, as indicated by the decrease of apoptosis rate and oxidative stress. The changes of mitochondria and lipid droplets results suggested that AG-BMSCs-CM can regulate metabolic remodeling of H9C2 cells to repair cell injury, and that AMPK was activated during this process. CONCLUSIONS: This study demonstrates, for the first time, the protective effect of AG-BMSCs-CM on GSDH-induced myocardial cell injury, providing a potential therapeutic strategy for clinical application.

Ferrostatin-1 improves BMSC survival by inhibiting ferroptosis.

OBJECTIVE: To investigate the effect of ferroptosis in BMSCs and explore the protective metabolism of ferrostatin-1 under GSDH treatment. METHODS: BMSCs were treated with GSDH to simulate the damaged microenvironment in vivo to establish a cell injury model. Propidium iodide and CCK8 were utilized to detect the ratio of dead cells and cell viability. DCFH-DA and Amplex Red, FerroOrange, and BPDIPY were used to visualize the cellular fluorescent images of ROS, Fe2+, and lipid droplets, respectively. The quantified detection of MDA was conducted by a Lipid Peroxidation MDA Assay Kit. JC-1 staining, Mito-Tracker staining, and TEM were implemented to detect the membrane potential, morphology, and ultrastructure of mitochondria, respectively. The expression levels of ferroptosis-related proteins such as GPX4 and FTH1 were measured by Western blotting. RESULTS: GSDH treatment induced ferroptosis in BMSCs based on an increased ratio of cell death, Fe2+, ROS, lipid droplets, and MDA in cells plus decreased protein levels of antioxidant systems, such as GPX4, and increased protein levels related to fatty acid synthesis. Compared to the blank group, mitochondria in the GSDH group underwent lower membrane potential, damaged morphology, and shrunken ultrastructure; Ferr-1 rescued the injured BMSCs to a certain extent as the declined ratio of cell death, Fe2+, ROS, lipid droplets, MDA, and the increased level antioxidant protein. AMPK was phosphorylated and activated after Ferr-1 treatment, and its downstream lipid peroxidation and antioxidation proteins changed accordingly. Inhibition of AMPK hindered the curative effect of Ferr-1. CONCLUSION: Ferr-1 rescued ferroptosis-induced injury to BMSCs under GSDH conditions, and AMPK might have a relationship with the mitigative effect of Ferr-1.