ABSTRACT
Induction of immunogenic cell death promotes antitumor immunity against cancer. However, majority of clinically-approved drugs are unable to elicit sufficient ICD. Here, our study revealed that mitochondria-targeted delivery of doxorubicin (DOX) massively amplified ICD via substantial generation of reactive oxygen species (ROS) after mitochondrial damage. The underlying mechanism behind increased ICD was further demonstrated to be ascribed to two pathways: (1) ROS elevated endoplasmic reticulum (ER) stress, leading to surface exposure of calreticulin; (2) ROS promoted release of various mitochondria-associated damage molecules including mitochondrial transcription factor A. Nevertheless, adaptive upregulation of PD-L1 was found after such ICD-inducing treatment. To overcome such immunosuppressive feedback, we developed a tumor stimuli-responsive nano vehicle to simultaneously exert mitochondrial targeted ICD induction and PD-L1 blockade. The nano vehicle was self-assembled from ICD-inducing copolymer and PD-L1 blocking copolymer, and possessed long-circulating property which contributed to better tumor accumulation and mitochondrial targeting. As a result, the nano vehicle remarkably activated antitumor immune responses and exhibited robust antitumor efficacy in both immunogenic and non-immunogenic tumor mouse models.
ABSTRACT
Multidrug resistance (MDR) has been considered as a huge challenge to the effective chemotherapy. Therefore, it is necessary to develop new strategies to effectively overcome MDR. Here, based on the previous research of -(2-hydroxypropyl)methacrylamide (HPMA) polymer-drug conjugates, we designed an effective system that combined drug-efflux circumvention and mitochondria targeting of anticancer drug doxorubicin (Dox). Briefly, Dox was modified with mitochondrial membrane penetrating peptide (MPP) and then attached to (HPMA) copolymers (P-M-Dox). Our study showed that macromolecular HPMA copolymers successfully bypassed drug efflux pumps and escorted Dox into resistant MCF-7/ADR cells endocytic pathway. Subsequently, the mitochondria accumulation of drugs was significantly enhanced with 11.6-fold increase by MPP modification. The excellent mitochondria targeting then resulted in significant enhancement of reactive oxygen species (ROS) as well as reduction of adenosine triphosphate (ATP) production, which could further inhibit drug efflux and resistant cancer cell growth. By reversing Dox resistance, P-M-Dox achieved much better suppression in the growth of 3D MCF-7/ADR tumor spheroids compared with free Dox. Hence, our study provides a promising approach to treat drug-resistant cancer through simultaneous drug efflux circumvention and direct mitochondria delivery.
ABSTRACT
Objective To explore the short-term influences of conventional internal medical treatment combined with escitalopram on cognitive function and cardiac function in elderly patients with chronic heart failure (CHF) complicated with depression disorder.Methods A total of 97 patients with CHF complicated with depression disorder in Chongqing Ninth People's Hospital,from October 2014 to October 2015,were selected and randomly divided into the antidepressant group and control group.Both groups were undergoing conventional internal medical treatment.Additionally,patients in the antidepressant group were administrated with escitalopram,while patients in the control group were treated with placebo.The degree of depression and anxiety and cognitive function were assessed by using 24-item Hamilton depression scale (HAMD-24),14-item Hamilton anxiety scale (HAMA-14) and Montreal cognitive assessment(MoCA) scale,and the plasma level of NT-proBNP,left ventricular end-diastolic dimension (LVEDD) and left ventricular ejection fraction (LVEF) were measured before and after 6-week treatment.Results After 6-week treatment,the HAMD-24 and HAMA-14 scores and plasma level of NT-proBNP in antidepressant group were lower than those in the control group,while the attention score and LVEF were greater than those in the control group,there were statistically significant differences(P＜0.05).After 6-week treatment,no statistically significant difference was found in other observed indicators between the two groups(P＞0.05).Conclnsion For elderly patients with chronic heart failure complicated with depression disorder,it is indicated that escitalopram could not only relieve their anxiety and depression,but also improve their cardiac function and attention.
ABSTRACT
Objective To establish the method of the GC fingerprints for Ligusticum chuanxiong essential oil and its quality control.Methods The temperature at both feed inlet and detector was 250℃,the carrier gas was nitrogen,and the flow rate was 2 mL/min.GC of the essential oil in ten batches of L.chuanxiong was analyzed by adopting temprature programmer and the fingerprint peaks were identified by GC-MS.Results To set up the GC fingerprints for L.chuanxiong essential oil,13 peaks were marked out altogether and the GC fingerprints were analyzed by similarity analysis.Conclusion The method is of high degree of presion,reproducibility,and stability.The resolving of each component in the essential oil is good.The established fingerprints could be used as one of the quality control index for L.chuanxiong essential oil.