Second Affiliated Hospital of Xinjiang Medical University

Autophagy is the process by which cells degrade and recycle proteins and organelles to maintain intracellular homeostasis. Generally, autophagy plays a protective role in cells, but disruption of autophagy mechanisms or excessive autophagic flux usually leads to cell death. Despite recent progress in the study of the regulation and underlying molecular mechanisms of autophagy, numerous questions remain to be answered. How does autophagy regulate cell death? What are the fine-tuned regulatory mechanisms underlying autophagy-dependent cell death (ADCD) and autophagy-mediated cell death (AMCD)? In this article, we highlight the different roles of autophagy in cell death and discuss six of the main autophagy-related cell death modalities, with a focus on the metabolic changes caused by excessive endoplasmic reticulum-phagy (ER-phagy)-induced cell death and the role of mitophagy in autophagy-mediated ferroptosis. Finally, we discuss autophagy enhancement in the treatment of diseases and offer a new perspective based on the use of autophagy for different functional conversions (including the conversion of autophagy and that of different autophagy-mediated cell death modalities) for the clinical treatment of tumors.

-methyladenosine; MEFs, mouse embryo fibroblasts; Mer, mutated estrogen receptor domains; METTL3, methyltransferase like 3; METTL14, methyltransferase like 14; mRFP, monomeric red fluorescent protein; MTORC1, mechanistic target of rapamycin kinase complex 1; NMVCs, neonatal mouse ventricular cardiomyocytes; PCNA, proliferating cell nuclear antigen; PE, phosphatidylethanolamine; PI, propidium iodide; PTMs, post-translational modifications; PVDF, polyvinylidenedifluoride; RIP, RNA-immunoprecipitation; siRNA, small interfering RNA; SQSTM1, sequestosome 1; TFEB, transcription factor EB; TUBA: tublin alpha; WTAP, WT1 associated protein; YTHDF, YTH N6-methyladenosine RNA binding protein.

We report a case of a 63-year-old female patient who developed a recurrent urinary tract infection (UTI) with extensively drug-resistant Klebsiella pneumoniae (ERKp). In the initial two rounds of phage therapy, phage resistant mutants developed within days. Although ERKp strains were completely resistant to sulfamethoxazole-trimethoprim, the combination of sulfamethoxazole-trimethoprim with the phage cocktail inhibited the emergence of phage resistant mutant in vitro, and the UTI of patient was successfully cured by this combination. Thus, we propose that non-active antibiotic and bacteriophage synergism (NABS) might be an alternative strategy in personalized phage therapy.

BACKGROUND: This study sought to investigate a possible correlation between the intestinal microbiota, Bacteroidetes and Firmicutes, and obesity in Kazakh school children, aged 7-13 (n = 175). RESULTS: Obese subjects had significantly greater systolic blood pressure, waist and hip circumference, as well as HOMA-IR as compared to normal and overweight participants. In addition, Bacteroides copy number and Bact/Firm ratios were significantly lower in the obese group as compared to the normal and overweight groups (P < 0.0167). This difference is only significant in girls, but not in boys when stratified by gender. Furthermore, a negative correlation between BMI and Bacteroidetes copy number (r = -0.18, P = 0.017) as well as Bact/Firm (r = -0.22, P = 0.003) was observed. CONCLUSION: An association between reduced gut Bacteroidetes and Bact/Firm ratio with obesity in female Kazakh children was identified. Further studies are necessary to elucidate the mechanism behind these changes as well as the value of determining their presence for predicting obesity.

Temozolomide (TMZ) is the most commonly used alkylating agent in glioma chemotherapy. However, growing resistance to TMZ remains a major challenge for clinicians. Recent evidence emphasizes the key regulatory roles of non-coding RNAs (lncRNAs and miRNAs) in tumor biology, including the chemoresistance of cancers. However, little is known about the role and regulation mechanisms of lncRNA cancer X-inactive specific transcripts (XIST) in glioma tumorigenesis and chemotherapy resistance. In the present study, higher XIST expression was observed in glioma tissues and cell lines, which was related to poorer clinicopathologic features and shorter survival time. XIST knockdown alone was sufficient to inhibit glioma cell proliferation and to amplify TMZ-induced cell proliferation inhibition. Moreover, XIST knockdown can sensitize TMZ-resistant glioma cells to TMZ. XIST can inhibit miR-29c expression by directly targetting TMZ-resistant glioma cells. DNA repair protein O6-methylguanine-DNA methytransferase (MGMT) plays a key role in TMZ resistance; transcription factor specificity protein 1 (SP1), a regulator of DNA mismatch repair (MMR) key protein MSH6, has been reported to be up-regulated in TMZ-resistant glioma cell lines. In the present study, we show that XIST/miR-29c coregulates SP1 and MGMT expression in TMZ-resistant glioma cell lines. Our data suggest that XIST can amplify the chemoresistance of glioma cell lines to TMZ through directly targetting miR-29c via SP1 and MGMT. XIST/miR-29c may be a potential therapeutic target for glioma treatment.

Long non-coding RNAs (lncRNAs) CCAT1 and HOTAIR have been shown to play an important regulatory role in cancer biology, and CCAT1 and HOTAIR are upregulated in several cancers, however, its value in the diagnosis of colorectal cancer (CRC) is unclear. Therefore, the aim of this study is to evaluate the clinical significance of plasma CCAT1 and HOTAIR as a biomarker in the screening of CRC. In our study, we found that the levels of HOTAIR (P < 0.05) and CCAT1 (P < 0.05) were significantly higher in plasma of CRC patients than that of the healthy control. Moreover, the levels of lincRNA-p21 (P < 0.05) were obviously decreased in plasma of CRC patients as compared to those of healthy control. There was highly correlated for CCAT1 (R = 0.752, mean differences = -0.06 ± 1.20), HOTAIR (R = 0.739, mean differences = -0.26 ± 0.76) and lincRNA-p21 (R = 0.848, mean differences = -0.41 ± 0.89) in plasma and serum. By receiver operating characteristic curve (ROC) analysis, plasma CCAT1 provided the higher diagnostic performance for detection of CRC (the area under the ROC curve (AUC), 0.836; P < 0.001; sensitivity, 75.7%; specificity, 85.3%). Moreover, CCAT1 combining with HOTAIR could provide a more effective diagnosis performance (AUC, 0.954, P < 0.001, sensitivity, 84.3%; specificity, 80.2%). Most importantly, this combination was effective to detect CRC at an early stage (85%). In conclusion, our results demonstrated that increased plasma HOTAIR and CCAT1 could be used as a predictive biomarker for CRC screening, and that combination of HOTAIR and CCAT1 had a higher positive diagnostic rate of CRC than HOTAIR or CCAT1 alone.

Rosacea is a chronic inflammatory skin disorder whose pathogenesis is unclear. Here, several lines of evidence were provided to demonstrate that mTORC1 signaling is hyperactivated in the skin, especially in the epidermis, of both rosacea patients and a mouse model of rosacea-like skin inflammation. Both mTORC1 deletion in epithelium and inhibition by its specific inhibitors can block the development of rosacea-like skin inflammation in LL37-induced rosacea-like mouse model. Conversely, hyperactivation of mTORC1 signaling aggravated rosacea-like features. Mechanistically, mTORC1 regulates cathelicidin through a positive feedback loop, in which cathelicidin LL37 activates mTORC1 signaling by binding to Toll-like receptor 2 (TLR2) and thus in turn increases the expression of cathelicidin itself in keratinocytes. Moreover, excess cathelicidin LL37 induces both NF-κB activation and disease-characteristic cytokine and chemokine production possibly via mTORC1 signaling. Topical application of rapamycin improved clinical symptoms in rosacea patients, suggesting mTORC1 inhibition can serve as a novel therapeutic avenue for rosacea.

Rosacea is significantly associated with dementia, particularly Alzheimer’s disease (AD). However, the common underlying molecular mechanism connecting these two diseases remains limited. This study aimed to reveal the common molecular regulatory networks and identify the potential therapeutic drugs for rosacea and AD. There were 747 overlapped DEGs (ol-DEGs) that were detected in AD and rosacea, enriched in inflammation-, metabolism-, and apoptosis-related pathways. Using the TF regulatory network analysis, 37 common TFs and target genes were identified as hub genes. They were used to predict the therapeutic drugs for rosacea and AD using the DGIdb/CMap database. Among the 113 predicted drugs, melatonin (MLT) was co-associated with both RORA and IFN-γ in AD and rosacea. Subsequently, network pharmacology analysis identified 19 pharmacological targets of MLT and demonstrated that MLT could help in treating AD/rosacea partly by modulating inflammatory and vascular signaling pathways. Finally, we verified the therapeutic role and mechanism of MLT on rosacea in vivo and in vitro . We found that MLT treatment significantly improved rosacea-like skin lesion by reducing keratinocyte-mediated inflammatory cytokine secretion and repressing the migration of HUVEC cells. In conclusion, this study contributes to common pathologies shared by rosacea and AD and identified MLT as an effective treatment strategy for rosacea and AD via regulating inflammation and angiogenesis.

Importance: Cigarette smoking has been associated with risk of neurodegenerative disorders, such as Alzheimer disease. The association between smoking and biomarkers of changes in human cerebrospinal fluid (CSF) is not fully understood. Objective: To investigate the association of cigarette smoking with CSF biomarkers of neurodegeneration, neuroinflammation, oxidation, and neuroprotection. Design, Setting, and Participants: In this case-control study of 191 adult men in China, biomarkers in the CSF of participants with and without significant cigarette exposure were examined. Participants who did not smoke and had no history of substance use disorder or dependence were assigned to the nonsmoking group. The active smoking group included participants who consumed at least 10 cigarettes per day for 1 year. Five-milliliter samples of CSF were obtained from routine lumbar puncture conducted before anterior cruciate ligament reconstruction surgery. Data collection took place from September 2014 to January 2016, and analysis took place from January to February 2016. Exposures: Cigarette smoking. Main Outcomes and Measures: CSF levels of β-amyloid 42 (Aβ42), which has diagnostic specificity for Alzheimer disease, tumor necrosis factor alpha (TNFα), brain-derived neurotrophic factor (BDNF), total superoxide dismutase (SOD), and nitric oxide synthase (NOS) were measured. Sociodemographic data and history of smoking were obtained. Results: Of 191 participants, 87 (45.5%) were included in the active smoking group and 104 (54.4%) in the nonsmoking group. Compared with the active smoking group, the nonsmoking group was younger (mean [SD] age, 34.4 [10.5] years vs 29.6 [9.5] years; P = .01), had more education (mean [SD] duration of education, 11.9 [3.1] years vs 13.2 [2.6] years; P = .001), and had lower body mass index (mean [SD], 25.9 [3.6] vs 24.9 [4.0]; P = .005). Comparing the nonsmoking group with the smoking group, mean (SD) CSF levels of Aβ42 (38.0 [25.9] pg/mL vs 52.8 [16.5] pg/mL; P < .001) and TNFα (23.0 [2.5] pg/mL vs 28.0 [2.0] pg/mL; P < .001) were significantly lower, while BDNF (23.1 [3.9] pg/mL vs 13.8 [2.7] pg/mL; P < .001), total SOD (15.7 [2.6] U/L vs 13.9 [2.4] U/L; P < .001), total NOS (28.3 [7.2] U/L vs 14.7 [5.6] U/L; P < .001), inducible NOS (16.0 [5.4] U/L vs 10.3 [2.7] U/L; P < .001), and constitutive NOS (12.4 [6.9] U/mL vs 4.4 [3.9] U/mL) were higher. In addition, in participants in the smoking group who were aged 40 years or older, total SOD levels were negatively correlated with Aβ42 levels (r = -0.57; P = .02). In those who smoked at least 20 cigarettes per day, TNFα levels were positively correlated with Aβ42 levels (r = 0.51; P = .006). The association of TNFα with Aβ42 production was stronger than that of total SOD with Aβ42 production (z = -4.38; P < .001). Conclusions and Relevance: This case-control study found that cigarette smoking was associated with at-risk biomarkers for Alzheimer disease, as indicated by higher Aβ42 levels, excessive oxidative stress, neuroinflammation, and impaired neuroprotection found in the CSF of participants in the active smoking group.

RIOK1 has recently been shown to play important roles in cancers, but its posttranslational regulation is largely unknown. Here we report that RIOK1 is methylated at K411 by SETD7 methyltransferase and that lysine-specific demethylase 1 (LSD1) reverses its methylation. The mutated RIOK1 (K411R) that cannot be methylated exhibits a longer half-life than does the methylated RIOK1. FBXO6 specifically interacts with K411-methylated RIOK1 through its FBA domain to induce RIOK1 ubiquitination. Casein kinase 2 (CK2) phosphorylates RIOK1 at T410, which stabilizes RIOK1 by antagonizing K411 methylation and impeding the recruitment of FBXO6 to RIOK1. Functional experiments demonstrate the RIOK1 methylation reduces the tumor growth and metastasis in mice model. Importantly, the protein levels of CK2 and LSD1 show an inverse correlation with FBXO6 and SETD7 expression in human colorectal cancer tissues. Together, this study highlights the importance of a RIOK1 methylation-phosphorylation switch in determining colorectal and gastric cancer development.

BACKGROUND: Little information is available on the reproducibility of nocturnal variations in blood pressure in type 2 diabetic hypertensive patients. OBJECTIVE: We aimed to compare the intrasubject short-term reproducibility of a nocturnal non-dipping pattern and the prevalence of cardiac and extracardiac signs of target organ damage, in a group of type 2 diabetic hypertensive patients and in an age/gender-matched group of non-diabetic hypertensive subjects. METHODS: Thirty-six treated hypertensive patients with long-lasting type 2 diabetes (> 10 years duration) consecutively attending our hospital out-patient hypertension clinic (group I; mean age, 65 +/- 9 years), and 61 untreated non-diabetic subjects with grade 1 and grade 2 uncomplicated essential hypertension, matched for age and gender, and chosen from patients attending an outpatient clinic (group II; mean age, 65 +/- 5 years), were considered for this analysis. All patients underwent blood sampling for routine blood chemistry, 24-h urine collection for microalbuminuria, two 24-h periods of ambulatory blood pressure monitoring (ABPM) within a 4-week period, echocardiography, and carotid ultrasonography. A dipping pattern was defined as a greater than 10% reduction in the average systolic and diastolic blood pressure at night compared with average daytime values. RESULTS: A reproducible nocturnal dipping and non-dipping profile was found in 11 (30.6%) and 21 (58.3%) diabetic patients, respectively; while only in four (11.1%) patients was a variable dipping profile observed. Of the 23 patients with a non-dipping pattern during the first ABPM period, 21 (91.3%) also had this type of pattern during the second ABPM recording. In group II (non-diabetic hypertensive patients), 30 patients (49.2%, P < 0.05) had a dipping pattern, 13 patients (21.3%, P < 0.01) had a non-dipping profile pattern and 18 patients (29.5%, P < 0.01) had a variable dipping pattern. Of the 20 patients with a non-dipping pattern during the first ABPM period, 13 (65.0%) confirmed this type of pattern during the second ABPM recording. Finally, the prevalence of left ventricular hypertrophy (77.7 versus 41.4%, P < 0.01), carotid plaques (80.5 versus 38.3%, P < 0.01), carotid intima-media thickening (54.3 versus 44.0%, P < 0.05) and microalbuminuria (11.1 versus 2.0%, P < 0.01) was significantly higher in group I than in group II. According to a logistic regression analysis, diabetes, left ventricular hypertrophy and carotid plaques were the main independent predictors of the non-dipping (pattern in the overall population. CONCLUSIONS: These findings indicate that intrasubject variability of non-dipper pattern is lower in diabetic than in non-diabetic hypertensive patients, that classification of diabetic hypertensive patients as dipper or non-dipper on the basis of a single ABP recording is more reliable than in non-diabetic patients, and that the more frequent and reproducible non-dipping (pattern in diabetic patients is associated with a more prominent cardiac and extracardiac target organ damage.

The NLR family pyrin domain containing 3 (NLRP3) inflammasome was reported to be regulated by autophagy and activated during inflammatory procession of Parkinson’s disease (PD). Berberine (BBR) is well-studied to play an important role in promoting anti-inflammatory response to mediate the autophagy activity. However, the effect of Berberine on NLRP3 inflammasome in PD and its potential mechanisms remain unclear. Hence, in this study, we investigated the effects of BBR on 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mice, by evaluating their behavioral changes, dopaminergic (DA) neurons loss, neuroinflammation, NLRP3 inflammasome and autophagic activity. BBR was also applied in BV2 cells treated with 1-methyl-4-pehnyl-pyridine (MPP+). The autophagy inhibitor 3-Methyladenine (3-MA) was administrated to block autophagy activity both in vivo and in vitro . In our in vivo studies, compared to MPTP group, mice in MPTP + BBR group showed significant amelioration of behavioral disorders, mitigation of neurotoxicity and NLRP3-associated neuroinflammation, enhancement of the autophagic process in substantia nigra (SN). In vitro , compared to MPP+ group, BBR significantly decreased the level of NLRP3 inflammasome including the expressions of NLRP3, PYD and CARD domain containing (PYCARD), cleaved caspase 1 (CASP1), and mature interleukin 1 beta (IL1B), via enhancing autophagic activity. Furthermore, BBR treatment increased the formation of autophagosomes in MPP+-treated BV2 cells. Taken together, our data indicated that BBR prevents NLRP3 inflammasome activation and restores autophagic activity to protect DA neurons against degeneration in vivo and in vitro , suggesting that BBR may be a potential therapeutic to treat PD.

Evidence suggests that curcumin, the phytochemical agent in the spice turmeric, might be a potential therapy for Alzheimer's disease (AD). Its antioxidant, anti-inflammatory properties have been investigated extensively. Studies have also shown that curcumin can reduce amyloid pathology in AD. The underlying mechanism, however, is complex and is still being explored. In this study, we used the APPswe/PS1dE9 double transgenic mice, an AD model, to investigate the effects and mechanisms of curcumin in the prevention and treatment of AD. The water maze test indicated that curcumin can improve spatial learning and memory ability in mice. Immunohistochemical staining and Western blot analysis were used to test major proteins in β-amyloid aggregation, β-amyloid production, and β-amyloid clearance. Data showed that, 3 months after administration, curcumin treatment reduced Aβ40 , Aβ42 , and aggregation of Aβ-derived diffusible ligands in the mouse hippocampal CA1 area; reduced the expression of the γ-secretase component presenilin-2; and increased the expression of β-amyloid-degrading enzymes, including insulin-degrading enzymes and neprilysin. This evidence suggests that curcumin, as a potential AD therapeutic method, can reduce β-amyloid pathological aggregation, possibly through mechanisms that prevent its production by inhibiting presenilin-2 and/or by accelerating its clearance by increasing degrading enzymes such as insulin-degrading enzyme and neprilysin.

Abstract Recent studies have strongly shown that cell‐to‐cell transmission of neuropathogenic proteins is a common mechanism for the development of neurodegenerative diseases. However, the underlying cause is complex and little is known. Although distinct processes are involved in the pathogenesis of various diseases, they all share the common feature of iron accumulation, an attribute that is particularly prominent in synucleinopathies. However, whether iron is a cofactor in facilitating the spread of α‐synuclein remains unclear. Here, we constructed a cell‐to‐cell transmission model of α‐synuclein using SN 4741 cell line based on adenovirus vectors. Cells were treated with FeCl 2, and α‐synuclein aggregation and transmission were then evaluated. In addition, the possible mechanisms were investigated through gene knockdown or over‐expression. Our results demonstrated that iron promoted α‐synuclein aggregation and transmission by inhibiting autophagosome‐lysosome fusion. Furthermore, iron decreased the expression of nuclear transcription factor EB ( TFEB ), a master transcriptional regulator of autophagosome‐lysosome fusion, and inhibited its nuclear translocation through activating AKT / mTORC 1 signaling. After silencing TFEB , ratios of α‐synuclein aggregation and transmission were not significantly altered by the presence of iron; on the other hand, when TFEB was over‐expressed, the transmission of α‐synuclein induced by iron was obviously reversed; suggesting the mechanism by which iron promotes α‐synuclein transmission may be mediated by TFEB . Taken together, our data reveal a previously unknown relationship between iron and α‐synuclein, and identify TFEB as not only a potential target for preventing α‐synuclein transmission, but also a critical factor for iron‐induced α‐synuclein aggregation and transmission. Indeed, this newly discovered role of iron and TFEB in synucleinopathies may provide novel targets for developing therapeutic strategies to prevent α‐synuclein transmission in Parkinson's disease. image

Adaptation to reduced energy production during aging is a fundamental issue for maintaining healthspan or prolonging life span. Currently, however, the underlying mechanism in long-lived people remains poorly understood. Here, we analyzed transcriptomes of 185 long-lived individuals (LLIs) and 86 spouses of their children from two independent Chinese longevity cohorts and found that the ribosome pathway was significantly down-regulated in LLIs. We found that the down-regulation is likely controlled by ETS1 (ETS proto-oncogene 1), a transcription factor down-regulated in LLIs and positively coexpressed with most ribosomal protein genes (RPGs). Functional assays showed that ETS1 can bind to RPG promoters, while ETS1 knockdown reduces RPG expression and alleviates cellular senescence in human dermal fibroblast (HDF) and embryonic lung fibroblast (IMR-90) cells. As protein synthesis/turnover in ribosomes is an energy-intensive cellular process, the decline in ribosomal biogenesis governed by ETS1 in certain female LLIs may serve as an alternative mechanism to achieve energy-saving and healthy aging.

Locally recurrent nasopharyngeal carcinoma (rNPC) after definitive IMRT occurs in 10% of all cases and represents a distinct clinical entity that has been selectively enriched by radio-resistant cancer cells. Therefore, we report of the outcomes of 77 patients who had repeat salvage-IMRT for rNPC after only a definitive course of IMRT. Various clinical outcomes were measured. Log-rank tests were used to detect differences in the survival outcomes between factor-defined subgroups. Multivariable analysis was performed using the Cox proportional hazard model. The median follow-up time was 25.7 months (range 3.0-75.7 months), measured from the time of recurrence. The median OS time and PFS time of the entire cohort was 37.0 and 20.5 months, respectively. Thirty-four patients (44.2%) died. Approximately 35% of these patients died from disease progression, but 53% were from treatment-induced severe adverse effects (SAEs) without evidence of disease progression. Higher T-classification of the recurrent tumor and the development of SAEs were found to be the only independent and significant adverse prognostic factors on multivariable analysis. These outcomes underscore the particularly virulent characteristics of rNPC after definitive IMRT. Concerning is the impact of re-irradiation toxicity on patient mortality.

BACKGROUND: The prevalence of carbapenem-resistant Klebsiella pneumoniae bloodstream infection (CRKP-BSI) is increasing worldwide. CRKP-BSI is associated with high rates of morbidity and mortality due to limited antibiotic choices. Here, we aim to identify the prevalence and risk factors for infection and mortality of CRKP BSI. METHODS: This was a retrospective study of the past data from January 1st, 2012 to December 31st, 2019 of adult patients with KP-BSI in Xiangya Hospital, China. RESULTS: Among the 706 incidences included in this study, 27.4% of them (212/753) being CR-KP strains. The occurrence of CRKP-BSI was increased from 20.69 to 37.40% from 2012 to 2019. Hematologic malignancies and ICU acquired infection were identified to be substantial risk factors of carbapenem resistance. The overall 28-day mortality rates of CRKP-BSI patients was significantly higher than that of CSKP-BSI (P < 0.001). Logistic regression analysis identified severe sepsis or septic shock incidents, inadequate empirical antimicrobial therapy and corticosteroids use preceding infection onset as the independent predictors of 28-day mortality of CRKP-BSI patients. However, high dose carbapenem combination therapy was identified as anticipated factors of low 28-day mortality. CONCLUSION: The occurrence of CRKP-BSI was significantly increased during the study period. Hematologic malignancies and ICU acquired infection were associated with the development of CRKP BSI. Severe sepsis or septic shock incidents, inadequate empirical antimicrobial therapy and corticosteroids use preceding infection onset caused significant increase of mortality rates in CRKP-BSI patients. High dose carbapenem combination therapy was associated with better outcome.

BACKGROUND: Mitochondria play a role in the occurrence, development, drug resistance, metastasis, and other functions of cancer and thus are a drug target. An acid-activated mitochondria-targeting drug nanocarrier with redox-responsive function was constructed in the present study. However, whether this vector can precisely delivery paclitaxel (PTX) to enhance therapeutic efficacy in drug-resistant lung cancer is unknown. RESULTS: Acid-cleavable dimethylmaleic anhydride (DA) was used to modify pluronic P85-conjugated mitochondria-targeting triphenylphosphonium (TPP) using disulfide bonds as intermediate linkers (DA-P85-SS-TPP and DA-P-SS-T). The constructed nanocarriers demonstrated enhanced cellular uptake and selective mitochondrial targeting at extracellular pH characteristic for a tumor (6.5) and were characterized by extended circulation in the blood. TPP promoted the targeting of the DA-P-SS-T/PTX nanomicelles to the mitochondrial outer membrane to decrease the membrane potential and ATP level, resulting in inhibition of P-glycoprotein and suppression of drug resistance and cancer metastasis. PTX was also rapidly released in the presence of high glutathione (GSH) levels and directly diffused into the mitochondria, resulting in apoptosis of drug-resistant lung cancer cells. CONCLUSIONS: These promising results indicated that acid-activated mitochondria-targeting and redox-responsive nanomicelles potentially represent a significant advancement in cancer treatment. GRAPHIC ABSTARCT.

BACKGROUND: Rosacea is a chronic inflammatory skin disorder of uncertain etiology. Evidence suggests the underlying pathogenesis is modulated by abnormal inflammatory and vascular responses. Thalidomide is a synthetic derivative acid with anti-inflammatory and anti-angiogenic properties. However, its effects on rosacea remain unknown. OBJECTIVES: To investigate the effects of thalidomide on the lesional alterations and molecular mechanisms in rosacea. METHODS: Mice were intradermally injected with LL37 to induce rosacea-like features and intraperitoneally administered with thalidomide. The severity of skin inflammation was evaluated. The mRNA levels of cytokines and chemokines associated with rosacea were assessed by qPCR. The number of CD4 positive infiltrated T helper cells and CD31 positive microvessels, and related-genes were measured by immunofluorescence, qPCR and ELISA. Moreover, the effect of thalidomide on inhibiting NF-κB activation was determined by immunofluorescence and western blot. RESULTS: T helper cell infiltration and downregulated Th1- and Th17-polarizing genes. In addition, thalidomide treatment lowered the microvessel density and vascular endothelial growth factor (VEGF) expression. We further demonstrated that thalidomide suppressed NF-κB activation in LL37-treated skin and in TNF-α-stimulated HaCaT keratinocytes in vitro. CONCLUSIONS: Our findings suggest thalidomide attenuates the inflammation and represses NF-κB activation in skin, which leads to assumptions that thalidomide may be a new therapeutic agent for rosacea.

Abstract Inflammation is one of the pathogenic processes in Parkinson’s disease (PD). Dopamine receptor agonist pramipexole (PPX) is extensively used for PD treatment in clinics. A number of studies show that PPX exerts neuroprotection on dopaminergic (DA) neurons, but the molecular mechanisms underlying the protective effects of PPX on DA neurons are not fully elucidated. In the present study, we investigated whether PPX modulated PD-related neuroinflammation and underlying mechanisms. PD model was established in mice by bilateral striatum injection of lipopolyssaccharide (LPS). The mice were administered PPX (0.5 mg·kg −1 ·d −1 , i.p.) 3 days before LPS injection, and for 3 or 21 days after surgery, respectively, for biochemical and histological analyses. We showed that PPX administration significantly alleviated the loss of DA neurons, and suppressed the astrocyte activation and levels of proinflammatory cytokine IL-1β in the substantia nigra of LPS-injected mice. Furthermore, PPX administration significantly decreased the expression of NLRP3 inflammasome-associated proteins, i.e., cleaved forms of caspase-1, IL-1β, and apoptosis-associated speck-like protein containing a caspase recruit domain (ASC) in the striatum. These results were validated in LPS+ATP-stimulated primary mouse astrocytes in vitro. Remarkably, we showed that PPX (100–400 μM) dose-dependently enhanced the autophagy activity in the astrocytes evidenced by the elevations in LC3-II and BECN1 protein expression, as well as the increase of GFP-LC3 puncta formation. The opposite effects of PPX on astrocytic NLRP3 inflammasome and autophagy were eliminated by Drd3 depletion . Moreover, we demonstrated that both pretreatment of astrocytes with autophagy inhibitor chloroquine (40 μM) in vitro and astrocyte-specific Atg5 knockdown in vivo blocked PPX-caused inhibition on NLRP3 inflammasome and protection against DA neuron damage. Altogether, this study demonstrates an anti-neuroinflammatory activity of PPX via a Drd3-dependent enhancement of autophagy activity in astrocytes, and reveals a new mechanism for the beneficial effect of PPX in PD therapy.