A noncanonical IRAK4-IRAK1 pathway counters DNA damage-induced apoptosis independently of TLR/IL-1R signaling.

Interleukin-1 receptor (IL-1R)-associated kinases (IRAKs) are core effectors of Toll-like receptors (TLRs) and IL-1R in innate immunity. Here, we found that IRAK4 and IRAK1 together inhibited DNA damage-induced cell death independently of TLR or IL-1R signaling. In human cancer cells, IRAK4 was activated downstream of ATR kinase in response to double-strand breaks (DSBs) induced by ionizing radiation (IR). Activated IRAK4 then formed a complex with and activated IRAK1. The formation of this complex required the E3 ubiquitin ligase Pellino1, acting structurally but not catalytically, and the activation of IRAK1 occurred independently of extracellular signaling, intracellular TLRs, and the TLR/IL-1R signaling adaptor MyD88. Activated IRAK1 translocated to the nucleus in a Pellino2-dependent manner. In the nucleus, IRAK1 bound to the PIDD1 subunit of the proapoptotic PIDDosome and interfered with platform assembly, thus supporting cell survival. This noncanonical IRAK signaling pathway was also activated in response to other DSB-inducing agents. The loss of IRAK4, of IRAK4 kinase activity, of either Pellino protein, or of the nuclear localization sequence in IRAK1 sensitized p53-mutant zebrafish to radiation. Thus, the findings may lead to strategies for overcoming tumor resistance to conventional cancer treatments.

Cyanidin-3-O-glucoside plays a protective role against renal ischemia/ reperfusion injury via the JAK/STAT pathway

Purpose: To investigate the role of cyanidin-3-O-glucoside (C3G) in renal ischemia/reperfusion (I/R) injury and the potential mechanisms. Methods: Mouse models were established by clamping the left renal vessels, and in vitro cellular models were established by hypoxic reoxygenation. Results: Renal dysfunction and tissue structural damage were significantly higher in the I/R group. After treatment with different concentrations of C3G, the levels of renal dysfunction and tissue structural damage decreased at different levels. And its protective effect was most pronounced at 200 mg/kg. The use of C3G reduced apoptosis as well as the expression of endoplasmic reticulum stress (ERS)-related proteins. Hypoxia/reoxygenation (H/R)-induced apoptosis and ERS are dependent on oxidative stress in vitro. In addition, both AG490 and C3G inhibited the activation of JAK/STAT pathway and attenuated oxidative stress, ischemia-induced apoptosis and ERS. Conclusions: The results demonstrated that C3G blocked renal apoptosis and ERS protein expression by preventing reactive oxygen species (ROS) production after I/R via the JAK/STAT pathway, suggesting that C3G may be a potential therapeutic agent for renal I/R injury.

Pin1 aggravates renal injury induced by ischemia and reperfusion in rats via Nrf2/HO-1 mediated endoplasmic reticulum stress

Purpose: To investigate the role of peptidyl-prolyl cis/trans isomerase 1 (Pin1) on renal ischemia-reperfusion (I/R) injury and underlying mechanism. Methods: By establishing the in vitro and in vivo models of renal I/R, the role of Pin1 was explored by using molecular assays. Results: In renal I/R, endogenous Pin1 level was up-regulated in I/R-impaired kidney. Suppression of Pin1 with juglone afforded protection against I/R-mediated kidney dysfunction, and reduced I/R-induced endoplasmic reticulum (ER) stress in vivo. Consistent with the in vivo results, repression of Pin1 with juglone or gene knockdown with si-Pin1 conferred cytoprotection and restricted hypoxia/reoxygenation (H/R)-driven ER stress in HK-2 cells. Simultaneously, further study uncovered that Nrf-2/HO-1 signals was the association between Pin1 and ER stress in response to renal I/R. In addition, Nrf-2/HO-1 signal pathway was inactivated after kidney exposed to I/R, as indicated by the down-regulation of Nrf-2/HO-1 levels. Furthermore, inhibition of Pin1 remarkably rescued the inactivation ofNrf-2/HO-1. Conclusions: Pin1 modulated I/R-mediated kidney injury in ER stress manner dependent on Nrf2-HO-1 pathway in I/R injury.

Association between polymorphisms of collagen genes and susceptibility to intervertebral disc degeneration: a meta-analysis.

BACKGROUND: Collagens are important structural components of intervertebral disc. A number of studies have been performed for association between polymorphisms of collagen genes and risk of intervertebral disc degeneration (IVDD) but yielded inconsistent results. Here, we performed a meta-analysis to investigate the association of collagen IX alpha 2 (COL9A2) Trp2, collagen IX alpha 3 (COL9A3) Trp3, collagen I alpha 1 (COL1A1) Sp1 and collagen XI alpha 1 (COL11A1) C4603T polymorphisms with susceptibility to IVDD. METHOD: Eligible studies were retrieved by searching MEDLINE, EMBASE, Web of Science prior to 31 March, 2021. Odds ratio (OR) and corresponding 95% confidence interval (CI) were calculated for association strength. RESULTS: A total of 28 eligible studies (31 datasets comprising 5497 cases and 5335 controls) were included. COL9A2 Trp2 carriers had an increased risk of IVDD than non-carriers in overall population (OR = 1.43, 95% CI 0.99-2.06, P = 0.058), which did not reach statistical significance. However, Trp2 carriers had 2.62-fold (95% CI 1.15-6.01, P = 0.022) risk than non-carriers in Caucasians. COL9A3 Trp3 was not associated with IVDD risk (OR = 1.28, 95% CI 0.81-2.02, P = 0.299). T allele and TT genotype of COL1A1 Sp1 (+ 1245G > T) were correlated with increased risk of IVDD. Significant associations were found between COL11A1 C4603T and IVDD risk under allelic (OR = 1.33, 95% CI 1.20-1.48), dominant (OR = 1.45, 95% CI 1.26-1.67), recessive (OR = 1.55, 95% CI 1.21-1.98) and homozygote model (OR = 1.81, 95% CI 1.40-2.34). CONCLUSIONS: COL1A1 Sp1 and COL11A1 C4603T polymorphism are associated with IVDD risk while the predictive roles of collagen IX gene Trp2/3 need verification in more large-scale studies.

The Risk Factors for Chinese Medical Economic Burden of Aging: A Cross-Sectional Study Based on Guangdong Province.

BACKGROUND: The proportion of aging in China is increasing, which needs more healthcare recourses. To analyze the risk factors of the direct medical economic burden of aging in China and provide the strategies to control the cost of treatment, the information was collected based on Guangdong Province's regular health expenditure accounting data collection plan. METHODS: The multiple linear regression models were used to explore the risk factors of inpatient expenses of the elderly in Guangdong province. RESULTS: The results revealed that hospital day, age, male patients, and patients who suffer from malignant tumors are key factors to increase the direct medical economic burden of aging. Moreover, the medical insurance for urban employees can reduce the medical economic burden, comparing with the medical insurance for urban residents. CONCLUSIONS: The basic medical insurance system and the serious illness insurance system should be improved. While striving to speed up the development of regional economy, the government should pay attention to the construction of basic medical institutions in economically backward areas, increase the allocation of health human resources, and facilitate the masses to seek medical treatment nearby.

Neuroinflammatory Responses and Parkinson' Disease: Pathogenic Mechanisms and Therapeutic Targets.

Parkinson's disease (PD) is the second most common age-related neurodegenerative disorders of the central nervous system, which mainly impairs the motor system. However, the pathogenic mechanisms are still unclear. Gene-environment complex interaction leads to selective dopaminergic neuron death in PD. Growing evidences supports that neuroinflammatory responses are involved in the pathogenesis of PD. This review critically discusses current studies on the inflammatory response of the pathological process of PD. The mechanisms and strategies of modifying inflammatory responses would be potential treatments for neurodegenerative diseases. Graphical abstract Activated microglia canpromote the damage ofdopaminergic neurons, which inturn aggravates the activation ofmicroglia in the process of PD. Atthe same time, microglia canactivate astrocytes throughproliferation and secretion ofinflammatory factors. The role ofastrocytes on the loss ofdopaminergic neurons is stillcontroversial in PD. (Nonsteroidalanti-inflammatory drugs,NSAIDs. adiposed-derived stemcells, ADSCs.nicotinamideadenine dinucleotide phosphate,NADPH. signal transducers andactivators of transcription,STAT.DJ-1,Aliases forPARK7.mesencephalic astrocytederivedneurotrophic factor,MANF.Ciliary neurotrophicfactor,CNTF.glial cell linederivedneurotrophic factor,GDNF.Wnt Family Member1,Wnt1). Graphical abstract Mitochondrial dysfunction causes neuroinflammation throughDAMPs and a series of factors such as oxidative stress andinflammatory bodies in PD. (Damage-associated molecular patterns,DAMPs. reactive oxygen species, ROS). Graphical abstract Various mechanismsparticipate in NLRP3 activation,causing microglia activation inPD. ( -synuclein, -syn.) TolllikeReceptor 2, TLR2. Toll-likeReceptor 4, TLR4. TumorNecrosis Factor, TNF.Apoptosisassociated speck like proteincontaining a CARD, ASC).

p38 MAPK-DRP1 signaling is involved in mitochondrial dysfunction and cell death in mutant A53T α-synuclein model of Parkinson's disease.

Abnormal accumulation of α-synuclein and mitochondria dynamics dysfunction are considered to be implicated in the pathogenesis of Parkinson's disease. However, the underlying mechanisms how α-synuclein abnormal accumulation causes mitochondrial dynamics dysfunction remains unclear. Here, we demonstrate that dynamin-related protein 1(DRP1) is a substrate for p38 MAPK, mutant α-synuclein overexpression in SN4741 cell caused p38 MAPK activation, p38 MAPK-mediated phosphorylation DRP1 at serine 616 to activate DRP1 and is associated with increased mitochondrial fission, which resulted in mitochondrial dysfunction and neuronal loss. Inhibition of p38 MAPK or expression of a kinase death form of p38 MAPK not only attenuates DRP1-mediated mitochondrial fission，but also restores the mitochondrial dysfunction and cell death in α-synuclein A53T model. These findings showed that inhibition of p38 MAPK-DRP1 signaling pathway may be a viable therapeutic strategy of PD on maintenance of mitochondrial homeostasis.

Effects of acarbose and metformin on the inflammatory state in newly diagnosed type 2 diabetes patients: a one-year randomized clinical study.

OBJECTIVE: This study aimed to investigate the changes in inflammatory biomarkers between newly diagnosed type 2 diabetes (T2DM) patients under one-year acarbose treatments and those under metformin managements. METHODS: Seventy patients with newly diagnosed T2DM and 32 volunteers with normal glucose tolerance (normal controls, NCs) were enrolled. Seventy patients with T2DM were randomly assigned to two subgroups and treated with acarbose (n=34) or metformin (n=36) for 1 year. Blood glucose, insulin, glycosylated hemoglobin (A1C), triglyceride (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and inflammatory biomarker levels (interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), interleukin-2 (IL-2), and ferritin) were detected at 0, 6 and 12 months. RESULTS: After adjusting for sex, the waist-to-hip ratio (WHR) and body mass index (BMI), higher fasting plasma glucose (FPG), standard meal test 1/2 hr and 2 hr glucose, TG, TC, LDL-C, IL-6, TNF-α, IL-2 and ferritin levels were observed in T2DM group than in NCs (P<0.05). After 6 months of treatment, TNF-α levels were significantly decreased in both subgroups, and IL-6 and ferritin levels were significantly decreased after 12 months (P<0.05). However, no significant differences in the IL-6, TNF-α and ferritin levels were observed between the two subgroups. Moreover, significantly higher IL-6 and TNF-α levels were detected in the T2DM group than in NCs after 12 months of treatment (P<0.05). CONCLUSION: Patients with newly diagnosed T2DM exhibited a marked chronic inflammatory state characterized by increased IL-6, TNF-α, IL-1ß, IL-2 and ferritin levels. After 1 year of treatment with acarbose or metformin, IL-6, TNF-α, IL-1ß and ferritin levels were significantly decreased compared with the baseline. The anti-inflammatory effects of acarbose and metformin were comparable and required a long-term treatment (1 year), but the characteristics were different. Further investigations are needed to determine whether this effect was independent of the hypoglycemic effects.

[Changes of leptin, tumor necrosis factor-alpha, neuropeptide Y levels and their association with insulin resistance and insulin secretion function in normal glucose tolerant first-degree relatives of familial type 2 diabetic pedigrees].

This investigation was made in regard to the changes of plasma Leptin, Tumor Necrosis Factor-alpha (TNF-alpha) and Neuropeptide Y (NPY) levels and their association with insulin resistance and beta-cell secretion function in normal glucose tolerant first-degree relatives of familial type 2 diabetic pedigrees in Chengdu area. Levels of Leptin, TNF-alpha, NPY and lipids (TG, TC, HDL-C) were determined in 86 type 2 diabetic mellitus (DM) patients, 73 normal glucose tolerant (NGT) first-degree relatives in familial type 2 diabetic pedigrees and 65 normal controls (NC) from non-diabetic families. All of the subjects underwent 75 g oral glucose tolerance test (OGTT). Plasma glucose, immunoreactive insulin (IRI) and true insulin (TI) levels were also determined. Fasting glucose and TI levels were used to calculate homeostasis model assessment-insulin resistance (HOMA-IR) and HOMA-beta cell indexes. After being adjusted for age and body mass index (BMI), the levels of Leptin in DM and NGT first-degree relatives were all significantly higher than that in normal controls (P < 0.05). Type 2 diabetic patients showed significantly elevated TNF-alpha levels than did the normal controls (P < 0.05). Furthermore, diabetic subjects showed significantly higher HOMA-IR and lower HOMA-B levels, compared with those in NGT and NC groups (P < 0.05). No statistically significant difference was found in regard to NPY among three groups. NGT first-degree relatives showed significantly higher levels of TG, fasting IRI, OGTT-2h IRI and HOMA-IR than did the normal controls (P < 0.05). Leptin was positively correlated with age, BMI, waist, A1c, fasting and OGTT-2h glucose, OGTT-2h TI and TNF-alpha in all subjects, and was negatively correlated with HOMA-B in females. Leptin levels were significantly elevated in NGT first-degree relatives, which implied that genetic defects of Leptin may play a role in the development of familial type 2 diabetic pedigrees.