Risk factors for low back pain in the Chinese population: a systematic review and meta-analysis.

BACKGROUND: In China, the world's largest developing country, low back pain (LBP) is a common public health issue affecting workability. This meta-analysis aimed to systematically assess the risk factors of LBP in the Chinese population. METHODS: Four English language and four Chinese databases were searched, and cross-sectional studies on the risk factors for LBP in Chinese populations were identified and collected. The search timeframe covered the period from the establishment of the database to November 2023. Two researchers independently reviewed the literature, extracted the data, and evaluated the risk of bias. Begg's and Egger's tests were used to evaluate publication bias. RESULTS: Fifteen cross-sectional studies involving 86,575 people were included. Seven risk factors for LBP were identified. Six risk factors were statistically significant: Cigarette smoking (odds ratio [OR] = 1.55; 95% confidence interval [CI]: 1.15, 2.08, P = 0.004, I2 = 72%), body mass index (BMI) ≥ 28 kg/m² (OR = 4.51; 95% CI: 3.36, 6.07, P < 0.00001, I2 = 8%), female sex (OR = 1.54; 95% CI: 1.25, 1.90, P < 0.0001, I2 = 63%), vibration exposure at work (OR = 1.65; 95% CI: 1.16, 2.34, P = 0.006, I2 = 84%), working overtime (OR = 2.57; 95% CI: 1.12, 5.91, P = 0.03, I2 = 85%), and lack of exercise (OR = 2.48; 95% CI: 1.62, 3.78, P < 0.0001, I2 = 0%). One risk factor that was not statistically significant was standing for long periods (OR = 1.02; 95% CI: 0.82, 1.26, P = 0.88, I2 = 73%). CONCLUSIONS: This study found that smoking, a BMI ≥ 28 kg/m², female sex, vibration exposure at work, working overtime, and lack of exercise may be risk factors for LBP in the Chinese population. Because the included studies were cross-sectional and the certainty of the evidence was very low, the results need to be interpreted cautiously. Multicentre, high-quality studies should be conducted in the future. To reduce the prevalence of LBP, the Chinese government and hospitals must develop early screening programs and implement effective preventive and interventional measures. TRIAL REGISTRATION: This study is registered in the PROSPERO database (No. CRD42023447857).

The cGAS/STING signaling pathway is involved in sevoflurane induced neuronal necroptosis via regulating microglia M1 polarization.

OBJECTIVE: The specific mechanisms of sevoflurane-induced neurotoxicity are still undetermined. The aim of the current study was to investigate the role of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway in sevoflurane-induced neuronal necroptosis. METHODS: BV2 microglial cells were divided into a control group and a 4% sevoflurane exposure group. Western blotting was used to detect expression of the M1 polarization marker inducible nitric oxide synthase (iNOS). RNA was collected for RNA sequencing analysis. After STING knockdown in microglia, western blotting was performed to examine expression of the pro-inflammatory markers CD16 and CD32. The tumor necrosis factor-α (TNF-α) level in media was detected using an enzyme-linked immunosorbent assay. BV2 microglia conditioned media was collected to incubate HT22 neuronal cells, and their cell activity was measured using a CCK8 assay. Calcium was observed by fluorescence. Western blotting was performed to evaluate receptor-interacting protein kinase 1 (RIPK1), RIPK3, and mixed lineage kinase domain-like (MLKL) expression. Neuronal necroptosis rate were detected using flow cytometry. RESULTS: Sevoflurane exposure promoted microglial M1 polarization. The cGAS/STING pathway was screened and identified by RNA sequencing analysis of sevoflurane-exposed microglia and the control group. Compared with the control group, STING knockdown in microglia rescued the amoeboid morphology, inhibited TNF-α release, and significantly decreased iNOS, CD16, and CD32 expression. Moreover, calcium ions and necroptosis within neurons were decreased, and RIPK1, RIPK3, and p-MLKL expression was markedly decreased in microglia media culture with STING knockdown. CONCLUSION: These results suggest that sevoflurane can regulate microglial M1 polarization by activating the cGAS/STING signaling pathway and increasing immune factor release, thus accelerating the neuronal necroptosis induced by calcium overload.

CT Quantification of Interstitial Lung Abnormalities and Changes of Agerelated Pathomorphology.

BACKGROUND: Interstitial lung abnormalities (ILA) are associated with further disease progression, increased mortality risk, and decline in lung function in the elderly, which deserves enough attention. OBJECTIVE: The objective of this study was to quantify the extent of interstitial lung abnormalities (ILA) in a non-smoking asymptomatic urban cohort in China using low-dose CT (LDCT) and to analyze the age-related pathological changes. METHODS: We retrospectively analyzed clinical data and chest LDCT images from a cohort of 733 subjects who were categorized into 3 groups: 18-39, 40-59, and ≥60 years old according to age. Furthermore, we selected 40 cases of wax-embedded lung tissue blocks archived after pulmonary bullectomy and the same age groups were categorized. Four representative CT signs of ILA, including interlobular septal thickening (ILST), intralobular interstitial thickening (ILIT), ground-glass opacity (GGO), and reticular shadow (RS), were semi-quantified based on the percentage of the affected area. The scores and distribution of four CT signs of ILA were compared between different sex and age groups. The age-related pathological changes were analyzed. RESULTS: The ILA findings were found predominantly in the lower lobes and the subpleural region. The semi-quantitative scores of four CT signs in all subjects under 40 were 0. However, in subjects over 40 years old, the scores gradually increased with age, although most of them remained low. The size of the alveoli increased, the number of alveoli decreased, the alveolar septum became thinner, and the number of ATII cells increased with age. A statistically significant difference was observed among the different age groups (χ2=50.624, P=0.033; χ2=80.000, P=0.043; χ2=33.833, P=0.000; χ2=13.525, P=0.031). The macrophage population and the percentage of collagen fibers in the alveolar septum increased, while the percentage of elastic fibers decreased with age. There was no significant difference among the different age groups (χ2=19.817, P=0.506; χ2=52.419, P=0. 682; χ2=54.868, P=0.518). CONCLUSION: When the four CT signs mentioned above are in the upper central area, and the score has a medium or high score, it is crucial to determine the underlying pathological causes. ILA may be the result of chronic lung injury.

Missense variants in CYP4B1 associated with increased risk of lung cancer among Chinese Han population.

INTRODUCTION: Understanding the etiology and risk factors of lung cancer (LC) is the key to developing scientific and effective prevention and control strategies for LC. CYP4B1 genetic polymorphism has been reported to be associated with susceptibility to various diseases. We aimed to explore the association between CYP4B1 genetic variants and LC susceptibility. METHODS: One thousand three hundred thirty-nine participants were recruited to perform an association analysis through SNPStats online software. Statistical analysis of this study was mainly completed by SPSS 22.0 software. False-positive report probability analysis (FPRP) to detect whether the positive findings were noteworthy. Finally, the interaction of SNP-SNP in LC risk was evaluated by multi-factor dimensionality reduction. RESULTS: We found evidence that missense variants in CYP4B1 (rs2297810, rs4646491, and rs2297809) are associated with LC susceptibility. In particular, genotype GA of CYP4B1-rs2297810 was significantly associated with an increased risk of LC in both overall and stratified analyses (genotype GA: OR (95% CI) = 1.35 (1.08-1.69), p = 0.010). CYP4B1-rs4646491 (overdominant: OR (95% CI) = 1.30 (1.04-1.62), p = 0.023) and CYP4B1-rs2297809 (genotype CT: OR (95% CI) = 1.26 (1.01-1.59), p = 0.046) are also associated with an increased risk of LC. FPRP analysis showed that all positive results in this study are noteworthy findings CONCLUSION: Three missense variants in CYP4B1 (rs2297810, rs4646491, and rs2297809) are associated with increasing risk of LC.

Scalp Tumor and Hydroureteronephrosis in Patients with Nephronophthisis and Homozygous NPHP1 Deletion.

Homozygous deletion of NPHP1 can lead to isolated nephronophthisis (NPHP) and syndromic disorders. However, the phenotype of scalp tumor and hydroureteronephrosis in NPHP patients with homozygous deletion of NPHP1 has not been reported. Clinical data, laboratory results, and genetic testing of 4 NPHP patients were collected. Examination of their eyes, heart, and urinary tract and of their hepatobiliary, skeletal, and central nervous systems was evaluated. Isolated NPHP was observed in 1 case, and syndromic disorders were observed in the other 3 patients. Their syndromic disorders showed NPHP combined with central nervous system defects, eye involvement, scalp tumor, arachnoid cyst, or hydroureteronephrosis. Large homozygous deletions covering the whole NPHP1 gene locus were identified in all 4 patients. We report a novel phenotype of scalp tumor and hydroureteronephrosis in NPHP patients with homozygous deletion of NPHP1, paving an avenue for further research on NPHP1-associated deformity in the skin and the urinary system.

Clinical characteristics of bronchopulmonary dysplasia in very preterm infants. / 极早早产儿支气管肺发育不良的临床特征.

OBJECTIVES: With the development of perinatal and neonatal intensive care medicine, the survival rate of very premature infants increases year by year. However, the incidence of bronchopulmonary dysplasia (BPD) increases year by year, which seriously affects the survival prognosis of very premature infants. How to prevent and treat BPD effectively has become the focus of neonatologists. This study aims to provide ideas for the prevention and treatment of BPD in very preterm infants via analyzing the clinical characteristics of BPD. METHODS: A total of 472 cases of very premature infants admitted to the Divison of Neonatology, Department of Pediatrics at the Second Xiangya Hospital of Central South University were retrospectively selected and assigned into a BPD group (n=147) and a non-BPD group (n=325) according to the diagnosis of BPD. Clinical data of each group were collected to find out the clinical characteristics of BPD in very preterm infants. Basic information, maternal pregnancy data, laboratory findings, nutritional support, respiratory support patterns and duration, and systemic complications were included. RESULTS: Compared with the non-BPD group, gestational age, birth weight, head circumference and body length in the BPD group were lower, the Apgar score in 1st min and 5th min and average body weight growth rate were lower (all P<0.05); the ratios of male, very low birth weight (VLBW), and extremely low birth weight (ELBW) in the BPD group were higher than those in the non-BPD group (all P<0.5); the incidence of maternal cervical insufficiency and the rate of using embryo transfer technology in the BPD group were higher than those in the non-BPD group, and the rate of using prenatal hormone in the BPD group was lower than that in the non-BPD group (all P<0.05). The positive rate of sputum culture in the BPD group was higher than that in the non-BPD group (P<0.05), and the white blood cell count, neutrophil ratio, and procalcitonin in the BPD group were higher than those in the non-BPD group (all P<0.05). The period of fasting, minimal feeding, total parenteral nutrition (TPN), and partial parenteral nutrition (PPN) in the BPD group were longer than those in the non-BPD group (all P<0.05). The duration of nasal catheter oxygen inhalation and mechanical ventilation in the BPD group was longer than that in the non-BPD group, and the rates of mechanical ventilation at Day 1, 3, 7, 14, 21 and 28 after birth were higher than those in the non-BPD group (all P<0.05). The incidence of respiratory distress syndrome, apnea of prematurity, respiratory failure, pneumonia, pulmonary hemorrhage, pleural effusion, persistent pulmonary hypertension, hemodynamic patent ductus arteriosus, cytomegalovirus infection, neonatal necrotic enterocolitis, cholestasis, anemia, abnormal blood system, hypothyroidism, retinopathy of prematurity, and internal environment disorders in the BPD group were significantly higher than those in non-BPD group (all P<0.05). CONCLUSIONS: There are significant differences between very premature infants with BPD and those without BPD in general information, maternal history, inflammatory indicators, nutritional support, respiratory support, comorbidities and complication rates. To ensure normal fetal development, reducing the inflammatory reaction of very premature infants, establishing enteral nutrition as early as possible, shortening the time of mechanical ventilation, and reducing the occurrence of complications are beneficial to decrease the incidence of BPD in very premature infants and improve the long-term prognosis of BPD.

4-Hydroxyisoleucine inhibits tumor growth by triggering endoplasmic reticulum stress and autophagy.

4-Hydroxyisoleucine（4-HIL）is a non-protein amino acid that is able to reduce obesity and improve insulin sensitivity in mice, and recently emerged as a drug candidate against hypoglycemia. For the first time, we found that 4-HIL exhibits a potent anti-tumor activity in various cancer cell lines in vitro and in vivo. Most importantly, 4-HIL has no cytotoxic effect on normal or non-malignant cells. Proteomic data analysis revealed changes in endoplasmic reticulum stress（ERS）related protein and autophagy related protein. Western blot revealed that molecular components of the ERS pathway were activated, including phosphorylation of perk and EIF2a increased, while levels of GRP78 reduced, the cellular process of ERS potentially contributed to the activation of autophagy, Transmission electron microscopy revealed the formation of autophagic vesicles under 4-HIL treatment, and LC3B was increased. Meanwhile, activation of ERS inhibits intracellular protein synthesis rate, our results suggest that 4-HIL exhibits anti-tumor activity in various cancer cell lines by increasing ERS and triggering autophagy responses without causing damage to normal cells.

[Repair impact of vibration exercise with different frequencies on articular cartilage of rats with early knee osteoarthritis and its JNK/NF-κB, SOX9 mechanisms].

Objective: To investigate the repair effect and JNK/NF-κB,SOX9 mechanisms of vibration exercise with different frequencies on articular cartilage in rats with early knee osteoarthritis. Methods: Forty-eight adult male SD rats were randomly divided into six groups(n=8):model control group(MC),high frequency vibration group 1 (GP1,60 Hz),high frequency vibration 2 group (GP2,40 Hz),medium frequency vibration group (ZP,20 Hz),minor frequency group(DP,10 Hz)and normal control group(NC). Except for NC group,the rats in each group were made into early knee osteoarthritis model after six weeks of knee joint cavity injection of papain solution and 2% mixture l-cysteine on the 1st,4 th and 7th day. Each exercise group was subjected vibration to 40 minutes a day with amplitude of 2～5 mm and 5 days a week. Four weeks later, the articular cartilage of the lateral femoral condyle of the both back leg knee joints were detected by HE staining,serine O staining and Mankin scores for morphological observation. The expression levels of JNK,NF-κB p65 and Sox9 mRNA in articular cartilage of the medial femoral condyle were detected by RT-qPCR,and the protein expressions of JNK,NF-κB p65 and Sox9 were detected by Western blot. Results: Compared with the NC group,the Mankin score in other groups was significantly higher (P＜0.01). Compared with the MC group,the Mankin score of each vibration group was significantly lower(P＜0.05),the mRNA and protein expressions of JNK and NF-κB p65 in each vibration training group were significantly lower (P＜0.01),the expressions of Sox9 mRNA and protein in vibration training group were increased significantly (P＜0.01). Compared with the higher frequency group,the Mankin score,the mRNA and protein expressions of JNK and NF-κB p65 of lower frequency group were significantly lower (P＜0.05 or P＜0.01). But the expressions of Sox9 mRNA and protein were significantly higher (P＜ 0.05 or P＜0.01). Conclusion: Vibration exercise of different frequencies may present varying degrees of cartilage repair impact in rats with early knee osteoarthritis,and the cartilage repair by low-frequency vibration training is better than that by high-frequency vibration. This can be one of the mechanisms on controlling collagen synthesis by down-regulating JNK/NF-κB expression and increasing SOX9 activity of OA articular cartilage.

[Effect of needle knife on mTOR/Atg/ULK1/Beclin-1 axis and chondrocyte autophagy in rats with knee osteoarthritis].

OBJECTIVE: To observe the effect of needle knife on chondrocyte autophagy and expressions of autophagy-related protein and mammalian target of rapamycin (mTOR) in rats with knee osteoarthritis (KOA), and to explore the possible mechanism of needle knife for KOA. METHODS: A total of 42 SD rats were randomly divided into a normal group, a model group and a needle knife group, 14 rats in each group. Except for the normal group, the other two groups were injected with the mixture of papain and L-cysteine into the left hind knee joint to establish the KOA model. After modeling, the rats in the needle knife group were treated with needle knife at strip or nodule around the quadriceps femoris and medial and lateral collateral ligament on the affected side, once a week for 3 times (3 weeks). The changes of left knee circumference in each group were observed; the chondrocytes and ultrastructure of left knee joint were observed by HE staining and electron microscope; the mRNA and protein expressions of autophagy-related genes (Atg5, Atg12, Atg4a), Unc-51 like autophagy activated kinase 1 (ULK1), autophagy gene Beclin-1 and mTOR in left knee cartilage were detected by real-time fluorescence quantitative PCR and Western blot. RESULTS: After modeling, the left knee circumferences in the model group and the needle knife group were increased compared with those before modeling and in the normal group (P<0.05); after intervention, the left knee circumference in the needle knife group was smaller than that in the model group and after modeling (P<0.05). Compared with the normal group, the number of chondrocytes was decreased, and a few cells swelled, nuclei shrank, mitochondria swelled and autophagosomes decreased in the model group; compared with the model group, the number of chondrocytes was increased , and most cell structures returned to normal, and autophagosomes was increased. Compared with the normal group, the mRNA and protein expressions of Atg5, Atg12, Atg4a, Beclin-1 and ULK1 in the knee cartilage in the model group were decreased (P<0.05); compared with the model group, the expressions of the above indexes in the needle knife group were increased (P<0.05). Compared with the normal group, the mRNA and protein expressions of mTOR in the knee cartilage in the model group were increased (P<0.05); compared with the model group, the expressions of the above indexes in the needle knife group were decreased (P<0.05). CONCLUSION: The needle knife intervention could improve knee cartilage injury in rats with KOA, and its mechanism may be related to reducing the expression of mTOR and up-regulating the expressions of Atg5, Atg12, Atg4a, ULK1 and Beclin-1, so as to promote chondrocyte autophagy and delay the aging and degeneration of chondrocytes.

The Influence of NDRG1 Single Nucleotide Polymorphisms on Glioma Risk and Prognosis in Chinese Han Population.

Glioma is a highly fatal malignant tumor with a high recurrence rate, poor clinical treatment effect, and prognosis. We aimed to determine the association between single nucleotide polymorphisms (SNPs) of NDRG1 and glioma risk and prognosis in the Chinese Han population. 5 candidate SNPs were genotyped by Agena MassARRAY in 558 cases and 503 controls; logistic regression was used to analyze the relationship between SNPs and glioma risk. We used multi-factor dimensionality reduction to analyze the interaction of 'SNP-SNP'; the prognosis analysis was performed by log-rank test, Kaplan-Meier analysis, and Cox regression model. Our results showed that the polymorphisms of rs3808599 was associated with the reduction of glioma risk in all participants (OR 0.41, p = 0.024) and the participants ≤ 40 years old (OR 0.30, p = 0.020). rs3802251 may reduce glioma risk in all participants (OR 0.79, p = 0.008), the male participants (OR 0.68, p = 0.033), and astrocytoma patients (OR 0.81, p = 0.023). rs3779941 was associated with poor glioma prognosis in all participants (HR = 2.59, p = 0.039) or astrocytoma patients (HR = 2.63, p = 0.038). We also found that the key factors for glioma prognosis may include surgical operation, radiotherapy, and chemotherapy. This study is the first to find that NDRG1 gene polymorphisms may have a certain association with glioma risk or prognosis in the Chinese Han population.

Assessment of interleukin 6 gene polymorphisms with rheumatoid arthritis.

BACKGROUND: Rheumatoid arthritis (RA) is complex autoimmune system disease and significant impact on the health of population in our world. Numerous studies confirmed that genetic factors play a crucial role in the pathogenesis of RA. In this current study, we aimed to investigate IL-6 polymorphisms and RA risk in Chinese Han population. METHODS: 508 RA patients and 494 age- and gender- matched healthy controls were recruited, all subjects were genotyped with an Agena MassARRAY platform. Subsequently, odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by unconditional logistic regression after adjusting for age and gender. RESULTS: Our results suggested that IL-6 rs2243289 allele and genotype frequencies were associated with reduced RA risk under all genetic models (all p < 0.05). Stratification analysis revealed that IL-6 rs2243289 polymorphism was significant associated with decreased the risk of RA in the old groups (age > 54) (all p < 0.05). However, IL-6 rs2069837 and rs1800796 polymorphisms were associated with increased risk of RA among the young groups (age ≤ 54) (all p < 0.05). In addition, subgroup analysis by gender suggested that IL-6 rs2069837 and rs1800796 polymorphism were interacted with increased the risk of RA in males (all p < 0.05). Besides, IL-6 rs2243289 was associated with reduced RA risk in females. CONCLUSIONS: In conclusion, our results demonstrated the correlation between IL and 6 polymorphisms and RA susceptibility and confirmed for the first time that the relationship was restricted to age and gender in Chinese Han population.

Irisin Protects Brain against Ischemia/Reperfusion Injury through Suppressing TLR4/MyD88 Pathway.

BACKGROUND: Inflammatory response exerts an important role in ischemia/reperfusion (I/R) injury. TLR4 and myeloid differentiation factor 88 (MyD88) are key components in inflammation and are involved in the cerebral I/R injury. Irisin is a skeletal muscle-derived myokine produced after exercise, which was found to suppress inflammation. In this study, we investigated whether irisin could protect the brain from I/R injury through the TLR4/MyD88 pathway. METHODS: Male Sprague Dawley rats (20 months, 190 ∼ 240 g) were pretreated with irisin at 10, 50, or 100 mg/kg for consecutive 3 days and then subjected to surgery of middle cerebral artery occlusion or sham operation. Infarct size and neuron loss were measured to evaluate brain damage. The mRNA and protein levels of TLR4 and MyD88 were measured by in situ hybridization and immunohistochemistry, respectively. NF-κB activation was assessed by electrophoretic mobility shift assay. Neurological function was evaluated by neurobehavior score test and passive avoidance test. RESULTS: Irisin could reduce neuronal damage and neurofunctional impairment after I/R injury. This effect was mediated by downregulating the TLR4/MyD88 and inhibiting NF-κB activation. CONCLUSION: Irisin plays a beneficial effect in I/R injury through regulating the TLR4/MyD88 pathway.

IL1R2 Polymorphisms are Associated with Increased Risk of Esophageal Cancer.

BACKGROUND: Esophageal cancer (EC) is the sixth leading cause of cancer death worldwide, and the overall incidence is increasing. OBJECTIVE: The aim of this study was to evaluate the association between single nucleotide polymorphisms in IL1R2 and EC risk in the Chinese population. METHODS: Genotyping of six SNPs of IL1R2 was performed with the Agena MassARRAY platform from 384 EC and 499 controls. The association between polymorphisms and EC risk was assessed by performing genetics models and haplotype analyses. RESULTS: Overall analysis results showed that the allele C of rs11674595 (odds ratio [OR] = 1.42, 95% confidence interval [CI]: 1.14-1.77, p = 0.002) and allele G of rs2072472 (allele: OR = 1.35, 95% CI: 1.08-1.69, p = 0.008) were associated with an increased EC risk. The rs11674595 and rs2072472 were found to be correlated with EC risk under the codominant, dominant, and additive models. Stratification analysis found that rs11674595 and rs2072472 were associated with increased EC risk in male and in age > 55 years old subgroup. In addition, Crs11674595Grs4851527 haplotype was significantly associated with 1.44-fold increased risk of EC (95% CI: 1.12-1.84, p = 0.004). CONCLUSION: Our results reveal the significant association between SNPs (rs11674595 and rs2072472) in the IL1R2 and EC risk in the Chinese Han population. The findings may provide meaningful reference for the prevention and treatment of EC.

Preconditioning with hydrogen sulfide ameliorates cerebral ischemia/reperfusion injury in a mouse model of transient middle cerebral artery occlusion.

Ischemic stroke and reperfusion injury are a common and serve medical situation in the elderly population. H2S is a gas neuromodulator which also possesses anti-oxidant and anti-inflammatory properties, and is found to play neuroprotective effect in neurodegenerative diseases. This study investigated the effect of endogenous and exogenous H2S in a mouse model of ischemic stroke. 129P2-Cbstm1Unc/J mice with heterozygous mutants in H2S generating enzyme cystathionine ß-synthase were used to study the effect of endogenous H2S. H2S donor NaHS was used as exogenous H2S. Animals were pretreated with H2S and then subjected to middle cerebral artery occlusion surgery. Behavioral outcome was evaluated by novel object recognition test. Inflammatory cytokines were measured using ELISA. Western blot was used to detect the activation of NF-κB. Aged 129P2-Cbstm1Unc/J mice showed exaggerated inflammation and more severe cognitive impairment after ischemia, while exogenous H2S treatment inhibited inflammation and attenuated behavioral impairment. The anti-inflammatory effect of H2S was mediated by inhibiting NF-κB. Our findings suggest that both endogenous and exogenous H2S are involved in the neuroprotection against ischemia/reperfusion-induced cerebral injury.

Cystathionine ß-Synthase-Derived Hydrogen Sulfide Correlates with Successful Aging in Mice.

Although learning and memory decline are associated with aging, some older individuals show high cognitive function. The mechanism underlying successful aging is not clear, although augmented N-methyl-D-aspartate receptor-independent long-term depression (LTD) has been found in successfully aged rats. We hypothesized that metabotropic glutamate receptor dependent LTD (mGluR-LTD) is associated with successful aging in mice and explored its molecular mechanisms. We divided aged mice into impaired and unimpaired groups and examined mGluR-LTD in the hippocampus. We examined the role of hydrogen sulfide (H2S) in mGluR-LTD establishment in aged mice and investigated the requirement of protein synthesis and intracellular calcium levels. We assessed learning and memory of mice treated with sodium hydrogen sulfide (NaHS) using behavior tests. We found that unimpaired mice elicited larger mGluR-LTD that correlated with H2S production which was blocked by inhibiting cystathionine synthase. Enhanced H2S production of NaHS treatment augmented mGluR-LTD in impaired group. mGluR-LTD establishment required protein synthesis, as well as intracellular calcium, although NaHS treatment leads to reduced sensitivity to calcium chelator 1,2-bis(o-amino phenoxy)ethane-N,N,N',N'-tetraacetic acid treatment. Finally, we found that NaHS treatment enhanced learning and memory of aged mice as indicated by behavioral assessments. Our results indicate that successful aging mice are associated with the function of H2S.

Mannan-Binding Lectin Suppresses Peptidoglycan-Induced TLR2 Activation and Inflammatory Responses.

Peptidoglycan (PGN), as the major components of the bacterial cell wall, is known to cause excessive proinflammatory cytokine production. Toll-like receptor 2 (TLR2) is abundantly expressed on immune cells and has been shown to be involved in PGN-induced signaling. Although more and more evidences have indicated that PGN is recognized by TLR2, the role of TLR2 PGN recognition is controversial. Mannan-binding lectin (MBL), a plasma C-type lectin, plays a key role in innate immunity. More and more evidences show that MBL could suppress the amplification of inflammatory signals. Whether MBL can alter PGN-elicited cellular responses through TLR2 in macrophages is still unknown, and possible mechanism underlying it should be investigated. In this study, we found that MBL significantly attenuated PGN-induced inflammatory cytokine production, including TNF-α and IL-6, in PMA-stimulated THP-1 cells at both mRNA and protein levels. The expression of TLR2 was strongly induced by PGN stimulation. Furthermore, the administration of TLR2-neutralized antibody effectively suppressed PGN-induced TNF-α and IL-6 expression. These results supplied the evidence that PGN from Saccharomyces cerevisiae could be recognized by TLR2. In addition, we also found that MBL decreased PGN-induced TLR2 expression and suppressed TLR2-mediated downstream signaling, including the phosphorylation of IκBα, nuclear translocation of NF-κBp65, and phosphorylation of MAPK p38 and ERK1/2. Administration of MBL alone did not have an effect on the expression of TLR2. Finally, our data showed that PGN-mediated immune responses were more severely suppressed by preincubation with MBL and indicated that MBL can combine with both TLR2 and PGN to block the inflammation cytokine expression induced by PGN. All these data suggest that MBL could downregulate inflammation by modulating PGN/TLR2 signaling pathways. This study supports an important role for MBL in immune regulation and signaling pathways involved in inflammatory responses.

Construction of High Sensitive CD133 Immune PLGA Magnetic Spheres Platform for Lung Cancer Stem Cells Isolation and Its Property Evaluation.

High sensitive immune CD133 PLGA magnetic spheres platform is constructed to isolate and enrich lung cancer stem cells in order to study their biological characteristics, such as their proliferation, self-renewal and invasion and metastasis in vitro. The expression of the specific transcription factors Oct 4 and Nanog genes of stem cells were detected by immunofluorescence and RT-PCR. The tumorigenic capacity of lung cancer cells were studied using the tumorigenesis experiment in nude mice in vivo. The results indicated that the CD133 immune PLGA magnetic beads (with diameter 356.25 ± 0.64 nm) can effectively separate more lung cancer stem cells under the serum-free suspension culture compared with MACS CD133 MicroBead Kit. Some A549 cells sorted magnetically could form stable tumor suspended spheres that were able to undergo passage stably after 3 to 6 days. The self-renewal, clonal formation and invasion and metastasis capacities of the suspended spheres were higher than those of the parent cells (P < 0.05). The expressions of Oct 4 and Nanog mRNA in stem cells were significantly elevated (P < 0.05), and the A549 suspended spheres could significantly improve the in vivo tumorigenic capacity of nude mice. Among the peripheral blood of 20 patients with lung adenocarcinoma, CD133+ cells were isolated from the peripheral blood of 14 (70%), and CD133+ cells sorted from 11 (55%) patients were cultured into spheres.

Structure-activity relationship study of small molecule inhibitors of the DEPTOR-mTOR interaction.

DEPTOR is a 48kDa protein that binds to mTOR and inhibits this kinase within mTORC1 and mTORC2 complexes. Over-expression of DEPTOR specifically occurs in the multiple myeloma (MM) tumor model and DEPTOR knockdown is cytotoxic to MM cells, suggesting it is a potential therapeutic target. Since mTORC1 paralysis protects MM cells against DEPTOR knockdown, it indicates that the protein-protein interaction between DEPTOR and mTOR is key to MM viability vs death. In a previous study, we used a yeast two-hybrid screen of a small inhibitor library to identify a compound that inhibited DEPTOR/mTOR binding in yeast. This therapeutic (compound B) also prevented DEPTOR/mTOR binding in MM cells and was selectively cytotoxic to MM cells. We now present a structure-activity relationship (SAR) study around this compound as a follow-up report of this previous work. This study has led to the discovery of five new leads - namely compounds 3g, 3k, 4d, 4e and 4g - all of which have anti-myeloma cytotoxic properties superior to compound B. Due to their targeting of DEPTOR, these compounds activate mTORC1 and selectively induce MM cell apoptosis and cell cycle arrest.

The prognostic landscape of tumor-infiltrating immune cell and immunomodulators in lung cancer.

Tumor-infiltrating immune cells are closely associated with clinical outcome. However, immunohistochemistry-based analysis of tumor infiltrates can be misleading as the representative marker of an immune subpopulation might be expressed in other cell types. In this study, based on a metagene approach (known as CIBERSORT) and an online databse, The Cancer Immunome Atlas (https://tcia.at/), we comprehensively analyzed the tumor-infiltrating immune cells present in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC). A total of 22 types of both adaptive and innate tumor-infiltrating immune cells were evaluated in LUAD (n=492) and LUSC (n=488). As a result, tumors lacking memory B cells or with increased number of M0 macrophages were associated with the poor prognosis in LUAD at early clinical stage. In LUSC, T follicular helper cells were associated with favorable outcome, while increased number of neutrophils predicted a poor outcome. Moreover, Kaplan-Meier analysis of the prognostic value of immune checkpoint molecules revealed that expression of ICOS was positively correlated the clinical outcome of patients with LUAD. Collectively, our data suggest that tumor-infiltrating immune cells in lung cancer are likely to be important determinants of both prognosis and response to immunotherapies.

Associations between genetic variants located in mature microRNAs and risk of lung cancer.

MiRNAs have been focused for their wide range of biological regulatory functions. Previous studies have suggested that individual miRNAs could influence tumorigenesis through their regulation of specific proto-oncogenes and tumor suppressor genes. This study was implemented to investigate the associations between SNPs in mature microRNAs (miRNAs) and development of lung cancer in a two-stage, case-control study, followed by some functional validations. First, 11 SNPs were analyzed in a case-control study of lung cancer, and the significant results were validated in an additional population. Our results showed that rs3746444 in mir-499 (allele C vs T: OR = 1.33; 95% CI = 1.15-1.54; P = 1.2 × 10-4) and rs4919510 in mir-608 (allele G vs C: OR = 1.27; 95% CI= 1.13-1.43; P = 5.1 × 10-5) were significantly associated with increased risk of lung cancer. Rs3746444 in mir-499 was also significantly associated with poor survival of lung cancer (HR, 1.35; 95% CI, 1.15-1.58; P = 0.0002). The expression levels of mir-499 and mir-608 were significantly lower than those of adjacent normal tissues (P < 0.0005), and the carriers of minor alleles have lower expression levels of mir-499 and mir-608 than those of major alleles (P < 0.001). These findings indicated that rs3746444 in mir-499 and rs4919510 in mir-608 might play a substantial role in the susceptibility to lung cancer.