Hyperbaric Lidocaine Aggravates Diabetic Neuropathic Pain by Targeting p38 MAPK/ERK and PINK1/Parkin-Mediated Mitophagy Signaling Pathway.

BACKGROUND: Diabetic neuropathic pain (DNP) is a complication of diabetes mellitus (DM). Hyperbaric lidocaine (HL), a local anesthetics drug, has neurotoxicity. The present study aims to study the effect and molecular mechanisms of HL on spinal nerve injury in DNP. METHODS: The DNP rat model was established through a high-fat-glucose diet in combination with Streptozotocin (STZ) administration. SB203580 and PD98059 were utilized to inhibit p38 mitogen-activated protein kinase (p38 MAPK) and extracellular signal-regulated kinase (ERK). The mechanical paw withdrawal threshold (PWT) and the thermal paw withdrawal latency (PWL) were tested to evaluate rats' mechanical allodynia and thermal hyperalgesia. Hematoxylin-eosin (H&E) and terminal deoxynucleotidyltransferase-mediated dUTP nick-end Labeling (TUNEL) staining were performed to evaluate the pathological changes and neuron apoptosis in spinal cord tissues of L4-5. Western blotting analysis and reverse transcription-polymerase chain reaction (RT-qPCR) assay were used to measure the levels of proteins and mRNAs, respectively. RESULTS: PWT and PWL were decreased in DNP rats with serious spinal nerve injury. HL administration downregulated the PWT and PWL and aggravated spinal nerve injury in DNP rats, but isobaric lidocaine had no effects on these changes. Meanwhile, p38 MAPK/ERK signaling and PTEN-induced kinase 1 (PINK1)-mediated mitophagy were activated in DNP, which was enhanced by HL but not isobaric lidocaine. Blocking p38 MAPK/ERK signaling could effectively attenuate HL-induced spinal nerve injury and inhibit mitophagy. CONCLUSION: In summary, HL can aggravate spinal cord tissue damage in DNP rats by inducing PINK1-mediated mitophagy via activating p38 MAPK/ERK signaling. Our data provide a novel insight that supports the potential role of p38 MAPK/ERK signaling in acting as a therapeutic target for HL-induced neurotoxicity.

Lidocaine induces neurotoxicity in spinal cord neurons in Goto-Kakizaki rats via AMPK-mediated mitophagy.

OBJECTIVE: Lidocaine has been reported to induce neurotoxicity, which is further enhanced by high glucose levels. This study is aimed to explore the underlying mechanisms of lidocaine neurotoxicity in spinal cord neurons of diabetes. METHODS: Take thirty specific pathogen-free (SPF) healthy Sprague-Dawley (SD) rats and thirty Goto-Kakizaki (GK) rats, aged 12 weeks, weighing 180-200 g. The spinal cord neurons of rats were isolated and cultured in vitro. Cell Counting Kit-8 was used to detect cell proliferation to determine the appropriate concentration and duration of lidocaine. Mitochondrial function was assessed using ATP content, cellular oxygen consumption rate, mitochondrial membrane potential, ROS production, and mitochondrial ultrastructure. Western blot was applied to detect the expression of autophagy- and mitophagy-related molecules PINK1, p-AMPK, LC-3II/LC3-I ratio and mTORC1. Immunofluorescent staining was used to detect the expression of PINK1 and LC3. RESULTS: Lidocaine decreased cell viability of spinal cord neurons in concentration- and time-dependent manners. And lidocaine treatment aggravated mitochondrial dysfunction in GK rats. Furthermore, mitophagy was activated in diabetes, and lidocaine exposure up-regulated mitophagy. AMPK activator MK8722 aggravated mitochondrial damage, increased the expression of PINK1, p-AMPK, LC-3II/LC3-I ratio, and decreased the expression of mTORC1, while AMPK inhibitor Compound C and autophagy inhibitor Bafilomycin A1 reduced mitochondrial damage and decreased the expression of PINK1, p-AMPK, LC-3II/LC3-I ratio, and increased the expression of mTORC1. CONCLUSIONS: Lidocaine induced neurotoxicity of spinal cord neurons in GK rats via AMPK-mediated mitophagy.

Unraveling the driving factors of the plastic waste trade network formation and dynamics.

International trade of plastic waste promotes the global plastic circular economy and improves resource efficiency, but exacerbates the ubiquitous plastic pollution. Understanding the drivers behind the evolution of the global plastic waste trade network (GPWTN) is pivotal for developing new international instruments to end plastic pollution and fostering clean solid-waste trade. Employing social network analysis (SNA) and quadratic assignment procedure (QAP) model, this study structures the GPWTN using bilateral trade data, revealing shifts from highly centralized to cross-layered networks and relevant drivers. It is suggested that Malaysia and Turkey has become the new key recipients of the GPWTN, replacing China, accompanied by the launch of new environmental regulations in some countries. Transportation cost is the most critical factor for the formation of the GPWTN, followed by gaps in resource demand, bio-based resource availability, and transportation accessibility. Trading partners in closer proximity, especially those with contiguous borders, are more likely to trade in waste plastics, while coastal countries play an important role in these partnerships. Economies with more abundant biomaterials, higher incomes, and greater environmental burdens are more likely to be exporters, while economies with scarcer resources and more compelling demands are more likely to import plastic waste. Countries involved in the trade in plastic waste, as either importers or exporters, receive varying degrees of economic benefits but bear potential environmental impacts. Therefore, global plastic pollution control and trade prosperity necessitates necessitate coordinated endeavors from nations and intergovernmental bodies for a mutually advantageous denouement.

SIRT1/P53 pathway is involved in the Arsenic induced aerobic glycolysis in hepatocytes L-02 cells.

Arsenic is a known human carcinogen. Low doses of arsenic can induce cell proliferation, but the mechanism remains elusive. Aerobic glycolysis, also known as the Warburg effect, is one of the characteristics of tumour cells and rapidly proliferating cells. P53 is a tumour suppressor gene that has been shown to be a negative regulator of aerobic glycolysis. SIRT1 is a deacetylase that inhibits the function of P53. In this study, we found that P53 was involved in low dose of arsenic-induced aerobic glycolysis through regulating HK2 expression in L-02 cells. Moreover, SIRT1 not only inhibited P53 expression but also decreased the acetylation level of P53-K382 in arsenic-treated L-02 cells. Meanwhile, SIRT1 influenced the expression of HK2 and LDHA, which then promoted arsenic-induced glycolysis in L-02 cells. Therefore, our study demonstrated that the SIRT1/P53 pathway is involved in arsenic-induced glycolysis, thereby promoting cell proliferation, which provides theoretical basis for enriching the mechanism of arsenic carcinogenesis.

Malignant growth of arsenic-transformed cells depends on activated Akt induced by reactive oxygen species.

Arsenic is an identified carcinogen for humans.In this study, chronic exposure of human hepatocyte L-02 to low-doses of inorganic arsenic caused cell malignant proliferation. Meanwhile, compared with normal L-02 cells, arsenic-transformed malignant cells, L-02-As displayed more ROS and significantly higher Cyclin D1 expression as well as aerobic glycolysis. Moreover, Akt activation is followed by the upregulation of Cyclin D1 and HK2 expression in L-02-As cells, since inhibition of Akt activity by Ly294002 attenuated the colony formation in soft agar and decreased the levels of Cyclin D1 and HK2. In addition, scavenging of ROS by NAC resulted in a decreased expression of phospho-Akt, HK2 and Cyclin D1, and attenuates the ability of anchorage-independent growth ofL-02-As cells, suggested that ROS mediated the Akt activation in L-02-As cells. In summary, our results demonstrated that ROS contributes to the malignant phenotype of arsenic-transformed human hepatocyte L-02-As via the activation of Akt pathway.

Research for type 2 diabetes mellitus in endemic arsenism areas in central China: role of low level of arsenic exposure and KEAP1 rs11545829 polymorphism.

Type 2 diabetes mellitus (T2DM) is one of the major public health problems worldwide; both genetic and environmental factors are its risk factors. Arsenic, an environmental pollutant, might be a risk factor for T2DM, but the association of low-to-moderate level arsenic exposure with the risk of T2DM is still inconsistent. Single nucleotide polymorphisms (SNPs) can affect the development of T2DM, but the study on KEAP1 rs11545829 (G>A) SNP is few. In this paper, we explored the effect of KEAP1 rs11545829 (G>A) SNP and low-to-moderate level arsenic exposure on risk of T2DM in a cross-sectional case-control study conducted in Shanxi, China. Total of 938 participants, including 318 T2DM cases and 618 controls, were enrolled. Blood glycosylated haemoglobin (HbA1c) was detected by Automatic Biochemical Analyzer, and participants with HbA1c≧6.5% were diagnosed as T2DM. Urinary total arsenic (tAs, mg/L), as the indicator of arsenic exposure, was detected by liquid chromatography-atomic fluorescence spectrometry (LC-AFS). Genomic DNA was extracted and the genotypes of KEAP1 rs11545829 SNP were examined by multiplex polymerase chain reaction (PCR). The urinary tAs concentration in recruited participants was 0.075 (0.03-0.15) mg/L, and was associated with an increased risk of T2DM (OR = 8.45, 95% CI 2.63-27.17); rs11545829 mutation homozygote AA genotype had a protective effect on risk of T2DM (OR = 0.42, 95 % CI 0.25-0.73). Although this protective effect of AA genotype was found in participants with higher urinary tAs level (>0.032 mg/L) (OR = 0.48, 95% CI 0.26-0.86), there was no interaction effect for arsenic exposure and rs11545829 SNP on risk of T2DM. In addition, BMI modified the association between rs11545829 SNP and the risk of T2DM (RERI = -1.11, 95% CI -2.18-0.04). The present study suggest that low-to-moderate level arsenic exposure may be a risk factor, while KEAP1 rs11545829 SNP mutation homozygote AA genotype may be a protective factor for risk of T2DM, especially for T2DM patients with urinary tAs level>0.032 mg/L.

miR-21-5p and canonical Wnt signaling pathway promote osteoblast function through a feed-forward loop induced by fluoride.

Long-term excessive exposure to fluoride from environmental sources can cause serious public health problems such as dental fluorosis and skeletal fluorosis. The aberrant activation of osteoblasts in the early stage is one of the critical steps during the pathogenesis of skeletal fluorosis and canonical Wnt signaling pathway participate in the progress. However, the specific mechanism that how canonical Wnt signaling pathway was mediated is not yet clear. In this study, we found that miR-21-5p induced the activation of canonical Wnt signaling pathway via targeting PTEN and DKK2 during fluoride induced osteoblasts activation and firstly demonstrated the forward loop between canonical Wnt signaling and miR-21-5p in the process. These findings suggested an important regulatory role of miR-21-5p on canonical Wnt signaling pathway during skeletal fluorosis and miR-21-5p might be a potential therapeutic target for skeletal fluorosis.

Association between fluoride exposure and kidney function in adults: A cross-sectional study based on endemic fluorosis area in China.

BACKGROUND: The kidney toxicity of fluoride exposure has been demonstrated in animal studies, and a few studies have reported kidney function injury in children with fluoride exposure. However, epidemiological information for the effects of long-term fluoride exposure on adult kidney function remains limited. METHODS: We conducted a cross-sectional investigation in Wenshui County, Shanxi Province to examine the association between fluoride exposure and kidney function in adults, and a total of 1070 adults were included in our study. Urinary fluoride concentrations were measured using the national standardized ion selective electrode method. And markers of kidney function injury (urinary NAG, serum RBP, serum Urea, serum C3, serum UA and serum αl-MG) were measured using automatic biochemical analyzer. Multivariate linear regression analysis and binary logistic regression model were used to assess the relationship between urinary fluoride and markers of kidney function injury. RESULTS: Urinary fluoride was positively correlated with urinary NAG and serum Urea, negatively correlated with serum C3. In multivariate linear regression models, every 1 mg/L increment of urinary fluoride was associated with 1.583 U/L increase in urinary NAG, 0.199 mmol/L increase in serum Urea, 0.037 g/L decrease in serum C3 after adjusting for potential confounding factors. In the binary logistic regression model, higher levels of urinary fluoride were associated with an increased risk of kidney function injury. Determination of kidney function based on urinary NAG, every 1 mg/L increment in the urinary fluoride concentrations was associated with significant increases of 22.8% in the risk of kidney function injury after adjusting for potential confounding factors. Sensitivity analysis for the association between urinary fluoride concentrations and markers of kidney function (urinary NAG, serum Urea, and serum C3) by adjusting for the covariates, it is consistent with the primary analysis. CONCLUSIONS: Our study suggests that long-term fluoride exposure is associated with kidney function in adults, and urinary NAG is a sensitive and robust marker of kidney dysfunction caused by fluoride exposure, which could be considered for the identification of early kidney injury in endemic fluorosis areas.

sKlotho is associated with the severity of brick tea-type skeletal fluorosis in China.

The change of serum soluble Klotho (sKlotho) content is related to a variety of osteoarthropathy. However, its association with the severity of skeletal fluorosis (SF) is not clear. Here, the association of tea fluoride exposure with serum sKlotho levels and the severity of SF were investigated and further verified in a rat model of fluorosis. A cross sectional case control study was conducted in residents over 50 years old from brick-tea drinking areas in Qinghai and Xinjiang Provinces, China. Concentrations of fluoride in brick tea water and urine were determined by ion selective electrode method, and the levels of serum sKlotho were determined by ELISA method. Linear regression and ordered logistic regression models were constructed to examine the relationship among fluoride exposure, serum sKlotho levels and the severity of SF. The kidney and small intestine of Wistar rats were isolated for detection of Klotho by immunohistochemistry (IHC), and femoral artery blood was sampled to measure the serum levels of sKlotho. An increase of 1 mg/day in tea fluoride intake (TFI) was associated with a 12.070 pg/mL (95% CI: 0.452-23.689) increase in serum sKlotho levels and a 1.163-fold (95% CI: 1.007-1.342) increase in the severity of SF after adjusting for age, gender, and ethnicity. Serum sKlotho levels were also positively associated with the severity of SF (P < 0.05). The mediation analysis showed that serum sKlotho levels mediated 17.76% of the increase in the severity of SF caused by an increase of 1 mg/day of TFI. Moreover, a significant increase of serum sKlotho levels in fluoride-exposed groups was also seen in the rat model. The present study suggests that serum sKlotho may be a potential mediator of SF in brick tea-type fluorosis endemic areas.

[Seroepidemiology of varicella among the healthy population aged 1-19 years in Harbin, China].

OBJECTIVE: To investigate the level of IgG antibody to varicella in the healthy population aged 1-19 years in Harbin, China. METHODS: Random sampling was performed to select 1 203 healthy individuals aged 1-19 years in Harbin. According to age, they were divided into ≥1 years group (n=240), ≥4 years group (n=396), ≥7 years group (n=364) and 14-19 years group (n=203). Enzyme-linked immunosorbent assay was used to measure the concentration of varicella-zoster virus (VZV)-IgG antibody in serum, and a concentration of VZV-IgG antibody of ≥100 mIU/mL was considered positive, suggesting that the subject had the ability to resist VZV infection. RESULTS: The overall positive rate of VZV-IgG antibody was 71.49% (860/1 203), and the concentration of VZV-IgG antibody was 447±17 mIU/mL. The concentration of VZV-IgG antibody tended to increase with age (P<0.05). The positive rate of VZV-IgG antibody in the urban population was significantly higher than that in the rural population (P<0.05). There was significant difference in the positive rate of VZV-IgG antibody between the populations with different doses of varicella vaccination (P<0.05), and the population with 2 doses of vaccination had the highest positive rate of VZV-IgG antibody. There was a significant difference in the concentration of VZV-IgG antibody between the populations with different medical histories (P<0.05), and the population with a past history of varicella had the highest concentration. CONCLUSIONS: Among the healthy population aged 1-19 years in Harbin, there is a significant difference in the level of VZV-IgG antibody between the urban and rural populations, as well as between different age groups. Varicella vaccination should be strengthened in areas with a low vaccination rate and the population aged <14 years.

A rubella outbreak investigation and BRD-II strain rubella vaccine effectiveness study, Harbin city, Heilongjiang province, China, 2010-2011.

BACKGROUND: In the 1990s, China introduced rubella vaccine into the private market using BRD-II virus strain, which is different than the globally used RA27/3 strain. In 2007, BRD-II rubella containing vaccine was introduced into the national immunization program and recommended for routine use. However, to our knowledge, there are no field vaccine effectiveness (VE) studies of BRD-II rubella vaccine. In April 2011, a rubella outbreak was detected in two daycare centers in Harbin city, China. We conducted an investigation to determine VE of BRD-II rubella vaccine. METHODS: Rubella cases were either laboratory-confirmed or epidemiologically linked to laboratory-confirmed cases. We collected demographic characteristics, migrant status, and history of rubella and measles vaccination from all children in the two daycare centers. RESULTS: The first case of rubella was on 22 November, 2010. Among the 143 children in the two daycare centers, 22 acquired rubella, for an overall attack rate (AR) of 15.4% (22/143). The AR in higher-grade classes (21.7%) was higher than in lower grade classes (3.9%). The AR among migrant children (47.8%) was higher than among local children (9.2%). Rubella vaccine coverage was 17% (24/143), while measles vaccine coverage was 100%. The AR among rubella-vaccinated children was 0% (0/24), and the AR among rubella-unvaccinated children was 18.5% (22/119), for a VE of 100% (P value=0.025, 95% CI: 35-100%). Rubella vaccine coverage among children born before 2007 was 10.2% (10/98), and was lower than that for children born in 2007 or after (31.1% (14/45), RR=0.33, 95%CI: 0.16-0.68). Emergency vaccination was conducted on 11 and 12 April 2011, and the outbreak stopped in one week later. CONCLUSIONS: Domestic BRD-II strain rubella vaccine showed high vaccine effectiveness against rubella. Rubella vaccine coverage through routine immunization was insufficient. Consideration should be given for measuring rubella vaccine coverage to determine the need for catch-up vaccination in China.