Differential impacts of nonsteroidal anti-inflammatory drugs on lifespan and healthspan in aged Caenorhabditis elegans.

Aging and age-related diseases are intricately associated with oxidative stress and inflammation. Nonsteroidal anti-inflammatory drugs (NSAIDs) have shown their promise in mitigating age-related conditions and potentially extending lifespan in various model organisms. However, the efficacy of NSAIDs in older individuals may be influenced by age-related changes in drug metabolism and tolerance, which could result in age-dependent toxicities. This study aimed to evaluate the potential risks of toxicities associated with commonly used NSAIDs (aspirin, ibuprofen, acetaminophen, and indomethacin) on lifespan, healthspan, and oxidative stress levels in both young and old Caenorhabditis elegans. The results revealed that aspirin and ibuprofen were able to extend lifespan in both young and old worms by suppressing ROS generation and enhancing the expression of antioxidant SOD genes. In contrast, acetaminophen and indomeacin accelerated aging process in old worms, leading to oxidative stress damage and reduced resistance to heat stress through the pmk-1/skn-1 pathway. Notably, the harmful effects of acetaminophen and indomeacin were mitigated when pmk-1 was knocked out in the pmk-1(km25) strain. These results underscore the potential lack of benefit from acetaminophen and indomeacin in elderly individuals due to their increased susceptibility to toxicity. Further research is essential to elucidate the underlying mechanisms driving these age-dependent responses and to evaluate the potential risks associated with NSAID use in the elderly population.

Inflammation in Metal-Induced Neurological Disorders and Neurodegenerative Diseases.

Essential metals play critical roles in maintaining human health as they participate in various physiological activities. Nonetheless, both excessive accumulation and deficiency of these metals may result in neurotoxicity secondary to neuroinflammation and the activation of microglia and astrocytes. Activation of these cells can promote the release of pro-inflammatory cytokines. It is well known that neuroinflammation plays a critical role in metal-induced neurotoxicity as well as the development of neurological disorders, such as Alzheimer's disease (AD), Parkinson's disease (PD), and multiple sclerosis (MS). Initially seen as a defense mechanism, persistent inflammatory responses are now considered harmful. Astrocytes and microglia are key regulators of neuroinflammation in the central nervous system, and their excessive activation may induce sustained neuroinflammation. Therefore, in this review, we aim to emphasize the important role and molecular mechanisms underlying metal-induced neurotoxicity. Our objective is to raise the awareness on metal-induced neuroinflammation in neurological disorders. However, it is not only just neuroinflammation that different metals could induce; they can also cause harm to the nervous system through oxidative stress, apoptosis, and autophagy, to name a few. The primary pathophysiological mechanism by which these metals induce neurological disorders remains to be determined. In addition, given the various pathways through which individuals are exposed to metals, it is necessary to also consider the effects of co-exposure to multiple metals on neurological disorders.

Response of cholangiocarcinoma with epigastric metastasis to lenvatinib plus sintilimab: A case report and review of literature.

BACKGROUND: Cholangiocarcinoma (CCA) poses a significant clinical challenge due to its low radical resection rate and a propensity for high postoperative recurrence, resulting in a poor dismal. Although the combination of targeted therapy and immunotherapy has demonstrated notable efficacy in several solid tumors recently, however, its application in CCA remains underexplored and poorly documented. CASE SUMMARY: This case report describes a patient diagnosed with stage IV CCA, accompanied by liver and abdominal wall metastases, who underwent palliative surgery. Subsequently, the patient received two cycles of treatment combining lenvatinib with sintilimab, which resulted in a reduction in abdominal wall metastasis, while intrahepatic metastasis displayed progression. This unexpected observation illustrates different responses of intrahepatic and extrahepatic metastases to the same therapy. CONCLUSION: Lenvatinib combined with sintilimab shows promise as a potential treatment strategy for advanced CCA. Genetic testing for related driver and/or passenger mutations, as well as an analysis of tumor immune microenvironment analysis, is crucial for optimizing drug combinations and eventually addressing the issue of non-response in specific metastatic sites.

Signal Transduction Associated with Mn-induced Neurological Dysfunction.

Manganese (Mn) is a heavy metal that occurs widely in nature and has a vital physiological role in growth and development. However, excessive exposure to Mn can cause neurological damage, especially cognitive dysfunction, such as learning disability and memory loss. Numerous studies on the mechanisms of Mn-induced nervous system damage found that this metal targets a variety of metabolic pathways, for example, endoplasmic reticulum stress, apoptosis, neuroinflammation, cellular signaling pathway changes, and neurotransmitter metabolism interference. This article reviews the latest research progress on multiple signaling pathways related to Mn-induced neurological dysfunction.

A comparison of pulsed radiofrequency and radiofrequency denervation for lumbar facet joint pain.

BACKGROUND: Lumbar facet joint pain is a common disorder. The main symptom is chronic lumbar pain, which can reduce quality of life. Radiofrequency has often been used to treat lumbar facet joint pain. However, the effectiveness of this technique has been controversial. This study was conducted to compare the effectiveness of pulsed radiofrequency (PRF) and radiofrequency denervation (RD) for lumbar facet joint pain. METHODS: One hundred and forty-two patients with lumbar facet joint pain were allocated to two treatment groups: PRF group (N = 72) and RD group (N = 70). Patients enrolled in the study were assessed using a visual analogue scale (VAS), Roland-Morris questionnaire (RMQ), Oswestry disability index (ODI) and Short-Form 36 (SF-36) questionnaire before therapy, 3 months and 12 months later. RESULTS: There were no significant differences in VAS, RMQ score, ODI score and SF-36 score at 3 months (p > 0.05). Significant differences in pain control were observed in both groups at 12 months (3.09 ± 1.72 vs. 2.37 ± 1.22, p = 0.006). There was a significant difference in RMQ score (11.58 ± 3.58 vs. 8.17 ± 2.34, p < 0.001) and ODI score (43.65 ± 11.01 vs. 35.42 ± 11.32, p < 0.001) at 12 months. The total SF-36 score was higher in the RD group than in the PRF group at 12 months (58.45 ± 6.97 vs. 69.36 ± 6.43, p < 0.001). In terms of complications, skin numbness occurred in three patients. Mild pain such as burning and pinking at the puncture site in two patients. One patient experienced a decrease in back muscle strength and back muscle fatigue. These complications disappeared in 3 weeks without any treatment. There were no serious adverse events in the PRF group. CONCLUSION: Radiofrequency is an effective and safe treatment option for patients with lumbar facet joint pain. RD could provide good and lasting pain relief, with significant improvement in lumbar function and quality of life at long-term follow-up.

Comparison of two distinct needle tip positions in pulsed radiofrequency for herpes zoster-related pain.

BACKGROUND: Herpes zoster (HZ)-related pain, characterized by chronic and persistent pain with a dermatomal distribution, is a relatively common complication of HZ. Pulsed radiofrequency (PRF) can effectively relieve HZ-related pain. There is no study on the effect of the needle tip position in patients with HZ for PRF treatment. This prospective study was conducted to compare two distinct needle tip positions in PRF for HZ-related pain. METHODS: Seventy-one patients suffering from HZ-related pain were enrolled in this study. According to the dorsal root ganglion (DRG) position and needle tip position, patients were randomly allocated to the IP group (group inside of the pedicle, n = 36) and OP group (group outside of the pedicle, n = 35). Quality of life and pain control were evaluated with the visual analog scale (VAS) and activities of daily living questionnaires (including 7 items: general activity, mood, walking ability, normal work, relations with other people, sleep, and enjoyment of life), which were administered before therapy and at intervals of 1, 7, 30, and 90 days after therapy. RESULTS: Before therapy, the mean pain score was found to be 6.03 ± 0.45 in the IP group and 6.00 ± 0.65 in the OP group (p = 0.555). No significant differences were found when the two groups were compared at 1 and 7 days after therapy (p > 0.05). But, the pain score was significantly lower in the IP group at 30 days (1.78 ± 1.31 vs. 2.77 ± 1.31, p = 0.006) and 90 days of follow-up (1.29 ± 1.19 vs. 2.15 ± 1.74, p = 0.041). Significant differences between the two groups in terms of general activity (2.39 ± 0.87 vs. 2.86 ± 0.77, p = 0.035), mood (1.97 ± 1.65 vs. 2.86 ± 1.50, p = 0.021), relations with other people (1.94 ± 0.92 vs. 2.51 ± 1.22, p = 0.037), sleep (1.64 ± 1.44 vs. 2.97 ± 1.44, p < 0.001), and enjoyment of life (1.58 ± 1.11 vs. 2.43 ± 1.33, p = 0.004) were detected after the 30-day follow-up. In addition, scores for the activities of daily living were significantly lower in the IP group than that in the OP group at 90 days after therapy (p < 0.05). CONCLUSION: The needle tip position had an influence on the PRF treatment in patients with HZ-related pain. Positioning the needle tip in the area between the medial and lateral edges of adjacent pedicles offered good pain relief and improved quality of life in HZ patients.

Risk factors and nomogram-based prediction of the risk of limb weakness in herpes zoster.

Background: Limb weakness is a less common complication of herpes zoster (HZ). There has been comparatively little study of limb weakness. The aim of this study is to develop a risk nomogram for limb weakness in HZ patients. Methods: Limb weakness was diagnosed using the Medical Research Council (MRC) muscle power scale. The entire cohort was assigned to a training set (from January 1, 2018 to December 30, 2019, n = 169) and a validation set (from October 1, 2020 to December 30, 2021, n = 145). The least absolute shrinkage and selection operator (LASSO) regression analysis method and multivariable logistic regression analysis were used to identify the risk factors of limb weakness. A nomogram was established based on the training set. The discriminative ability and calibration of the nomogram to predict limb weakness were tested using the receiver operating characteristic (ROC) curve, calibration plots, and decision curve analysis (DCA). A validation set was used to further assess the model by external validation. Results: Three hundred and fourteen patients with HZ of the extremities were included in the study. Three significant risk factors: age (OR = 1.058, 95% CI: 1.021-1.100, P = 0.003), VAS (OR = 2.013, 95% CI: 1.101-3.790, P = 0.024), involving C6 or C7 nerve roots (OR = 3.218, 95% CI: 1.180-9.450, P = 0.027) were selected by the LASSO regression analysis and the multivariable logistic regression analysis. The nomogram to predict limb weakness was constructed based on the three predictors. The area under the ROC was 0.751 (95% CI: 0.673-0.829) in the training set and 0.705 (95% CI: 0.619-0.791) in the validation set. The DCA indicated that using the nomogram to predict the risk of limb weakness would be more accurate when the risk threshold probability was 10-68% in the training set and 15-57% in the validation set. Conclusion: Age, VAS, and involving C6 or C7 nerve roots are potential risk factors for limb weakness in patients with HZ. Based on these three indicators, our model predicted the probability of limb weakness in patients with HZ with good accuracy.

Sodium para-aminosalicylic acid ameliorates lead-induced hippocampal neuronal apoptosis by suppressing the activation of the IP3R-Ca2+-ASK1-p38 signaling pathway.

Lead (Pb) is a naturally occurring heavy metal, which can damage the brain and affect learning and memory. Sodium para-aminosalicylic acid (PAS-Na), a non-steroidal anti-inflammatory drug, can readily cross the blood-brain barrier. Our previous studies have found that PAS-Na alleviated Pb-induced hippocampal ultrastructural damage and neurodegeneration, but the mechanism has yet to be defined. Here, we investigated the molecular mechanisms that mediate Pb-induced apoptosis in hippocampal neurons, and the efficacy of PAS-Na in alleviating its effects. This work showed that juvenile developmental Pb exposure impaired rats cognitive ability by inducing apoptotic cell death in hippocampal neurons. Pb-induced neuronal apoptosis was accompanied by increased inositol 1,4,5-trisphosphate receptor (IP3R) expression and enhanced intracellular calcium [Ca2+]i levels, which resulted in increased phosphorylation of neuronal apoptosis signal-regulating kinase 1 (ASK1) and p38. Activation of ASK1 and p38 was blocked by IP3R inhibitor and a Ca2+ chelator. Importantly, PAS-Na treatment improved the Pb-induced effects on cognitive deficits in rats, concomitant with rescued neuronal apoptosis. In addition, PAS-Na reduced the expression of IP3R and the ensuing increase in intracellular Ca2+ and decreased the phosphorylation of ASK1 and p38 in Pb-exposed neurons. Taken together, this study demonstrates that the IP3R-Ca2+-ASK1-p38 signaling pathway mediates Pb-induced apoptosis in hippocampal neurons, and that PAS-Na, at a specific dose-range, ameliorates these changes. Collectively, this study sheds novel light on the cellular mechanisms that mediate PAS-Na efficacy, laying the groundwork for future research to examine the treatment potential of PAS-Na upon Pb poisoning.

The Therapeutic Efficacy of Pulsed Radiofrequency Alone Versus a Dexamethasone and Pulsed Radiofrequency Combination in Patients With Trigeminal Postherpetic Neuralgia: A Double-blind, Randomized Controlled Trial.

BACKGROUND: Pulsed radiofrequency (PRF) of the Gasserian ganglion is a common surgical intervention used to treat trigeminal postherpetic neuralgia (PHN). Dexamethasone has been reported to possess anti-inflammatory effects and potential analgesic benefits. OBJECTIVES: The primary objective of our study was to compare the therapeutic efficacies of PRF alone versus a combination of PRF and dexamethasone for trigeminal PHN. STUDY DESIGN: A prospective, double-blind, randomized controlled trial. SETTING: Department of Pain Management, Wuhan First Hospital. METHODS: A total of 103 patients diagnosed with trigeminal PHN were randomly assigned into 2 groups (the PRF group and PRF plus dexamethasone [PRF+D] group). Digital subtraction angiography-guided puncture of the Gasserian ganglion was performed. All patients received PRF of the Gasserian ganglion first, and then a local injection was administered into the Gasserian ganglion. Patients in the PRF+D group received PRF therapy and one mL of 5 mg dexamethasone in the Gasserian ganglion, while patients in the PRF group received PRF therapy and one mL of normal saline in the Gasserian ganglion. The primary outcome was pain intensity, measured by the visual analog scale (VAS). The secondary outcome was quality of life, assessed by the Short Form-36 questionnaire (SF-36). The dosage of pregabalin administered was recorded to assess treatment effectiveness. RESULTS: Compared with the PRF group in this study, the PRF+D group showed more promising outcome results in pain relief as measured by the VAS; quality of life enhancement, as measured by the SF-36; and a reduced requirement for antiepileptic drugs (P < 0.01). LIMITATIONS: Single center study, relatively small number of patients. CONCLUSIONS: The therapeutic efficacy of PRF combined with a dexamethasone injection into the Gasserian ganglion was superior to that of PRF{and saline injection} alone of the Gasserian ganglion for trigeminal PHN.

Therapeutic Effects of Sodium Para-Aminosalicylic Acid on Cognitive Deficits and Activated ERK1/2-p90RSK/NF-κB Inflammatory Pathway in Pb-Exposed Rats.

Lead (Pb) is a toxic heavy metal and environmental pollutant that adversely affects the nervous system. However, effective therapeutic drugs for Pb-induced neurotoxicity have yet to be developed. In the present study, we investigated the ameliorative effect of sodium para-aminosalicylic acid (PAS-Na) on Pb-induced neurotoxicity. Male Sprague-Dawley rats were treated with (CH3COO)2 Pb•4H2O (6 mg/kg) for 4 weeks, followed by 3 weeks of PAS-Na (100, 200, and 300 mg/kg). The results showed that subacute Pb exposure significantly decreased rats body-weight gains and increased liver coefficient, and impaired spatial learning and memory. HE staining showed that Pb damaged the structure of the hippocampus. Moreover, Pb activated the ERK1/2-p90RSK/ NF-κB pathway concomitant with increased inflammatory cytokine IL-1ß levels in rat hippocampus. PAS-Na reversed the Pb-induced increase in the liver coefficient as well as the learning and memory deficits. In addition, PAS-Na reduced the phosphorylation of ERK1/2, p90RSK and NF-κB p65, decreasing IL-1ß levels in hippocampus. Our findings indicated that PAS-Na showed efficacy in reversing Pb-induced rats cognitive deficits and triggered an anti-inflammatory response. Thus, PAS-Na may be a promising therapy for treating Pb-induced neurotoxicity.

Risk Factors for Acute Kidney Injury in Critically Ill Neonates: A Systematic Review and Meta-Analysis.

Background and Objective: Acute kidney injury (AKI) is recognized as an independent risk factor for mortality and long-term poor prognosis in neonates. The objective of the study was to identify the risk factors for AKI in critically ill neonates to provide an important basis for follow-up research studies and early prevention. Methods: The PubMed, Embase, Web of Science, Cochrane Library, China National Knowledge Infrastructure, WanFang Med, SinoMed, and VIP Data were searched for studies of risk factors in critically ill neonates. Studies published from the initiation of the database to November 19, 2020, were included. The quality of studies was assessed by the Newcastle-Ottawa Scale and the Agency for Healthcare Research and Quality (AHRQ) checklist. The meta-analysis was conducted with Stata 15 and drafted according to the guidelines of the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) statement. Results: Seventeen studies (five cohort studies, ten case-control studies, and two cross-sectional studies) were included in meta-analysis, with 1,627 cases in the case group and 5,220 cases in the control group. The incidence of AKI fluctuated from 8.4 to 63.3%. Fifteen risk factors were included, nine of which were significantly associated with an increased risk of AKI in critically ill neonates: gestational age [standardized mean difference (SMD) = -0.31, 95%CI = (-0.51, -0.12), P = 0.002], birthweight [SMD = -0.37, 95%CI = (-0.67, -0.07), P = 0.015], 1-min Apgar score [SMD = -0.61, 95%CI = (-0.78, -0.43), P = 0.000], 5-min Apgar score [SMD = -0.71, 95%CI = (-1.00, -0.41), P = 0.000], congenital heart disease (CHD) [odds ratio (OR) = 2.94, 95%CI = (2.08, 4.15), P = 0.000], hyperbilirubinemia [OR = 2.26, 95%CI = (1.40, 3.65), P = 0.001], necrotizing enterocolitis (NEC) [OR = 6.32, 95%CI = (2.98, 13.42), P = 0.000], sepsis [OR = 2.21, 95%CI = (1.25, 3.89), P = 0.006], and mechanical ventilation [OR = 2.37, 95%CI = (1.50, 3.75), P = 0.000]. Six of them were not significantly associated with AKI in critically ill neonates: age [SMD = -0.25, 95%CI = (-0.54, 0.04), P = 0.095], male sex [OR = 1.10, 95%CI =(0.97, 1.24), P = 0.147], prematurity [OR = 0.90, 95%CI(0.52, 1.56), P = 0.716], cesarean section [OR = 1.52, 95%CI(0.77, 3.01), P = 0.234], prenatal hemorrhage [OR = 1.41, 95%CI = (0.86, 2.33), P = 0.171], and vancomycin [OR = 1.16, 95%CI = (0.71, 1.89), P = 0.555]. Conclusions: This meta-analysis provides a preliminary exploration of risk factors in critically ill neonatal AKI, which may be useful for the prediction of AKI. Systematic Review Registration: PROSPERO (CRD42020188032).

Complications of thoracoscopic talc insufflation for the treatment of malignant pleural effusions: a meta-analysis.

BACKGROUND: Talc pleurodesis is an effective treatment for malignant pleural effusions (MPEs). This study was designed to estimate complication rates of thoracoscopic talc insufflation. METHODS: Literature search was conducted in electronic databases and studies were selected if they reported complication rates of thoracoscopic talc insufflation in cancer patients with MPEs. Meta-analyses of proportions were performed to obtain incidence rates of complications. RESULTS: Twenty-six studies (4482 patients; age 62.9 years [95% confidence interval (CI): 61.5, 64.4]; 50% [95% CI: 43, 58] females) were included. Intraoperative, perioperative, 30-day, and 90-day mortality rates were 0% [95% CI: 0, 1], 2% [95% CI: 0, 4], 7% [95% CI: 3, 13] and 21% [95% CI: 5, 43] respectively. Incidence rates [95% CI] of various complications were: pain (20% [1, 2]), fever (14% [3, 4]), dyspnea (13% [5, 6]), pneumothorax (6% [7, 8]) pneumonia (4% [0, 12]), emphysema (3% [3, 7]), prolonged air leakage (3% [0, 7]), prolonged drainage (3% [9, 10]), thromboembolism (3% [9, 11]), lung injury (2% [7, 12]), respiratory insufficiency (2% [0, 5]), re-expansion pulmonary edema (1% [0, 3]), empyema (1% [0, 2]), respiratory failure (0% [0, 1]), and acute respiratory distress syndrome (ARDS; 0% [0, 1]. CONCLUSIONS: Whereas pain and fever were the most frequent complications of thoracoscopic talc insufflation, the incidence of ARDS was low. Pneumothorax, pneumonia, emphysema, prolonged air leakage, pulmonary embolism, arrythmia, re-expansion pulmonary edema, and empyema are important complications of thoracoscopic talc insufflation.

[Point electro-cauterization versus holmium laser cauterization in the treatment of post-ejaculation hematuria].

OBJECTIVE: To investigate the advantages and disadvantages of point electro-cauterization (PEC) and holmium laser cauterization (HLC) in the treatment of post-ejaculation hematuria. METHODS: From January 2015 to December 2018, 73 patients with post-ejaculation hematuria, aged 24－63 (36.8 ± 4.2) years, underwent PEC (n = 35) or HLC (n = 38) after failure to respond to 3 months of conservative treatment. We compared the hospital days, total hospitalization expenses, maximum urinary flow rate (Qmax), average urinary flow rate (Qavg), Hamilton Anxiety Rating Scale (HAMA) score, postoperative duration of hematuria, and recurrence rate at 3 and 6 months after surgery. RESULTS: All the patients experienced first ejaculation but no post-ejaculation hematuria at 1 month after operation. The recurrence rates were lower in the PEC than in the HLC group at 3 months (5.71% vs 2.63%, P > 0.05) and 6 months postoperatively (8.57% vs 5.26%, P > 0.05). Compared with the baseline, the Qmax was decreased from (18.56 ± 2.53) ml/s to (13.68 ± 3.31) ml/s (P < 0.05) and the Qavg from (14.35 ± 2.26) ml/s to (9.69±1.84) ml/s in the PEC group at 1 month after surgery (P < 0.01), but neither showed any statistically significant difference in the HLC group. Mild to moderate anxiety was prevalent in the patients preoperatively, particularly in those without job or regular income and those with a long disease course or frequent onset, the severity of which was not correlated with age, education or marital status. The HAMA score was decreased from18.65 ± 4.33 before to 12.35 ± 3.63 after surgery in the PEC group (P < 0.01), and from 16.88 ± 2.11 to 6.87 ± 4.36 in the HLC group (P < 0.01). The mean hospital stay was significantly longer in the former than in the latter group (ï¼»5.2 + 1.3ï¼½ vs ï¼»3.4 ± 0.5ï¼½ d, P < 0.01), while the total cost markedly lower (ï¼»6.35 ± 1.20ï¼½ vs ï¼»12.72 ± 2.15ï¼½ thousand RMB ¥, P < 0.05). CONCLUSIONS: Both PEC and HLC are safe and effective for the treatment of post-ejaculation hematuria, with no significant difference in the recurrence rate at 3 and 6 months after operation, but their long-term effect needs further follow-up studies. PEC may increase the risk of negative outcomes of the postoperative urinary flow rate, while HLC has the advantages of better relieving the patient's anxiety, sooner discharge from hospital and earlier recovery from postoperative hematuria, though with a higher total cost than the former.

Lumbar sympathetic pulsed radiofrequency combined with continuous epidural infusion for treatment of painful diabetic neuropathy: A report of two cases and a literature review.

Diabetic neuropathy (DN), one of the most common late complications of diabetes mellitus, significantly affects distinct regions of the nervous system. Pain management is challenging in DN as no effective therapies exist that reverse the pathological course of DN. Several drugs are recommended as the first-line treatment for painful DN, but these are associated with various side-effects in the long term. This report presents two cases with painful DN who underwent lumbar sympathetic pulsed radiofrequency combined with continuous epidural infusion. The two cases were followed for 30 days. Lumbar sympathetic pulsed radiofrequency combined with continuous epidural infusion offered effective pain relief and improved the health-related quality of life in two patients with DN over this time period.

The role of iron in Parkinson's disease monkeys assessed by susceptibility weighted imaging and inductively coupled plasma mass spectrometry.

Mounting evidences indicated that elevated iron levels in the substantia nigra (SN) have been concerned as the underlying mechanisms of neurodegenerative diseases, including Parkinson's disease (PD). The present study used the 1-Methyl-4-phenyl-1, 2, 3, 6 -tetrahydropyridine (MPTP)-treated cynomolgus monkeys for PD to evaluate the usability of SWI for assessing iron deposition in the cerebral nuclei of PD. The results showed that susceptibility-weighted imaging (SWI) phase values of the ipsilateral (MPTP-lesion side) SN of MPTP-treated monkeys were lower than those in the contralateral SN of MPTP-treated monkeys and the same side of Control monkeys, suggesting that iron deposition were elevated in the affected side SN of MPTP-treated monkeys. Whereas MPTP has not effects on the SWI phase values in other detected brain regions of monkeys, including red nucleus (RN), putamen (PUT) and caudate nucleus (CA). Furthermore, ICP-MS results showed that MPTP increased the iron levels in MPTP injection side, but no in the ipsilateral striatum. Additionally, MPTP treatment did not affect the calcium and manganese levels in the detected brain regions of monkeys. However, Pearson correlation analysis results indicated that there were not relationship between SWI phase values in MPTP-lesion side of SN with the behavioral score, tyrosine hydroxylase (TH)-positive cells number and iron levels in the MPTP-lesion side of midbrain. Taken together, the results confirm the involvement of SN iron accumulations in the MPTP-treated monkey models for PD, and indirectly verify the usability of SWI for the measurement of iron deposition in the cerebral nuclei of PD.

Sodium Para-aminosalicylic Acid Reverses Changes of Glutamate Turnover in Manganese-Exposed Rats.

Sodium para-aminosalicylic acid (PAS-Na) has been used to treat patients with manganism, a neurological disease caused by manganese (Mn) toxicity, although the exact molecular mechanisms are yet unclear. The present study aims to investigate the effect of PAS-Na on glutamate (Glu) turnover of Mn-exposed rats. The results showed that Mn concentrations in the hippocampus, thalamus, striatum, and globus pallidus were increased in Mn-exposed rats. Moreover, the results also demonstrated that subacute Mn exposure (15 mg/kg for 4 weeks) interrupted the homeostasis of Glu by increasing Glu levels but decreasing glutamine (Gln) levels in the hippocampus, thalamus, striatum, and globus pallidus in male Sprague-Dawley rats. These effects lasted even after Mn exposure had been ceased for a period of 6 weeks. Meanwhile the main Glu turnover enzymes [Gln synthetase (GS) and phosphate-activated glutaminase (PAG)] and transporters [Glu/aspartate transporter (GLAST) and Glu transporter-1 (GLT-1)] were also affected by Mn treatment. Additionally, PAS-Na treatment recovered the aforementioned changes induced by Mn. Taken together, these results indicate that Glu turnover might be involved in Mn-induced neurotoxicity. PAS-Na treatment could promote Mn excretions and recover the changes in Glu turnover induced by Mn, and a prolonged PAS-Na treatment may be more effective.

Triclosan induces PC12 cells injury is accompanied by inhibition of AKT/mTOR and activation of p38 pathway.

Triclosan (TCS) has been widely used as a disinfectant and antiseptic in multiple consumer and healthcare products due to its clinical effectiveness against various bacteria, fungi and protozoa. Recently, several studies have reported the adverse effects of TCS on various nerve cells, arousing concerns about its potential neurotoxicity. The present study aimed to investigate the neurotoxicity of TCS in rat pheochromocytoma PC12 cells. After differentiation, the stabilized PC12 cells were treated with 1, 10, 50 µM TCS for 12 h. At the end of the treatment, the generation of reactive oxygen species (ROS), protein expression of apoptotic-related genes, AMPK-AKT/mTOR, as well as p38 in PC12 cells were determined. The concentrations were chosen based on the results of cell viability and lactic dehydrogenase (LDH) assays in response to TCS treatment (ranging from 0.001 to 100 µM) for varied time periods. The results showed that TCS is cytotoxic to PC12 cells, causing decreased cell viability accompanied by increased LDH release. TCS treatment at 10 and 50 µM for 12 h increased the mRNA and protein expression of the pro-apoptotic gene Bax, while Bcl-2 levels remained unchanged. Moreover, an increase in the generation of reactive oxygen species (ROS) was found in TCS-treated PC12 cells at the concentrations of 1 and 10 µM. Pretreatment with 100 µM N-acetyl cysteine (NAC- ROS scavenger) for 1 h normalized the ROS generations in TCS-treated PC12 cells. Additionally, the suppression of the phosphorylation of Akt and mTOR was observed in TCS-treated PC12 cells at 10 and 50 µM for 12 h, concomitant with the activation of p38 MAPK pathway at 50 µM TCS. However, there were no effects of TCS on the phosphorylation of AMPK in these cells. Taken together, these results suggest that TCS may cause adverse effects and oxidative stress in PC12 cells accompanied by inhibition of Akt/mTOR and activation of p38.

PLGA scaffold carrying icariin to inhibit the progression of osteoarthritis in rabbits.

Icariin, the main effective component extracted from epimedium, has been shown to stimulate osteogenic differentiation and bone formation and to increase synthesis of the cartilage extracellular matrix. However, there has been little study on the effects of icariin on osteoarthritis. In this study, we loaded icariin onto poly(lactic-co-glycolic acid) (PLGA) electrospinning. The aim of this study was to explore a composite scaffold and to inhibit the progression of osteoarthritis. Our main experimental results demonstrated that the PLGA/icariin composite spinning scaffold had higher hydrophilicity, and icariin was released slowly and steadily from the scaffold. According to the results of an MTT test, immunofluorescence staining, an alkaline phosphate activating assay and a real-time polymerase chain reaction (RT-PCR) assay, the PLGA/icariin composite scaffold had good biocompatibility. In models of osteoarthritis, the results of a RT-PCR assay indicated that the PLGA/icariin scaffold promoted the synthesis of the extracellular matrix. The results of X-ray microtomography and histological evaluation demonstrated that the PLGA/icariin scaffold maintained the functional morphology of articular cartilage and inhibited the resorption of subchondral bone trabeculae. These findings indicated that the PLGA and icariin composite scaffold has therapeutic potential for use in the treatment of osteoarthritis.

Effects of Sub-Acute Manganese Exposure on Thyroid Hormone and Glutamine (Gln)/Glutamate (Glu)-γ- Aminobutyric Acid (GABA) Cycle in Serum of Rats.

Excessive manganese (Mn) exposure may adversely affect the central nervous system, and cause an extrapyramidal disorder known as manganism. The glutamine (Gln)/glutamate (Glu)-γ-aminobutyric acid (GABA) cycle and thyroid hormone system may be involved in Mn-induced neurotoxicity. However, the effect of Mn on the Gln/Glu-GABA cycle in the serum has not been reported. Herein, the present study aimed to investigate the effects of sub-acute Mn exposure on the Gln/Glu-GABA cycle and thyroid hormones levels in the serum of rats, as well as their relationship. The results showed that sub-acute Mn exposure increased serum Mn levels with a correlation coefficient of 0.733. Furthermore, interruption of the Glu/Gln-GABA cycle in serum was found in Mn-exposed rats, as well as thyroid hormone disorder in the serum via increasing serum Glu levels, and decreasing serum Gln, GABA, triiodothyronine (T3) and thyroxine (T4) levels. Additionally, results of partial correlation showed that there was a close relationship between serum Mn levels and the detected indicators accompanied with a positive association between GABA and T3 levels, as well as Gln and T4 levels in the serum of Mn-exposed rats. Unexpectedly, there was no significant correlation between serum Glu and the serum T3 and T4 levels. In conclusion, the results demonstrated that both the Glu/Gln-GABA cycle and thyroid hormone system in the serum may play a potential role in Mn-induced neurotoxicity in rats. Thyroid hormone levels, T3 and T4, have a closer relationship with GABA and Gln levels, respectively, in the serum of rats.

Preventive impacts of PAS-Na on the slow growth and activated inflammatory responses in Mn-exposed rats.

BACKGROUND: Sodium para-aminosalicylic acid (PAS-Na), an anti-tuberculosis drug, has been demonstrated its function in facilitating the Mn elimination in manganism patients and Mn-exposed models in vivo and improving the symptoms of Mn poisoning. But whether it can improve the growth retardation and inflammatory responses induced by Mn have not been reported. OBJECTIVES: This study was designed to investigate the preventive effects of PAS-Na on the development of retardation and inflammatory responses in Mn-exposed rats. METHODS: Male Sprague Dawley (SD) rats (8 weeks old, weighing 180 ± 20 g) were randomly divided into normal control group and Mn-exposed group in the 4 weeks experiment observation and normal control group, Mn-exposed group, PAS-Na preventive group and PAS-Na control group in the 8 weeks experiment observation. The Mn-exposed group received an intraperitoneal injection (i.p.) of 15 mg/kg MnCl2 and the normal control group i.p. physiological Saline in the same volume once a day for 4 or 8 weeks, 5 days per week. The PAS-Na preventive group i.p. 15 mg/kg MnCl2 along with back subcutaneous (s.c.) injection of 240 mg/kg PAS-Na once a day for 8 weeks, 5 days per week. PAS-Na control group received s.c. injection of 240 mg/kg PAS-Na along with i.p. injection of saline once daily. The body weight was determined once a week until the end of the experiment. The manganese contents in the blood were detected by graphite furnace atomic absorption spectrometry. The inflammatory factor levels (TNF-α, IL-1ß, IL-6, and PGE2) in the blood were detected by using enzyme-linked immunosorbent assay (Elisa) and each organ taking from rats were weighed and recorded. RESULTS: Mn exposure significantly suppressed the growth in rats and increased heart, liver, spleen and kidney coefficients as compared with the control group. The whole blood Mn level and serum levels of IL-1ß, IL-6, PGE2, and TNF-α in sub-chronic Mn-exposure group were markedly higher than those in the control group. However, preventive treatment with PAS-Na obviously reduced the whole blood Mn level, the spleen and liver coefficients of the Mn-exposed rats. And serum levels of IL-1ß and TNF-α were significantly reduced by 33.9% and 14.7% respectively in PAS-Na prevention group. CONCLUSIONS: PAS-Na could improve the growth retardation and alleviate inflammatory responses in Mn-exposed rats.