Synthesis and preliminary biological evaluation of naproxen-probenecid conjugate for central nervous system (CNS) delivery.

Naproxen, known as the most potent non-steroid anti-inflammatory drugs, is vitally crucial in the treatment of neurodegenerative diseases. However, due to the poor brain penetration ability, it causes serious adverse effects with the therapeutic doses. Predictably, these unfavorable factors have hindered its further application. In this study, a novel brain-targeting conjugate, Nap-Pro, was designed and synthesized. The chemical stability and metabolic stability of this conjugate were determined in phosphate buffer, blood serum and brain homogenate, respectively. The cytotoxicity of Nap-Pro was evaluated in b End. 3 cells. In addition, the brain targeting capacity of Nap-Pro was also investigated in vivo. Importantly, Nap-Pro showed excellent capacity to cross the brain-blood barrier (BBB), suggesting probenecid was a super carrier that enhanced the delivery of drugs into brain. Collectively, the probenecid modification was a promising strategy to develop the novel drug delivery systems for brain targeting.

Associations of air pollution exposures in preconception and pregnancy with birth outcomes and infant neurocognitive development: analysis of the Complex Lipids in Mothers and Babies (CLIMB) prospective cohort in Chongqing, China.

OBJECTIVES: To investigate the associations of traffic-related air pollution exposures in early pregnancy with birth outcomes and infant neurocognitive development. DESIGN: Cohort study. SETTING: Eligible women attended six visits in the maternity clinics of two centres, the First Affiliated Hospital of Chongqing Medical University and Chongqing Health Centre for Women and Children. PARTICIPANTS: Women who were between 20 and 40 years of age and were at 11-14 weeks gestation with a singleton pregnancy were eligible for participation. Women were excluded if they had a history of premature delivery before 32 weeks of gestation, maternal milk allergy or aversion or severe lactose intolerance. 1273 pregnant women enrolled in 2015-2016 and 1174 live births were included in this analysis. EXPOSURES: Air pollution concentrations at their home addresses, including particulate matter with diameter ≤2.5 µm (PM2.5) and nitrogen dioxide (NO2), during pre-conception and each trimester period were estimated using land-use regression models. OUTCOME MEASURES: Birth outcomes (ie, birth weight, birth length, preterm birth, low birth weight, large for gestational age and small for gestational age (SGA) status) and neurodevelopment outcomes measured by the Chinese version of Bayley Scales of Infant Development. RESULTS: An association between SGA and per-IQR increases in NO2 was found in the first trimester (OR: 1.57, 95% CI: 1.06 to 2.32) and during the whole pregnancy (OR: 1.33, 99% CI: 1.01 to 1.75). Both PM2.5 and NO2 exposure in the 90 days prior to conception were associated with lower Psychomotor Development Index scores (ß: -6.15, 95% CI: -8.84 to -3.46; ß: -2.83, 95% CI: -4.27 to -1.39, respectively). Increased NO2 exposure was associated with an increased risk of psychomotor development delay during different trimesters of pregnancy. CONCLUSIONS: Increased exposures to NO2 during pregnancy were associated with increased risks of SGA and psychomotor development delay, while increased exposures to both PM2.5 and NO2 pre-conception were associated with adverse psychomotor development outcomes at 12 months of age. TRIAL REGISTRATION NUMBER: ChiCTR-IOR-16007700.

A study of the effect of a visual arts-based program on the scores of Jefferson Scale for Physician Empathy.

BACKGROUND: The effect of visual arts interventions on development of empathy has not been quantitatively investigated. A study was conducted on the effect of a visual arts-based program on the scores of the Jefferson Scale for Physician Empathy (JSPE). METHODS: A total of 110 clerks (n = 92) and first-year postgraduate residents (PGY1s) (n = 18) participating in the program were recruited into this study. The 4-hr program covered the subjects of learning to interpret paintings, interpreting paintings relating to medicine, illness and human suffering, the related-topics of humanitarianism and the other humanities fields and values and meaning. The JSPE was completed at the beginning (pretest) and the end (posttest) of the program. RESULTS: There was no significant difference between the pretest and posttest JSPE scores. The average of the scores for the pretest was lower in the subgroup of PGY1s than the subgroup of clerks (p = 0.0358). An increased but not significantly mean posttest JESPE score was noted for the subgroup of PGY1s. Neither the females nor the males had higher posttest JSPE scores than the pretest scores. CONCLUSIONS: Although using a structured visual arts-based program as an intervention may be useful to enhance medical students' empathy, our results failed to show a positive effect on the JSPE Scores for a group of clerks and PGY1s. This suggests that further experimental studies are needed if quantitative evaluation of the effectiveness of visual-arts based programs on empathy is to be investigated.

Antimicrobial Peptides Relieve Transportation Stress in Ragdoll Cats by Regulating the Gut Microbiota.

Transportation is common in cats and often causes stress and intestinal disorders. Antimicrobial peptides (AMPs) exhibit a broad spectrum of antibacterial activity, and they may have the capacity for antioxidant and immune regulation. The objective of this study was to investigate the effects of dietary supplementation with AMPs on stress response, gut microbiota and metabolites of cats that have undergone transport stress. A total of 14 Ragdoll cats were randomly allocated into 2 treatments: basal diet (CON) and a basal diet supplemented with 0.3% AMPs. After a 6-week feeding period, all cats were transported for 3 h and, then, fed for another week. The results show that the diarrhea rate of cats was markedly reduced by supplementation with AMPs throughout the trial period (p < 0.05). In addition, AMPs significantly reduced serum cortisol and serum amyloid A (p < 0.05) and increased apolipoprotein 1 after transportation (p < 0.05). Moreover, AMPs reduced the level of inflammatory factors in the serum caused by transportation stress, including tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1ß) (p < 0.05). The AMPs enhanced the activities of glutathione peroxidase (p < 0.01) and superoxide dismutase (p < 0.05). Furthermore, cats fed AMPs had higher levels of branched chain fatty acids (BCFAs) and a relative abundance of Blautia and a lower relative abundance of Negativibacillus after transportation (p < 0.05). The serum metabolome analysis further revealed that AMPs markedly regulated lipid metabolism by upregulating cholic acid expression. In conclusion, AMP supplementation alleviated oxidative stress and inflammatory response in transportation by regulating the gut microbiota and metabolites, thereby relieving stress-induced diarrhea and supporting gut and host health in cats.

Gallnut Tannic Acid Exerts Anti-stress Effects on Stress-Induced Inflammatory Response, Dysbiotic Gut Microbiota, and Alterations of Serum Metabolic Profile in Beagle Dogs.

Stress exposure is a potential threat to humans who live or work in extreme environments, often leading to oxidative stress, inflammatory response, intestinal dysbiosis, and metabolic disorders. Gallnut tannic acid (TA), a naturally occurring polyphenolic compound, has become a compelling source due to its favorable anti-diarrheal, anti-oxidative, anti-inflammatory, and anti-microbial activities. Thus, this study aimed to evaluate the anti-stress effects of gallnut TA on the stress-induced inflammatory response, dysbiotic gut microbiota, and alterations of serum metabolic profile using beagle models. A total of 13 beagle dogs were randomly divided into the stress (ST) and ST + TA groups. Dietary supplementation with TA at 2.5 g/kg was individually fed to each dog in the ST + TA group for 14 consecutive days. On day 7, all dogs were transported for 3 h from a stressful environment (days 1-7) to a livable site (days 8-14). In our results, TA relieved environmental stress-induced diarrheal symptoms in dogs and were shown to protect from myocardial injury and help improve immunity by serum biochemistry and hematology analysis. Also, TA inhibited the secretion of serum hormones [cortisol (COR), glucocorticoid (GC), and adrenocorticotropic hormone (ACTH)] and the expression of heat shock protein (HSP) 70 to protect dogs from stress-induced injury, thereby relieving oxidative stress and inflammatory response. Fecal 16S rRNA gene sequencing revealed that TA stimulated the growth of beneficial bacteria (Allobaculum, Dubosiella, Coriobacteriaceae_UCG-002, and Faecalibaculum) and suppressed the growth of pathogenic bacteria (Escherichia-Shigella and Streptococcus), thereby increasing fecal butyrate levels. Serum metabolomics further showed that phytosphingosine, indoleacetic acid, arachidonic acid, and biotin, related to the metabolism of sphingolipid, tryptophan, arachidonic acid, and biotin, respectively, could serve as potential biomarkers of stress exposure. Furthermore, Spearman's correlation analysis showed strong relationships between the four potential serum biomarkers and differential bacteria. Overall, gallnut TA may be a potential prebiotic for the prevention and treatment of stress-induced metabolic disorders by targeting intestinal microbiota.

Fecal microbiota and metabolomics revealed the effect of long-term consumption of gallic acid on canine lipid metabolism and gut health.

Gallic acid (GA) is a natural polyphenolic compound with many health benefits. To assess the potential risk of long-term consumption of GA to gut health, healthy dogs were fed a basal diet supplemented with GA (0%, 0.02%, 0.04%, and 0.08%) for 45 d, and fecal microbiota and metabolomics were evaluated. This study demonstrated that GA supplementation regulated serum lipid metabolism by reducing serum triglyceride, fat digestibility, and Bacteroidetes/Firmicutes ratio. In addition, the relative abundance of Parasutterella was significantly lower, and the SCFAs-producing bacteria were increased along with fecal acetate and total SCFAs contents accumulation in the 0.08% GA group. Metabolomics data further elucidated that 0.08% GA significantly affected carbohydrate metabolism by downregulating succinic acid in fece, thereby alleviating inflammation and oxidative stress. Overall, this study confirmed the beneficial effects of long-term consumption of GA on lipid metabolism and gut health, and the optimal level of GA supplementation was 0.08%.

TRPM8 contributes to liver regeneration via mitochondrial energy metabolism mediated by PGC1α.

Impairment of liver regeneration leads to severe morbidity in acute and chronic severe liver disease. Transient receptor potential melastain 8 (TRPM8) is involved in a variety of processes, including temperature sensing, ion homeostasis, and cell proliferation. However, whether TRPM8 contributes to liver regeneration is still unclear. We assessed the effect and mechanism of TRPM8 in liver regeneration and hepatocyte proliferation in vivo and in vitro. In this study, we found that TRPM8 deficiency impairs liver regeneration in mice. Mechanistically, the results revealed that mitochondrial energy metabolism was attenuated in livers from TRPM8 knockout (KO) mice. Furthermore, we found that TRPM8 contributes to the proliferation of hepatocytes via PGC1α. Taken together, this study shows that TRPM8 contributes to liver regeneration in mice after hepatectomy. Genetic approaches and pharmacological approaches to regulate TRPM8 activity may be beneficial to the promotion of liver regeneration.

Transient Receptor Potential Vanilloid-1 (TRPV1) Alleviates Hepatic Fibrosis via TGF-ß Signaling.

Hepatic fibrosis is a major global health problem and considered a leading cause of liver-related morbidity and mortality worldwide. Although previous studies have suggested that transient receptor potential vanilloid-1 (TRPV1) is protective against cardiac and renal fibrosis, its functional role in hepatic fibrosis has remained elusive. Herein, we characterize the effects of TRPV1 on carbon tetrachloride- (CCl4-) induced mice, in vitro transforming growth factor-ß- (TGF-ß-) treated hepatic stellate cells (HSCs), and human fibrosis specimens. Finally, our results demonstrated the significant TRPV1 downregulation in human liver fibrosis tissues. Knocking out TRPV1 significantly increased the expression of various hepatic fibrosis markers, while the expression of these biomarkers declined markedly in capsaicin-activated mice. Moreover, our study revealed that knocking down TRPV1 would enhance the promotive effect of TGF-ß on HSC proliferation, cell cycle, cell apoptosis, and ECM expression. Also, such promotive effect can be partially reversible by capsaicin, an exogenous activator of TRPV1. Collectively, the obtained data suggest that TRPV1 may alleviate CCl4-induced hepatic fibrosis and attenuate the effect of TGF-ß on HSC activation, proliferation, and apoptosis, which overall implies that targeting TRPV1 channel activity may be an effective therapeutic strategy for treating hepatic fibrosis.

Air pollution and pregnancy outcomes based on exposure evaluation using a land use regression model: A systematic review.

This review systematically assessed those studies investigating the association between air pollution and birth outcomes using land use regression (LUR) models for exposure assessment. Fifty-four studies were identified which were published between 2007 and 2019. Most of these were conducted in America, Spain and Canada, while only five were conducted in China. One hundred and ninety-seven LUR models were developed for different pollutants. The main pollutants that these studies assessed were NO2 and PM2.5, and the main pregnancy outcomes investigated were preterm birth (PTB), small for gestational age (SGA) and birth weight. Studies consistently found that NO2 exposure during pregnancy was associated with reduced fetal growth and development. The effect of NO2 on other adverse pregnancy outcomes is unclear. In addition, it was found that increased PM2.5 (aerodynamic equivalent diameter ≤ 2.5 um) exposure during pregnancy reduced birth weight. The effect of PM2.5 on other adverse pregnancy outcomes is also unclear. The relationship between other pollutants and adverse pregnancy outcomes is uncertain based on the existing research. Exposure assessment with LUR modeling has been widely used in Europe and North America, but used less in China. Future studies are recommended to use LUR modeling for individual exposure evaluation in China to better characterize the relationship between air pollution and adverse pregnancy outcomes. In addition, further research is required given that a lot of the associations looked at in the review were inconclusive.

Using the Metabolome to Understand the Mechanisms Linking Chronic Arsenic Exposure to Microglia Activation, and Learning and Memory Impairment.

The activation of microglia is a hallmark of neuroinflammation and contributes to various neurodegenerative diseases. Chronic inorganic arsenic exposure is associated with impaired cognitive ability and increased risk of neurodegeneration. The present study aimed to investigate whether chronic inorganic arsenic-induced learning and memory impairment was associated with microglial activation, and how organic (DMAV 600 µM, MMAV 0.1 µM) and inorganic arsenic (NaAsO2 0.6 µM) affect the microglia. Male C57BL/6J mice were divided into two groups: a control group and a group exposed to arsenic in their drinking water (50 mg/L NaAsO2 for 24 weeks). The Morris water maze was performed to analyze neuro-behavior and transmission electron microscopy was used to assess alterations in cellular ultra-structures. Hematoxylin-eosin and Nissl staining were used to observe pathological changes in the cerebral cortex and hippocampus. Flow cytometry was used to reveal the polarization of the arsenic-treated microglia phenotype and GC-MS was used to assess metabolomic differences in the in vitro microglia BV-2 cell line model derived from mice. The results showed learning and memory impairments and activation of microglia in the cerebral cortex and dentate gyrus (DG) zone of the hippocampus, in mice chronically exposed to arsenic. Flow cytometry demonstrated that BV-2 cells were activated with the treatment of different arsenic species. The GC-MS data showed three important metabolites to be at different levels according to the different arsenic species used to treat the microglia. These included tyrosine, arachidonic acid, and citric acid. Metabolite pathway analysis showed that a metabolic pathways associated with tyrosine metabolism, the dopaminergic synapse, Parkinson's disease, and the citrate cycle were differentially affected when comparing exposure to organic arsenic and inorganic arsenic. Organic arsenic MMAV was predominantly pro-inflammatory, and inorganic arsenic exposure contributed to energy metabolism disruptions in BV-2 microglia. Our findings provide novel insight into understanding the neurotoxicity mechanisms of chronic arsenic exposure and reveal the changes of the metabolome in response to exposure to different arsenic species in the microglia.

Camellia oil (Camellia oleifera Abel.) attenuates CCl4-induced liver fibrosis via suppressing hepatocyte apoptosis in mice.

Liver fibrosis is a common part of the pathological development of many chronic liver diseases. As liver fibrosis progresses, it may lead to cirrhosis, portal hypertension, liver decompensation, liver tumours, and death. Camellia oil (Camellia oleifera Abel.) is widely used as an edible oil in China. It has a wide range of biological activities and is used as a traditional medicine to treat conditions such as burns and stomach pains. However, whether camellia oil can ameliorate liver fibrosis remains unclear. We constructed a liver fibrosis model induced by carbon tetrachloride (CCl4) and then confirmed the role of camellia oil in liver fibrosis by biochemical examination, histopathological morphology, immunohistochemistry, and western blot analysis. We found that camellia oil ameliorated histopathological lesions, improved liver function and antioxidant capacity, decreased the expression of TGF-ß1 and α-SMA proteins, and downregulated the expression of the pro-apoptotic proteins in CCl4-induced liver fibrosis. Therefore, these results suggest that camellia oil attenuates CCl4-induced liver fibrosis in mice, and its mechanism may function via reduction of hepatocyte apoptosis to inhibit hepatic stellate cell (HSC) activation. Camellia oil may provide a potential new treatment for liver fibrosis as an auxiliary treatment by addition of the edible oil to the daily diet.

Beta-Bungarotoxin induction of neurite outgrowth in NB41A3 cells.

In this study, different concentrations of beta-Bgt were used to treat cultured NB41A3 cells. Inverted phase contrast microscopy was then used 24h after treatment to observe the outgrowth of neurite. We found a clear outgrowth of neurite at beta-Bgt concentrations of 357 nM. However, using a cytotoxicity assay to study apoptosis, we found no significant difference in the rate of cell death in cell cultures treated with either 357 nM or 714 nM. Western blotting showed that after treatment with beta-Bgt, there was a notable decrease in small G protein Cdc42 and a marked increase in RhoA protein. Flow cytometry revealed that beta-Bgt did not alter the calcium influx in NB41A3 cells. The neurite outgrowth induced by beta-Bgt was not affected by extracellular EGTA, suggesting that the internalization of beta-Bgt from extracellular was independent of phospholipase. Taken together, our results suggest the beta-Bgt-induced outgrowth of neurite from NB41A3 cells may be mediated by small G proteins.

Tight correlation between FoxM1 and FoxP3+ Tregs in gastric cancer and their clinical significance.

The aim of the present study was to investigate the expression of Forkhead box transcription M1 (FoxM1) and Forkhead box transcription P3 (FoxP3) in gastric cancer tissues in order to reveal any correlation between FoxM1, FoxP3 and clinicopathological parameters. Their clinical significance in gastric cancer was also investigated. Immunohistochemistry was used to detect the expression of FoxM1 and FoxP3 in gastric cancer and para-cancer tissues. The clinical significance of FoxM1 and FoxP3 in gastric cancer was explored, and the association between FoxM1 and FoxP3 was further analyzed. As a result, the overexpression of FoxM1 and FoxP3 was evident in gastric cancer (P < 0.001). FoxM1 overexpression was showed to be correlated with late AJCC stage (P = 0.025), while positive tumoral FoxP3 expression was associated with deeper invasion (P = 0.020), lymph node metastasis (P = 0.019) and later AJCC stage (P = 0.024). Overexpression of FoxM1 or FoxP3 was revealed to be negative prognostic factors for survival duration (P < 0.05), whereas only FoxM1 was shown to be independently associated with prognosisin gastric cancer after multivariate analysis (P = 0.020). A significant and positive correlation between FoxM1 and FoxP3 expressions was finally confirmed (P = 0.001). This significantly positive correlation between FoxM1 and FoxP3 prompts that FoxM1 may induce immune inhibition by recruiting FoxP3+ Tregs, leading to the progression of carcinogenesis, invasion and metastasis.

Detection of chylothorax and cervical cystic hygroma in hydrops fetalis using lymphoscintigraphy.

A 2-month-old boy was diagnosed as having nonimmune hydrops fetalis. Lymphoscintigraphy of the lower extremities revealed accumulation of radiotracer in the middle mediastinum on both sides indicating leakage of lymphatic flow from the thoracic duct at 1 hour. There was visualization of radiotracer in both lung fields suggestive of chylothorax. Radioactivity was noted accumulating in the neck consistent with the areas of cystic hygromas on the 4-hour image. Visualization of the cystic hygromas was believed to be the result of feeding of the lymphatic flow from the tributaries of the right lymphatic trunk and thoracic duct or aberrant lymphatic drainage pathways.

Incremental value of ischemic stunning on the detection of severe and extensive coronary artery disease in dipyridamole Tl-201 gated myocardial perfusion imaging.

The sensitivity of nuclear myocardial perfusion imaging in detecting coronary artery disease is high. However, false-negative results may be encountered if all the myocardial territories were uniformly affected. Ischemic stunning after dipyridamole-stress on gated SPECT may be an indicator of severe and extensive coronary artery disease, and can help the interpretation of borderline perfusion images and the elimination of false-negatives secondary to relatively balanced lesions in three-vessel disease.

Synchronous parathyroid and papillary thyroid carcinoma.

Concomitant thyroid disease is not unusual among patients with primary hyperparathyroidism. However, the simultaneous occurrence of parathyroid and thyroid carcinoma is extremely rare. We report a 38-year-old man with primary hyperparathyroidism who presented with osteitis fibrosa cystica complicated with pathologic femoral neck fracture. Preoperative investigation for exclusion of multiple endocrine neoplasia did not find evidence of medullary thyroid carcinoma or pheochromocytoma, but imaging studies revealed the presence of nodules in the right lobe and a parathyroid lesion over the left inferior pole of the thyroid gland. Total thyroidectomy, left parathyroidectomy, and bipolar hemiarthroplasty of the left hip were then performed simultaneously. The resected specimens were pathologically identified as papillary thyroid carcinoma and parathyroid carcinoma, respectively. After the operation, 131I ablation therapy was administered at a dose of 120 mCi. Additional doses of 30 mCi were given yearly as serum thyroglobulin level became elevated. Serum calcium level remained normal during yearly follow-up. Although parathyroid carcinoma is an uncommon cause of parathyroid hormone-dependent hypercalcemia, it should nonetheless be given due consideration because its surgical approach differs from that of parathyroid adenoma. As the coexistence of parathyroid and non-medullary thyroid carcinoma has previously been reported, the possibility of both malignancies must also be considered in the setting of primary hyperparathyroidism with thyroid nodules. If confirmed with preoperative parathyroid scintigraphic and other laboratory studies, an optimal outcome may be achieved with complete resection of both tumors at the time of initial operation, followed by adjunctive therapy.

Performance of thallium-201 electrocardiography-gated myocardial perfusion single photon emission computed tomography to assess left ventricular function.

This study evaluated the performance of gated single photon emission computed tomography (SPECT) with thallium-201 (201Tl) in assessing left ventricular ejection fraction (LVEF), end-diastolic volume (EDV), and end-systolic volume (ESV) in Taiwanese by determining repeatability and correlation with two-dimensional (2D) echocardiography. A total of 18 patients underwent two sequential gated SPECT acquisitions within 30 minutes in the resting state to assess repeatability. Another 28 patients who underwent gated SPECT and 2D echocardiography within 7 days were included for comparison. The two sequential measurements were well correlated with respect to LVEF, EDV, and ESV (r = 0.97, 0.95, and 0.97, respectively, all p < 0.0001). Bland-Altman analysis revealed that two standard deviations of the absolute difference between the two sequential measurements for LVEF, EDV, and ESV were 6.4%, 16.8 mL, and 8.6 mL, respectively. For LVEF, EDV, and ESV, correlations between redistribution 201Tl-gated SPECT and echocardiography were also excellent (all r = 0.83, p < 0.0001). LVEF was similar with 201Tl-gated SPECT and echocardiography, but EDV and ESV were significantly higher with echocardiography (p < 0.05). Our study revealed that 201Tl-gated SPECT has high repeatability and excellent correlation with echocardiography for the assessment of LVEF and volumes in Taiwanese. These results support the clinical application of gated SPECT in routine 201Tl myocardial perfusion imaging in Taiwanese.

Scintigraphic findings of Mycobacterium avium complex tenosynovitis of the index finger in a patient with systemic lupus erythematosus.

The presented case is a 36-year-old woman with a history of systemic lupus erythematosus for 10 years. She had progressively painful swelling of the right index finger that later proved to be a rare case of tenosynovitis caused by Mycobacterium avium complex. Serial images of 3-phase bone scans, gallium scan, and magnetic resonance imaging demonstrate the area of involvement.

Hydrophylita (Lutzimicron) emporos Shih & Polaszek (Hymenoptera: Trichogrammatidae) from Taiwan, parasitising eggs, and phoretic on adults, of the damselfly Psolodesmus mandarinus mandarinus (Zygoptera: Calopterygidae).

Hydrophylita emporos n. sp. reared from eggs of Psolodesmus mandarinus mandarinus McLachlan (Zygoptera: Calopterygidae) in Taiwan is described. This is the first species of Hydrophylita to be described from the Old World, and the first record of phoresy in the genus. Adult females were observed aggregating at the base of the female damselfly's abdomen. When the damselfly begins ovipositing, females move to the tip of the abdomen, enter the water and quickly locate eggs for parasitising. The article contains links to video footage of this process.