Near-Infrared Light and Acid/Base Dual-Regulated Polymerization Utilizing Imidazole-Anion-Fused Perylene Diimides as Photocatalysts.

This work presents the first example of acid/base-responsive and near-infrared (NIR)-absorbing photocatalysts based on imidazole-anion-fused perylene diimide chromophores. The photocatalysts were in situ generated by deprotonation of imidazole-fused perylene diimide under an alkaline environment. NIR (λ = 730 nm, 128 mW/cm2) photoinduced atom transfer radical polymerization (ATRP) was implemented, exhibiting high efficiency and excellent livingness under ppm level of photocatalysts (15 ppm relative to monomer) and Cu(II) complex (10 ppm relative to monomer) concentrations. The method showed capabilities to polymerize behind opaque barriers (i.e., paper and pig skin) and under aerobic condition. Notably, this work demonstrated a dual temporal control of polymerization by adding weak base/acid and switching NIR light on/off. The polymerization can even be halted by bubbling CO2 and was then fully recovered by adding triethylamine. The NIR photoATRP of acrylamide monomers in aqueous solution was also performed, which can be regulated by the change of pH.

Recent advances in targeting leucine-rich repeat kinase 2 as a potential strategy for the treatment of Parkinson's disease.

Parkinson's disease (PD) is the second most common neurodegenerative disease. Several single gene mutations involved in PD have been identified such as leucine-rich repeat kinase 2 (LRRK2), the most common cause of sporadic and familial PD. Its mutations have attracted much attention to therapeutically targeting this kinase. To date, many compounds including small chemical molecules with diverse scaffolds and RNA agents have been developed with significant amelioration in preclinical PD models. Currently, five candidates, DNL201, DNL151, WXWH0226, NEU-723 and BIIB094, have advanced to clinical trials for PD treatment. In this review, we describe the structure, pathogenic mutations and the mechanism of LRRK2, and summarize the development of LRRK2 inhibitors in preclinical and clinical studies, trying to provide an insight into targeting LRRK2 for PD intervention in future.

Ligustilide Prevents Radiation Enteritis by Targeting Gch1/BH4/eNOS to Improve Intestinal Ischemia.

There is a high incidence of radiation enteritis (RE) after abdominal radiotherapy. The occurrence of RE seriously affects the treatment and quality of life of patients; however, its pathogenesis is complex and there are no effective drugs for its prevention or treatment. Intestinal ischemia plays an important role in the occurrence of enteritis. Previous studies have shown that targeting GTP-cyclohydrolase 1 (Gch1) to improve intestinal ischemia could be a new strategy to prevent and treat RE. A high content of the naturally occurring phthalide derivative ligustilide (LIG) has been found in the plant drug Rhizoma Ligustici Chuanxiong for the treatment of cardiovascular diseases. The purpose of this study was to evaluate the protective effects of LIG on RE. Ionizing radiation (IR) rat and endothelial cell models were used to observe and record rat body weights and stool morphologies, measure intestinal blood perfusion by laser Doppler blood flow imaging, determine the diastolic functions of mesenteric arteries, detect the levels of Gch1/BH4/eNOS pathway-related proteins and regulatory molecules in the mesenteric arteries and endothelial cells, and predict affinity by molecular docking technology. The results showed that LIG significantly improved the body weights, loose stools, intestinal villi lengths, intestinal perfusion and vasodilatory functions of IR rats. LIG also significantly improved Gch1 protein and BH4 levels in the mesenteric arteries and endothelial cells after IR, increased the NO content, reduced superoxide accumulation, and improved p-eNOS (Ser1177) levels in endothelial cells. LIG has good affinity for Gch1, which significantly improves its activity. These results indicate that LIG is the preferred compound for the prevention and treatment of RE by improving intestinal ischemia through the Gch1/BH4/eNOS pathway. This study provides a theoretical basis and new research ideas for the development of new drugs for RE.

Psychological and occupational impact on healthcare workers and its associated factors during the COVID-19 outbreak in China.

PURPOSE: China was affected by an outbreak of coronavirus disease 2019 (COVID-19) in 2019-2020. Research data are needed to develop evidence-driven strategies to reduce the adverse psychological and occupational impacts on healthcare workers (HCWs). METHODS: From March 1, 2020, to March 8, 2020, 946 HCWs in China completed a survey consist of sociodemographic data, precautionary measures against COVID-19, and concerns about COVID-19. Self-administered questionnaire were collected to assess psychological and occupational adverse outcomes of HCWs. Multivariable logistic regression analysis was performed to identify factors associated with the outcomes. RESULTS: A total of 55.0%, 56.0% and 48.3% of the HCWs experienced burnout, psychological distress and posttraumatic stress, respectively. A total of seven factors were independently associated with burnout: good health status (OR 0.51, 95% CI 0.36-0.71), fear of contagion (OR 1.31, 95% CI 1.003-1.79), avoiding contact with children (OR 1.40, 95% CI 1.03-1.91), enough staff support at the workplace (OR 0.59, 95% CI 0.38-0.92), having to work overtime (OR 1.37, 95% CI 1.03-1.83), maladaptive coping (OR 3.28, 95% CI 2.42-4.45) and adaptive coping (OR 0.47, 95% CI 0.35-0.62). A total of 11 factors were independently associated with high psychological distress: having one child (OR 0.54, 95% CI 0.38-0.77), good health status (OR 0.57, 95% CI 0.39-0.83), alcohol abuse (OR 1.51, 95% CI 1.02-2.25), thinking the epidemic would continue for quite a long time (OR 1.59, 95% CI 1.08-2.34), wearing extra-work clothes (OR 1.51, 95% CI 1.06-2.15),effective protective equipment (OR 0.45, 95% CI 0.22-0.90), enough staff support at the workplace (OR 0.55, 95% CI 0.34-0.89), unable to take care of families (OR 1.99, 95% CI 1.42-2.78), economic losses (OR 1.62, 95% CI 1.14-2.31), maladaptive coping (OR 6.88, 95% CI 4.75-9.97),and adaptive coping (OR 0.29, 95% CI 0.21-0.41). These factors were independently associated with posttraumatic stress: living with the elderly (OR 1.46, 95% CI 1.04-2.05), alcohol abuse (OR 1.41, 95% CI 1.002-1.98), working at a 3A hospital(OR 0.66, 95% CI 0.49-0.88), acquaintances confirmed COVID-19 (OR 2.14, 95% CI 1.20-3.84), fear of contagion (OR 1.87, 95% CI 1.40-2.50), believing they would survive if infected (OR 0.63, 95% CI 0.46-0.86), self-disinfected after arriving home (OR 1.43, 95% CI 1.01-2.02), interpersonal isolation (OR 1.65, 95% CI 1.21-2.26), unable to take care of families (OR 1.41, 95% CI 1.05-1.88) and maladaptive coping (OR 3.09, 95% CI 2.32-4.11). CONCLUSION: The variance in adverse outcomes was explained by the effect of various factors, which will help policymakers better prepare for subsequent potential outbreaks of COVID-19.

Polysaccharides extracted from Rheum tanguticum ameliorate radiation-induced enteritis via activation of Nrf2/HO-1.

Radiation-induced enteritis is a major side effect in cancer patients undergoing abdominopelvic radiotherapy. The Nrf2/HO-1 pathway is a critical endogenous antioxidant stress pathway, but its precise role in radiation-induced enteritis remains to be clarified. Polysaccharides extracted from Rheum tanguticum (RTP) can protect the intestinal cells from radiation-induced damage, but the underlying mechanism is unknown. SD rats and IEC-6 cells were exposed to 12 or 10 Gy X-ray radiation. Rat survival, and histopathological and immunohistochemical profiles were analyzed at different time points. Indicators of oxidative stress and inflammatory response were also assessed. Cell viability, apoptosis and Nrf2/HO-1 expression were evaluated at multiple time points. Significant changes were observed in the physiological and biochemical indexes of rats after radiation, accompanied by significant oxidative stress response. The mRNA and protein expression of Nrf2 peaked at 12 h after irradiation, and HO-1 expression peaked at 48 h after irradiation. RTP administration reduced radiation-induced intestinal damage, upregulated Nrf2/HO-1, improved physiological indexes, significantly decreased apoptosis and inflammatory factors, and upregulated HO-1, particularly at 48 h after irradiation. In conclusion, Nrf2 is activated in the early stage of radiation-induced intestinal injury and plays a protective role. RTP significantly ameliorates radiation-induced intestinal injury via the regulation of Nrf2 and its downstream protein HO-1.

Ionizing radiation induces BH4 deficiency by downregulating GTP-cyclohydrolase 1, a novel target for preventing and treating radiation enteritis.

Radiation enteritis (RE) is a common side effect after radiotherapy for abdominal cancer. RE pathogenesis is complicated, with no drugs available for prevention or treatments. Intestinal ischemia is a key factor in the occurrence and development of enteritis. The effect of ionizing radiation (IR) on intestinal ischemia is unknown. Deficiency of tetrahydrobiopterin (BH4) produced by GTP-cyclohydrolase 1 (Gch1) is important in ischemic diseases. This study focused on the relationship of Gch1/BH4 between intestinal ischemia in radiation enteritis. BH4 levels were analyzed by high-performance liquid chromatography in humans and rats after radiotherapy. Intestinal blood perfusion was measured by laser doppler flow imaging. Vascular ring tests determined the diastolic functions of rat mesenteric arteries. Gene, protein, and immunohistochemical staining experiments and inhibitor interventions were used to investigate Gch1 and endothelial NOS (eNOS) in rat mesenteric arteries and endothelial cells. The results showed that IR decreased BH4 levels in patients and rats after radiotherapy and decreased intestinal blood perfusion in rats. The degree of change in intestinal ischemia was consistent with intestinal villus injury. Gch1 mRNA and protein levels and nitric oxide (NO) production significantly decreased, while eNOS uncoupling in arterial and vascular endothelial cells strongly increased. BH4 supplementation improved eNOS uncoupling and NO levels in vascular endothelia after IR. The results of this study showed that downregulation of Gch1 in intestinal blood vessels after IR is an important target in RE. BH4 supplementation may prevent intestinal ischemia and improve vascular endothelial function after IR. These findings have clinical significance for the prevention and treatment of RE.