Artesunate restores mitochondrial fusion-fission dynamics and alleviates neuronal injury in Alzheimer's disease models.

Alzheimer's disease (AD) remains a leading cause of dementia and no therapy that reverses underlying neurodegeneration is available. Recent studies suggest the protective role of artemisinin, an antimalarial drug, in neurological disorders. In this study, we investigated the therapeutic potential of artesunate, a water-soluble derivative of artemisinin, on amyloid-beta (Aß)-treated challenged microglial BV-2, neuronal N2a cells, and the amyloid precursor protein/presenilin (APP/PS1) mice model. We found that Aß significantly induced multiple AD-related phenotypes, including increased expression/production of pro-inflammatory cytokines from microglial cells, enhanced cellular and mitochondrial production of reactive oxygen species, promoted mitochondrial fission, inhibited mitochondrial fusion, suppressed mitophagy or biogenesis in both cell types, stimulated apoptosis of neuronal cells, and microglia-induced killing of neurons. All these in vitro phenotypes were attenuated by artesunate. In addition, the over-expression of the mitochondrial fission protein Drp-1, or down-regulation of the mitochondrial fusion protein OPA-1 both reduced the therapeutic benefits of artesunate. Artesunate also alleviated AD phenotypes in APP/PS1 mice, reducing Aß deposition, and reversing deficits in memory and learning. Artesunate protects neuronal and microglial cells from AD pathology, both in vitro and in vivo. Maintaining mitochondrial dynamics and simultaneously targeting multiple AD pathogenic mechanisms are associated with the protective effects of artesunate. Consequently, artesunate may become a promising therapeutic for AD.

Construction of efficient enzyme systems for preparing chiral ethyl 3-hydroxy-3-phenylpropionate.

Ethyl 3-hydroxy-3-phenylpropionate (EHPP), (R)-EHPP or (S)-EHPP, is an important chiral intermediate for pharmaceuticals. Its synthesis from ethyl benzoyl acetate (EBA) by alcohol dehydrogenase is regarded as a green method. However, scarcely any alcohol dehydrogenase has been reported competent in asymmetric synthesis of chiral EHPP at high EBA loading. Present study developed two robust and efficient bio-catalysts Mu-S2 and Mu-R4 for preparation of (S)-EHPP and (R)-EHPP respectively by rational design of alcohol dehydrogenase PcSDR from Pedobacter chitinilyticus based on molecular dynamics (MD) simulation analysis. BtGDH, a glucose dehydrogenase from Bacillus toyonensis catalyzing the oxidation of glucose for cofactor regeneration, was co-expressed with the screened mutants to form enzyme systems Mu-S2-BtGDH and Mu-R4-BtGDH. After reaction condition optimization, Mu-S2-BtGDH and Mu-R4-BtGDH were efficient in the synthesis of (S)-EHPP (94% conv. and 99% e.e.) and (R)-EHPP (99% conv. and 98% e.e.) respectively in 100 mL scale under 500 mM of EBA loading in 10 h following a substrate continuous feeding mode. After purifying, the isolated yield for each EHPP enantiomer is > 93%. This work not only provides potential biocatalysts for the industrial production of (R)-EHPP and (S)-EHPP, but also enriches the constructure-function relationship of alcohol dehydrogenases.

Bilobalide alleviates neuroinflammation and promotes autophagy in Alzheimer's disease by upregulating lincRNA-p21.

EGb 761 has some protective effects on AD and can improve the cognitive functions of AD mice. However, the underlying molecular mechanisms are unknown. Here, we investigated the function of bilobalide, the effective component of EGb 761, in neuroinflammation and autophagy during AD. LPS-treated BV-2 cells were used as an in vitro model for neuroinflammation. The APP/PS1 AD mouse line was used to examine the function of bilobalide in AD. ELISA and qRT-PCR were used to measure the levels of proinflammatory cytokines, including TNF-α, IL-6 and IL-1ß. Western blotting was employed to determine the protein levels of p-p65, iNOS, COX-2, LC3, beclin-1, p62 and p-STAT3. Immunostaining was applied to examine the number of autophagosomes. LPS treatment induced inflammatory responses and inhibited autophagy in BV-2 cells. Bilobalide suppressed LPS-induced neuroinflammation and promoted autophagy. Furthermore, bilobalide treatment increased the lincRNA-p21 levels, which suppressed STAT3 signalling. Knockdown of lincRNA-p21 reversed the effects of bilobalide. Overexpression of lincRNA-p21 promoted autophagy and inhibited neuroinflammation as well while STAT3 inhibitor blocked the effects of si-lincRNA-p21. In vivo experiments revealed that bilobalide improved the learning and memory capabilities of APP/PS1 AD mice. Bilobalide improves the cognitive functions of APP/PS1 AD mice. Mechanistically, bilobalide suppresses inflammatory responses and promotes autophagy possibly by upregulating lincRNA-p21 levels.

The Efficacy of Percutaneous Patent Foramen Ovale Closure on Migraine: a Meta-Analysis of Randomized Controlled Trials and Observational Studies.

OBJECTIVES: Whether patent foramen ovale (PFO) closure is effective on migraine is controversial. This article was aimed at assessing the efficacy of PFO closure on migraine based on randomized controlled trials (RCTs) and observational studies. METHODS: We searched PubMed, Embase, and Cochrane databases up to October 2020 evaluating PFO closure versus control in patients with migraine, then conducted a meta-analysis of all RCTs and observational studies, respectively. The main outcomes were (1) respond rate: complete cessation of migraine; (2) reduction in the frequency of migraine attacks per month; and (3) reduction in migraine days per month. RESULTS: Seven studies (3 RCTs and 4 observational studies), containing 887 migraine patients, were identified. (1) The respond rate of PFO closure on migraine was significantly higher than control group both in RCT subgroup and observational studies subgroup (OR 3.86, 95% CI 1.35-11.04, P = 0.01 in RCTs; OR 8.28, 95% CI 2.31-29.67, P = 0.001 in observational studies). (2) Reduction in frequency of migraine attacks was higher in PFO closure group compared with control group in the RCT subgroup analysis (mean difference (MD) = 0.57, 95% CI 0.23-0.90, P = 0.0009). (3) Reduction in migraine days was also higher in PFO closure group compared with control group in the RCT subgroup analysis (MD = 1.33, 95% CI 0.35-2.31, P = 0.008). CONCLUSIONS: PFO closure might be suitable for migraine patients, especially for migraine with aura, by cessation of migraine headaches or reducing migraine attacks and migraine days.

The role of oxygen in cluster headache.

High-flow oxygen inhalation is one of the most effective acute treatments for cluster headache. The therapy was first described for the treatment of cluster headache in 1952 by Horton, and has exhibited some advantages and efficacy compared to other acute medicines. The mechanism is not very clear, but some evidence has demonstrated its relationship to the trigeminovascular system and neuroinflammation. High-flow oxygen inhalation via a non-rebreather mask during cluster headache attacks has been widely recommended. Patients with frequent attacks and/or intolerance to drugs may prefer the oxygen treatment.

A new central post-stroke pain rat model: autologous blood injected thalamic hemorrhage involved increased expression of P2X4 receptor.

Stroke is the leading cause of disability and death in the world. Central post-stroke pain (CPSP), a central neuropathic pain syndrome occurring after cerebral stroke, is a serious problem. But on account of the lack of reliable animal models, the mechanisms underlying CPSP remains poorly understood. To better understand of the pathophysiological basis of CPSP, we developed and characterized a new rat model of CPSP. This model is based on a hemorrhagic stroke lesion with intra-thalamic autologous blood (ITAB) injection in the ventral posterolateral nucleus of the thalamus. Behavioral analysis demonstrated that the animals displayed a significant decrease in mechanical allodynia threshold. We found a significant increase in P2 × 4 receptor expression in microglia in thalamic peri-lesion tissues post-hemorrhage. The mechanical allodynia in rats with CPSP were reversed by blocking P2 × 4 receptors. A significant alleviation of mechanical allodynia was achieved following the administration of adrenergic antidepressants and antiepileptics. Meanwhile, we found a significant decrease in P2 × 4 receptor expression after treatment with these drugs. Taken together, our results suggest that targeting P2 × 4 receptor may be effective in the treatment of CPSP.

[Comparative study on the effect of highly active antiretroviral therapy (HAART) in patients with HIV infection acquired by blood transfusion and paid plasma donation].

OBJECTIVE: To study the effect of HAART in patients with AIDS acquire by blood transfusion and paid plasma donation. METHODS: All AIDS patients whose disease was caused by blood transfusion and commercial plasma donation came from the domicile of Hebei Province. In the group of cases of blood transfusion in whom the infection was caused by one-time blood transfusion before and after 1995, there were 189 cases, of whom 105 cases on HAART were designated as observation group, and 84 cases who were not on HAART were designated as control group. The group of AIDS patients who were former commercial plasma donors (FCPDs) had 120 patients who were identified in the survey of 1995, of whom 63 cases on HAART were designated as observation group and 57 cases who were not on HAART were as control group. Onset dates were defined as the dates into the queue. Death due to AIDS was regarded as an outcome event. Subjects who were enrolled into the observation group and control group were epidemiologically followed up regularly. Observation was ended on December 31, 2010. RESULTS: Mortality of patients after HAART from groups of FCPDs and blood recipients were 4.42/100 person-years and 6.13/100 person-years, respectively. The survival rates of HAART groups were 80% in FCPDs for 110 months and 72% in blood recipients for 90 months, respectively. Meanwhile the mortality of no HAART groups were 182.05/100 person-years and 250.66/100 person-years, respectively. Mean survival of patients whose disease was caused by plasma donation and blood transfusion were 4 months and 3 months, respectively. CONCLUSIONS: Whether the HIV infection was caused by plasmapheresis or blood transfusion, the effects of HAART did not show difference. HAART cold reduce the death intensity and prolong survival.

[A retrospective cohort study on the natural history of AIDS caused by blood transfusion].

OBJECTIVE: To study the natural history of AIDS, caused by blood transfusion. METHODS: All HIV infections and AIDS patients were from Hebei province, including those infected through blood transfusion around 1995, that were identified as through general census of former commercial plasma donors (FCPDs). Among those objects being observed during the incubation period, 354 had HIV infections (including 142 cases infected via plasmapheresis and 212 cases caused by transfusion) but had not been treated by HAART before the onset of disease. Objects being observed during the survival period, 141 were AIDS patients (including 57 cases infected via plasmapheresis and 84 cases causes by transfusion) but had not been treated by HAART before and after the onset of disease. All infectors and AIDS patients were under follow-up on the progress of illness or death, respectively. RESULTS: By December 31, 2010, the cumulative incidence among HIV infections was 88.70% (314/354), with the incidence density as 9.14/100 person-years (314/3435.75) and the median incubation period was 113 months. Of 142 HIV infections in the blood donation group and 212 infections in the blood transfusion group, the incubation periods were 112 months and 115 months, respectively. All of the 141 patients died 34 months after the onset, with the death-strength as 204.70/100 person-years (141/68.88) and the period of survival was 4 months. Among those 57 FCPDs infections, they were all died 24 months after the onset, with the death-strength as 250.66/100 person-years (57/22.74) and the survival was 3 months. The other 84 infections who were blood recipients, all died 34 months after the onset, with the death-strength as 182.05/100 person-years (84/ 46.14) and the survival was 4 months. CONCLUSION: Through this study, we noticed that the natural history of all the AIDS patients was caused by blood transmission. It was important to evaluate the natural history of HIV epidemics among both FCPDs and blood recipients, occurred before and after 1995.

[Retrospective cohort study on period of incubation and survival among former commercial plasma donors infected with HIV in Hebei province].

OBJECTIVE: To examine the state of incubation period and survival time of former commercial plasma donors (FCPDs) infected with HIV. METHODS: All objects infected with HIV were from Hebei province and found from general investigation for FCPDs in 1995. The infector cohort by 142 cases was used to estimate incubation period. In the infector cohort, the time which infectors entered the cohort was their infection time, which was the middle value of the origin date, which was January 1, 1995. The onset of AIDS was defined as an outcome event. End point of observation was Dec 31, 2010. There were 192 months in all from beginning to end. The AIDS cohort by 57 cases was used to estimate the survival of the patients. In the patient cohort, the time of AIDS onset was defined as the time entering the cohort, and death of AIDS was defined as an outcome event. The cumulative incidence ratio, cumulative mortality, illness intensity and mortality intensity were analyzed through Kaplan-Meier. RESULTS: During the observation period, 123 cases of 142 infectors developed into AIDS, the cumulative incidence was 86.42% (123/142) and the intensity was 8.53/100 person-years and the median time of incubation period was 112.0 months (95%CI: 108.8 - 115.2). The death dates of 57 patients were from 1 to 24 months after onset. The cumulative mortality was 100%, and the intensity was 250.66/100 person-years and the median survival time was 3.0 months (95%CI: 1.8 - 4.2). It was estimated that the median time was 115.0 months (9.6 years) from infection to death. CONCLUSION: The median times of incubation and median survival time were 112.0 and 3.0 months, respectively.

[Retrospective cohort study on the rate of mother-to-child transmission among mothers infected with human immunodeficiency virus type 1 through blood transfusion].

OBJECTIVE: To study the rate of mother-to-child transmission (MTCT) on HIV-1. METHODS: All local residents from 8 townships in a region were screened for mothers who had a history of only one blood transfusion and 63 were found HIV-1 positive. A further study on these HIV-1 positive mothers and their children was conducted with the emphasis on the date of receiving blood transfusion, date and type of nationality, history regarding breastfeeding and so on. Sera specimens from 84 children born from 63 HIV-1 positive mothers were screened, using ELISA for HIV-1 antibody, and positive specimens were confirmed by Western-blot. RESULTS: The rate of MTCT was 32.1% (27/84) for children with all risk factors related to MTCT. Another 36.8% (7/19) were related to factors on intrauterine, intrapartum and breastfeeding, 35.7% (5/14) to intrapartum and breastfeeding factors, 14.3% (2/14) to intrauterine and intrapartum factors, 37.9% (11/29) to breastfeeding factor alone. By group combination analysis, the MTCT rate was 36.9% (24/65) with breastfeeding, 11.8% (2/17) with artificial feeding, and the former was significantly higher than the latter. CONCLUSION: HIV-1 MTCT rate among mothers caused by a single blood transfusion varied with different risk factors. Breastfeeding played an important role in MTCT, appeared in our study.

[Investigation on status of HIV-1 infection among blood recipients from 1994 to 1998 in certain areas of China].

OBJECTIVE: To study the infection status of HIV-1 among blood recipients from 1994 to 1998 in certain areas of Hebei province. METHODS: A general investigation was set up among all the people in 15 townships of certain areas from November 2003 to February 2005. An epidemiological investigation was conducted among people who had received blood from donors, during 1994 and 1998. Blood samples were collected. ELISA was used in preliminary screening and Western-blot (WB) was used among people who showed a positive result in the preliminary screening. RESULTS: The infection rate of HIV-1 after blood receipt was 15.54% (92/592), and the infected persons were all appeared in five medical centers of 6 townships which located at the west part of the area. HIV-1 infection happened over the years, and reaching the zenith in the year 1995. Most of the infected persons were young women. Procreation was the main cause of blood transfusion for women and trauma was for men. CONCLUSION: A typical HIV outbreak happened in certain areas after blood transfusion in Hebei.

[Following surveillance on HIV infection after blood transfusion].

OBJECTIVE: To study epidemiological features of HIV infection after blood transfusion and the situation of transmission among members of family. METHODS: The persons infected with HIV through blood transfusion and their intrafamilial transmission in some city were analyzed and testing methods of ELISA, Western-blot, RT-PCR and subtype analyzing were used. The whole surveillance data came from residents investigation around problem medical centres and HIV monitoring network around Hebei province. RESULTS: 173 people infected with HIV after blood transfusion in some city, including 89 cases found in hospital and 84 cases in CDC, accounted for 68.7% (173/252) of all of infected persons by blood transfusion in Hebei province. The rate of intrafamilial transmission, spousal transmission and mother-to-child transmission((MTCT) were 32.0% (49/153),17.0% (26/153) and 32.7% (32/98), respectively. Most of persons infected with HIV were youth among who the female were more than the male. Childbearing and women's ailments were the main cause of blood transfusion from 1990 to 1999, and traumatism surgery took second place. Infected persons by HIV blood, whose time to diagnostic were the year from 1999 to 2009, spread over Kangtai hospital and other hospital which accounted for 45.1% (78/173) and 42.2% (73/173), respectively. The genetype of all patients were B' subtype. CONCLUSION: The medical centers at the grass-roots level in some city resulted in outbreak of infected persons by HIV blood because of having no screening test antibody of HIV for liid blood donors.