Parkinson’s disease (PD) is strongly associated with life style, especially dietary habits, which have gained attention as disease modifiers. Here, we report a fasting mimicking diet (FMD), fasting ...3 days followed by 4 days of refeeding for three 1-week cycles, which accelerated the retention of motor function and attenuated the loss of dopaminergic neurons in the substantia nigra in 1-methyl-4-phenyl-1,2,3,6-tetrathydropyridine (MPTP)-induced PD mice. Levels of brain-derived neurotrophic factor (BDNF), known to promote the survival of dopaminergic neurons, were increased in PD mice after FMD, suggesting an involvement of BDNF in FMD-mediated neuroprotection. Furthermore, FMD decreased the number of glial cells as well as the release of TNF-α and IL-1β in PD mice, showing that FMD also inhibited neuro-inflammation. 16S and 18S rRNA sequencing of fecal microbiota showed that FMD treatment modulated the shifts in gut microbiota composition, including higher abundance of
Firmicutes
,
Tenericutes
, and
Opisthokonta
and lower abundance of
Proteobacteria
at the phylum level in PD mice. Gas chromatography-mass spectrometry and liquid chromatography-mass spectrometry revealed that FMD modulated the MPTP-induced lower propionic acid and isobutyric acid, and higher butyric acid and valeric acid and other metabolites. Transplantation of fecal microbiota, from normal mice with FMD treatment to antibiotic-pretreated PD mice increased dopamine levels in the recipient PD mice, suggesting that gut microbiota contributed to the neuroprotection of FMD for PD. These findings demonstrate that FMD can be a new means of preventing and treating PD through promoting a favorable gut microbiota composition and metabolites.
The abnormal production of short chain fatty acid (SCFAs) caused by gut microbial dysbiosis plays an important role in the pathogenesis and progression of Parkinson’s disease (PD). This study sought ...to evaluate how butyrate, one of SCFAs, affect the pathology in a subacute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP) treated mouse model of PD. Sodium butyrate (NaB; 165 mg/kg/day i.g
.
, 7 days) was administrated from the day after the last MPTP injection. Interestingly, NaB significantly aggravated MPTP-induced motor dysfunction (
P
< 0.01), decreased dopamine (
P
< 0.05) and 5-HT (
P
< 0.05) levels, exacerbated declines of dopaminergic neurons (34%,
P
< 0.05) and downregulated expression of tyrosine hydroxylase (TH, 47%,
P
< 0.05), potentiated glia-mediated neuroinflammation by increasing the number of microglia (17%,
P
< 0.05) and activating astrocytes (28%,
P
< 0.01). In vitro study also confirmed that NaB could significantly exacerbate pro-inflammatory cytokines expression (IL-1β, 4.11-fold,
P
< 0.01; IL-18, 3.42-fold,
P
< 0.01 and iNOS, 2.52-fold,
P
< 0.05) and NO production (1.55-fold,
P
< 0.001) in LPS-stimulated BV2 cells. In addition, NaB upregulated the expression of pro-inflammatory cytokines (IL-6, 3.52-fold,
P
< 0.05; IL-18, 1.72-fold,
P
< 0.001) and NLRP3 (3.11-fold,
P
< 0.001) in the colon of PD mice. However, NaB had no effect on NFκB, MyD88 and TNF-α expression in PD mice. Our results indicate that NaB exacerbates MPTP-induced PD by aggravating neuroinflammation and colonic inflammation independently of the NFκB/MyD88/TNF-α signaling pathway.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Mitogen‐activated protein kinases (MPKs) play essential roles in guard cell signaling, but whether MPK cascades participate in guard cell ethylene signaling and interact with hydrogen peroxide ...(H2O2), nitric oxide (NO), and ethylene‐signaling components remain unclear. Here, we report that ethylene activated MPK3 and MPK6 in the leaves of wild‐type Arabidopsis thaliana as well as ethylene insensitive2 (ein2), ein3, nitrate reductase1 (nia1), and nia2 mutants, but this effect was impaired in ethylene response1 (etr1), nicotinamide adenine dinucleotide phosphate oxidase AtrbohF, mpk kinase1 (mkk1), and mkk3 mutants. By contrast, the constitutive triple response1 (ctr1) mutant had constitutively active MPK3 and MPK6. Yeast two‐hybrid, bimolecular fluorescence complementation, and pull‐down assays indicated that MPK3 and MPK6 physically interacted with MKK1, MKK3, and the C‐terminal region of EIN2 (EIN2 CEND). mkk1, mkk3, mpk3, and mpk6 mutants had typical levels of ethylene‐induced H2O2 generation but impaired ethylene‐induced EIN2 CEND cleavage and nuclear translocation, EIN3 protein accumulation, NO production in guard cells, and stomatal closure. These results show that the MKK1/3–MPK3/6 cascade mediates ethylene‐induced stomatal closure by functioning downstream of ETR1, CTR1, and H2O2 to interact with EIN2, thereby promoting EIN3 accumulation and EIN3‐dependent NO production in guard cells.
The MKK1/3‐MPK3/6 cascade mediates ethylene‐induced stomatal closure by functioning downstream of ETR1, CTR1, and H2O2 to interact with EIN2, thereby promoting the cleavage and nuclear localization of EIN2 CEND, leading to EIN3 accumulation and EIN3‐dependent NO production in guard cells.
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FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK
This study aimed to investigate the efficiency, safety and cost‐efficiency of blood purification (BP) in treating patients with severe‐acute pancreatitis (SAP). A literature search was conducted ...using PubMed, OVID, International Clinical Trials Register (ICTRP), and Cochrane Central Register of Controlled Trials (CENTRAL). A total of 11 prospective studies and 6 retrospective studies, which reported the mortality of 1279 SAP patients, were included for analysis. Decreased short‐term mortality and incidence rate of infection were observed in the high‐volume hemofiltration (HVHF) group, but not in patients treated with other types of BP. There was no significant difference in the incidence of multiple‐organ dysfunction (MODS), duration of hospital stay, or cost of hospitalization between the BP and non‐BP groups. The starting time point, substitution fluid flow rate, filter membrane type, hemofilter change interval, anticoagulation, and sustaining times of BP varied across studies. In conclusion, HVHF may reduce the short‐term mortality (<4 weeks), not long‐term mortality, of SAP patients by decreasing the incidence of infection, while other types of BP did not show a significant beneficial effect. Neither HVHF nor other BP patterns affect the duration of hospital stay, cost of hospitalization, or incidence of MODS in SAP patients.
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DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
Psoralen is a major component of Fructus Psoraleae that could induce liver injury. In this study, C57BL/6J mice were administered with psoralen at doses of 80 mg/kg for 3, 7 and 14 days. Blood and ...liver samples were collected for serum biochemistry and histopathology examinations, respectively. Psoralen led to liver injury with significantly increased liver weight and liver coefficient and up regulated serum ALT, AST and TG but down regulated serum TC and TP. The expression of bile acid‐associated transporters and enzymes was detected by western blot, and the results showed that psoralen significantly down‐regulates the expressions of CYP7A1, CYP27A1, BSEP and OSTα protein while up‐regulates the expressions of HMGCR and FASN, resulting in the obstacles of bile acid efflux in the liver. The contents of 24 kinds of bile acids in the liver were measured by LC–MS/MS, and the results showed that psoralen led to the accumulation of unconjugated bile acids in the liver, such as ALCA and CA, which were more severe in male mice than female mice. It was indicated that psoralen may disrupt the balance of bile acid metabolism by inhibiting the expression of the efflux transporter, which then leads to liver damage.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Coronavirus disease 2019 is a global pandemic. Studies suggest that folic acid has antiviral effects. Molecular docking shown that folic acid can act on SARS-CoV-2 Nucleocapsid Phosphoprotein ...(SARS-CoV-2 N).
To identify novel molecular therapeutic targets for SARS-CoV-2.
Traditional Chinese medicine targets and virus-related genes were identified with network pharmacology and big data analysis. Folic acid was singled out by molecular docking, and its potential target SARS-CoV-2 N was identified. Inhibition of SARS-CoV-2 N of folic acid was verified at the cellular level.
In total, 8355 drug targets were potentially involved in the inhibition of SARS-CoV-2. 113 hub genes were screened by further association analysis between targets and virus-related genes. The hub genes related compounds were analysed and folic acid was screened as a potential new drug. Moreover, molecular docking showed folic acid could target on SARS-CoV-2 N which inhibits host RNA interference (RNAi). Therefore, this study was based on RNAi to verify whether folic acid antagonises SARS-CoV-2 N. Cell-based experiments shown that RNAi decreased mCherry expression by 81.7% (p < 0.001). This effect was decreased by 8.0% in the presence of SARS-CoV-2 N, indicating that SARS-CoV-2 N inhibits RNAi. With increasing of folic acid concentration, mCherry expression decreased, indicating that folic acid antagonises the regulatory effect of SARS-CoV-2 N on host RNAi.
Folic acid may be an antagonist of SARS-CoV-2 N, but its effect on viruses unclear. In future, the mechanisms of action of folic acid against SARS-CoV-2 N should be studied.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Aggregation of α-Synuclein is central to the pathogenesis of Parkinson's disease (PD). However, these α-Synuclein inclusions are not only present in brain, but also in gut. Enteroendocrine cells ...(EECs), which are directly exposed to the gut lumen, can express α-Synuclein and directly connect to α-Synuclein-containing nerves. Dysbiosis of gut microbiota and microbial metabolite short-chain fatty acids (SCFAs) has been implicated as a driver for PD. Butyrate is an SCFA produced by the gut microbiota. Our aim was to demonstrate how α-Synuclein expression in EECs responds to butyrate stimulation. Interestingly, we found that sodium butyrate (NaB) increases α-Synuclein mRNA expression, enhances Atg5-mediated autophagy (increased LC3B-II and decreased SQSTM1 (also known as p62) expression) in murine neuroendocrine STC-1 cells. Further, α-Synuclein mRNA was decreased by the inhibition of autophagy by using inhibitor bafilomycin A1 or by silencing Atg5 with siRNA. Moreover, the PI3K/Akt/mTOR pathway was significantly inhibited and cell apoptosis was activated by NaB. Conditioned media from NaB-stimulated STC-1 cells induced inflammation in SH-SY5Y cells. Collectively, NaB causes α-Synuclein degradation by an Atg5-dependent and PI3K/Akt/mTOR-related autophagy pathway.
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•Sodium butyrate (NaB) elevates α-Synuclein mRNA expression in enteroendocrine cells.•NaB elevates α-Synuclein mRNA expression through an Atg5-dependent autophagy pathway. .•NaB modulates autophagy via inhibiting PI3K/Akt/mTOR signaling pathway. .•NaB induces cell apoptosis and increases pro-inflammatory cytokines expression. .
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Osteosarcoma (OS) is the most common primary malignant tumor of the bone affecting children and adolescents. Chemotherapy is now considered as a standard component of OS treatment, not only for ...children, but also for adults. However, chemoresistance continues to pose a challenge to therapy. Inhibition of autophagy has been demonstrated to decrease chemoresistance in OS. Moreover, microRNA‑22 (miR‑22) inhibits autophagy, leading to an improvement in the sensitivity of cisplatin (CDDP) in OS. The aim of the present study was therefore to investigate whether miR‑22 could mediate the CDDP resistance of OS cells by inhibiting autophagy via the phosphoinositide 3‑kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway. Cell proliferation assay, LC3 flow cytometry assay and monodansylcadaverine staining in MG63 cells and CDDP resistance cells (MG63/CDDP) were performed to explore to role of miR‑22 and CDDP in OS chemoresistance. Inoculation of tumor cells in an in vivo model, reverse transcription‑quantitative PCR (RT‑qPCR) assay, western blot analysis, and immunohistochemistry analysis were performed to investigate the role of miR‑22 and CDDP in the PI3K/Akt/mTOR pathway as it is affected by autophagy. The results revealed that miR‑22 inhibited the proliferation of MG63 and MG63/CDDP cells, and enhanced the anti‑proliferative ability of CDDP in vivo and in vitro. miR‑22 mediated the CDDP resistance of OS cells by inhibiting autophagy and decreasing CDDP‑induced autophagy via downregulation of the expression of PI3K, Akt, and mTOR at the mRNA level, and the expression of PI3K, phosphorylated (p)‑Akt, and p‑mTOR at the protein level. It was also convincingly demonstrated that miR‑22 mediates the CDDP resistance of OS by inhibiting autophagy via the PI3K/Akt/mTOR pathway. Furthermore, in the MG63 cells that were affected by CDDP, the role of miR‑22 was shown to be similar to that of the investigated inhibitor of PI3K (wortmannin) in terms of regulating the PI3K/Akt/mTOR pathway, and wortmannin could also promote the effect of miR‑22. Interestingly, CDDP was demonstrated to induce autophagy by inhibiting the PI3K/Akt/mTOR pathway, whereas the pathway was upregulated in the state of chemoresistance. In conclusion, downregulation of the PI3K/Akt/mTOR pathway was shown to assist in the process of preventing chemoresistance.
Recently, attention has focused on the impact of global climate change on infectious diseases. Storm flooding is an extreme weather phenomenon that not only impacts the health of the environment but ...also worsens the spread of pathogens. This poses a significant challenge to public health security. However, there is still a lack of research on how different levels of storm flooding affect susceptible enteric infectious diseases over time.
Data on enteric infectious diseases, storm flooding events, and meteorology were collected for Changsha, Hunan Province, between 2016 and 2020. The Wilcoxon Rank Sum Test was used to identify the enteric infectious diseases that are susceptible to storm flooding. Then, the lagged effects of different levels of storm flooding on susceptible enteric infectious diseases were analyzed using a distributed lag nonlinear model.
There were eleven storm flooding events in Changsha from 2016 to 2020, concentrated in June and July. 37,882 cases of enteric infectious diseases were reported. During non-flooding days, the daily incidence rates of typhoid/paratyphoid and bacillary dysentery were 0.3/100,000 and 0.1/100,000, respectively. During flooding days, the corresponding rates increased to 2.0/100,000 and 0.8/100,000, respectively. The incidence rates of both diseases showed statistically significant differences between non-flooding and flooding days. Correlation analysis shows that the best lags for typhoid/paratyphoid and bacillary dysentery relative to storm flooding events may be 1 and 3 days. The results of the distributed lag nonlinear model showed that typhoid/paratyphoid had the highest cumulative RR values of 2.86 (95% CI: 1.71-4.76) and 8.16 (95% CI: 2.93-22.67) after 4 days of general flooding and heavy flooding, respectively; and bacillary dysentery had the highest cumulative RR values of 1.82 (95% CI: 1.40-2.35) and 3.31 (95% CI: 1.97-5.55) after 5 days of general flooding and heavy flooding, respectively.
Typhoid/paratyphoid and bacillary dysentery are sensitive enteric infectious diseases related to storm flooding in Changsha. There is a lagging effect of storm flooding on the onset of typhoid/paratyphoid and bacillary dysentery, with the best lagging periods being days 1 and 3, respectively. The cumulative risk of typhoid/paratyphoid and bacillary dysentery was highest at 4/5 days lag, respectively. The higher of storm flooding, the higher the risk of disease, which suggests that the authorities should take appropriate preventive and control measures before and after storm flooding.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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