Sodium oligomannate activates the enteroendocrine-vagal afferent pathways in APP/PS1 mice.

Enteroendocrine cells (EECs) and vagal afferent neurons constitute functional sensory units of the gut, which have been implicated in bottom-up modulation of brain functions. Sodium oligomannate (GV-971) has been shown to improve cognitive functions in murine models of Alzheimer's disease (AD) and recently approved for the treatment of AD patients in China. In this study, we explored whether activation of the EECs-vagal afferent pathways was involved in the therapeutic effects of GV-971. We found that an enteroendocrine cell line RIN-14B displayed spontaneous calcium oscillations due to TRPA1-mediated calcium entry; perfusion of GV-971 (50, 100 mg/L) concentration-dependently enhanced the calcium oscillations in EECs. In ex vivo murine jejunum preparation, intraluminal infusion of GV-971 (500 mg/L) significantly increased the spontaneous and distension-induced discharge rate of the vagal afferent nerves. In wild-type mice, administration of GV-971 (100 mg· kg-1 ·d-1, i.g. for 7 days) significantly elevated serum serotonin and CCK levels and increased jejunal afferent nerve activity. In 7-month-old APP/PS1 mice, administration of GV-971 for 12 weeks significantly increased jejunal afferent nerve activity and improved the cognitive deficits in behavioral tests. Sweet taste receptor inhibitor Lactisole (0.5 mM) and the TRPA1 channel blocker HC-030031 (10 µM) negated the effects of GV-971 on calcium oscillations in RIN-14B cells as well as on jejunal afferent nerve activity. In APP/PS1 mice, co-administration of Lactisole (30 mg ·kg-1 ·d-1, i.g. for 12 weeks) attenuated the effects of GV-971 on serum serotonin and CCK levels, vagal afferent firing, and cognitive behaviors. We conclude that GV-971 activates sweet taste receptors and TRPA1, either directly or indirectly, to enhance calcium entry in enteroendocrine cells, resulting in increased CCK and 5-HT release and consequent increase of vagal afferent activity. GV-971 might activate the EECs-vagal afferent pathways to modulate cognitive functions.

Dioscin ameliorates murine ulcerative colitis by regulating macrophage polarization.

Restoring immune balance by targeting macrophage polarization is a potentially valuable therapeutic strategy for ulcerative colitis (UC). Dioscin is a steroidal saponin with potent anti-inflammatory, immunoregulatory, and hypolipidemic effects. This study examined the protective effect of Dioscin on UC in mice and explored the underlying mechanisms. Mice were induced colitis by dextran sulfate sodium (DSS) and concurrently treated with Dioscin oral administration. RAW264.7 cells were skewed to M1 macrophage polarization by lipopolysaccharide (LPS) and interferon-γ (INF-γ) in vitro, and received Dioscin treatment. The results showed that Dioscin ameliorated colitis in mice, reduced macrophage M1 polarization, but markedly promoted M2 polarization in mice colon. Dioscin inhibited mammalian target rapamycin complex 1 (mTORC1)/hypoxia-inducible factor-1α (HIF-1α) signaling and restrained glycolysis in RAW264.7; however, it activated mammalian target rapamycin complex 2 (mTORC2)/peroxisome proliferator-activated receptor-γ (PPAR-γ) signal and facilitated fatty acid oxidation (FAO). The modulation of mTORs signaling may inhibit M1, but promote M2 polarization. Furthermore, the effect of Dioscin on M2 polarization was neutralized by the FAO inhibitor Etomoxir and the mTORC2 inhibitor JR-AB2-011. In parallel, the inhibitory effect of Dioscin on M1 polarization was mitigated by the mTORC1 agonist L-leucine. Both JR-AB2-011 and L-leucine blocked the therapeutic effect of Dioscin in mice with UC. Therefore, Dioscin ameliorated UC in mice, possibly by restraining M1, while skewing M2 polarization of macrophages. Regulation of mTORC1/HIF-1α and mTORC2/PPAR-γ signals is a possible mechanism by which Dioscin inhibited aerobic glycolysis and promoted FAO of macrophages. In summary, Dioscin protected mice against DSS-induced UC by regulating mTOR signaling, thereby adjusting macrophage metabolism and polarization.

Stress-related arterial hypertension in Gper-deficient rats.

Numerous studies have demonstrated that estrogens may exert multifaceted effects on the cardiovascular system via activating the classical nuclear receptors ERα or ERß and the novel G protein coupled estrogen receptor (Gper). However, some studies have reported inconsistent cardiovascular phenotypes in Gper-deficient mice. The current study was aimed to reveal the effects of genetic deletion of Gper on the arterial blood pressure (ABP) and heart rate in rats. Gper-deficient Sprague-Dawley rats were generated by utilizing the CRISPR-Cas9 gene-editing technique. ABP of 10-week old male (n = 6) and 12-week old female (n = 6) Gper-deficient rats and age-matched wild type (WT) rats (6 females and 6 males) were measured under awake and restrained conditions through the non-invasive tail-cuff method daily for 8 (females) or 9 days (males). In the male WT rats, ABP and heart rate were slightly higher in day 1 to 4 than those in day 5 to 9, indicative of stress-related sympathoexcitation in the first few days and gradual adaptation to the restrained stress in later days. Gper-deficient rats had significantly higher ABP initially (male: day 1 to day 5; female: day 1 to day 3) and similar ABP in later days of measurement compared with the WT rats. The heart rate of male Gper-deficient rats was consistently higher than that of the male WT rats from day 1 to day 8. Both male and female Gper-deficient rats appeared to show slower body weight gain than the WT counterparts during the study period. Under anesthesia, ABP of Gper-deficient rats was not significantly different from their WT counterparts. These results indicate that Gper-deficient rats may be more sensitive to stress-induced sympathoexcitation and highlight the importance of Gper in the regulation of the cardiovascular function in stressful conditions.

Epidemiological survey of elderly patients diagnosed with COVID-19 at mobile field hospitals.

BACKGROUND: During the COVID-19 pandemic, the mobile field hospital, a rapidly deployable healthcare facility for emergency care, was effective in ensuring rapid diagnosis and treatment of patients with mild or asymptomatic SARS-CoV2 infections, effectively preventing the spread of COVID-19. OBJECTIVE: We conducted a survey to gain a thorough understanding of the epidemiological traits among the elderly who contracted the Omicron variant of the SARS-CoV-2 virus at a mobile field hospital set up at the National Exhibition and Convention Center (Shanghai). METHODS: A cross-sectional study approach was employed to examine various factors such as demographic characteristics, clinical features, vaccination status, and nucleic acid testing. We utilized the DezhenTech Integrated Electronic Medical Record Platform (Municipal Isolation Hospital) to collect data and focused on elderly individuals infected with COVID-19 in the fifth isolation zone of the mobile field hospital set up at the National Exhibition and Convention Center (Shanghai). The patients were categorized into different age groups for analysis. RESULTS: Among the 3,183 elderly patients, 54.7% were males and 45.3% were females, with an average age of 65.32 ± 4.41 years. Among them, 47.8% (1523/3183) were 60-64 years old, 34.0% (1082/3183) were 65-69 years old, 14.0% (444/3183) were 70-74 years old, 3.2% (103/3183) were 75-79 years old, and 1.0% (31/3183) were ⩾ 80 years old. The majority (95.7%) of the elderly patients with chronic conditions had hypertension, diabetes, and coronary heart disease. The first viral nucleic acid screening showed a higher positive rate in the community and hospital fever clinics. The cumulative positive rate of the nucleic acid test in the mobile field hospital was 38.7%. The average CT value of the COVID-19 ORF1ab gene was 34.56 ± 5.98, while the average CT value of the N gene was 33.10 ± 6.50. The patients took an average of 3.40 ± 0.45 days to test negative, with a positive rate of 15.4% and an average hospital stay of 7.45 ± 0.53 days. The overall rate of COVID-19 vaccine coverage was 68.0%, with an enhanced coverage rate of 40% and a non-coverage rate of 29.3%. CONCLUSIONS: The overall prognosis for elderly patients who experienced a mild or asymptomatic SARS-CoV-2 Omicron infection at the mobile field hospital was favorable, although the vaccination rate in general was not high. By effectively managing underlying health conditions, the duration of their hospital stay in the mobile field hospital was reduced.

Palmatine attenuated dextran sulfate sodium (DSS)-induced colitis via promoting mitophagy-mediated NLRP3 inflammasome inactivation.

Activation of NLRP3 inflammasomes is crucial in the pathological process of Ulcerative colitis (UC), which could be negatively regulated by PINK1/Parkin-driven mitophagy. Palmatine is a herb derived isoquinoline alkaloid with potent anti-inflammatory and anti-bacteria activities. In present study, we evaluated the effect of palmatine on dextran sulfate sodium (DSS)-induced mice colitis and examined whether its effect is exerted by promoting mitophagy-mediated NLRP3 inflammasome inactivation. The result showed that palmatine (40, 100 mg/kg) significantly prevented bodyweight loss and colonic shortening in DSS mice, and reduced the disease activity index and histopathologic score. The levels of MPO, IL-1ß, TNF-α and the number of F4/80+ cells in colon of DSS mice were remarkably decreased by palmatine. Moreover, palmatine suppressed NLRP3 inflammasomes activation, but enhanced the expression of the mitophagy-related proteins involving LC3, PINK1 and Parkin in colonic tissue of DSS mice. These effects was consistent with the in vitro data revealing that palmatine inhibited the activation of NLRP3 inflammasomes, while promoted the expression and mitochondrial recruitment of PINK1 and Parkin in THP-1 cell differentiated macrophages. Furthermore, the effect of palmatine on THP-1 cells was neutralized by a mitophagy inhibitor Cyclosporin A (CsA) and PINK1-siRNA. In parallel, CsA significantly attenuated the therapeutic effect of palmatine in DSS mice, illustrating that the anti-colitis effect of palmatine is closely related to mitophagy. Taken together, the current results demonstrated that palmatine protected mice against DSS-induced colitis by facilitating PINK1/Parkin-driven mitophagy and thus inactivating NLRP3 inflammasomes in macrophage.

[Treatment of Stroke Patients with Shoulder-wrist Syndrome by Acupoint Catgut Embedding and Surface Electromyogram Biofeedback Therapy].

OBJECTIVE: To observe the clinical effectiveness of acupoint catgut embedding and surface electromyogram biofeedback therapy (sEMGBF) in the treatment of stroke patients complicated with shoulder-hand syndrome (SHS). METHODS: A total of 90 stroke patients with SHS were randomly divided into acupoint catgut embedment (ACE), sEMGBF and ACE+sEMGBF (combined treatment) groups (n=30 cases/group). The catgut embedment was performed at Jianliao (LI 14), Jianyu (LI 15), Quchi (LI 11), Waiguan (TE 5) on the affected side, once every 3 weeks, twice altogether. The electromyographic biofeedback therapy (30-50 Hz, pulse duration 200 µs, 6 s-on and 10 s-off, appropriate strength) was applied to the skin area co-vering the deltoid muscle, flexor muscle of wrist and wrist extensor for 20 min, once per day, 5 times/week, for 6 weeks. The total effective rate was assessed by using Liao's and Zhu's methods (1996), the pain severity assessed using visual analogue scale (VAS), and Fugl-Meyer assessment (FMA, 66-points) scale and the patients' activities of daily living function (ADL, 100-points) were also scored. RESULTS: Before treatment, the VAS, FMA and ADL points of the three groups were not significantly different (P>0.05). After the treatment, the total effective rate (93.33%), FMA and ADL scores of the combined treatment group were significantly higher than those of the ACE and sEMGBF groups (P<0.05), while the VAS score of the combined treatment group was significantly lower than those of the ACE and sEMGBF groups (P<0.05). The total effective rates, FMA and ADL scores of the ACE and sEMGBF groups were comparable (P>0.05). The VAS score of the ACE group was markedly lower than that of the sEMGBF group (P<0.05). CONCLUSION: The combined administration of ACE and sEMGBF has a better therapeutic effect for stroke patients complicated with SHS relevant to simple ACE and simple sEMGBF therapy in improving the upper limb function, relieving pain, and enhancing the daily life quality.