Possibility of magnesium supplementation for supportive treatment in patients with COVID-19.

Magnesium as an enzymatic activator is essential for various physiological functions such as cell cycle, metabolic regulation, muscle contraction, and vasomotor tone. A growing body of evidence supports that magnesium supplementation (mainly magnesium sulfate and magnesium oxide) prevents or treats various types of disorders or diseases related to respiratory system, reproductive system, nervous system, digestive system, and cardiovascular system as well as kidney injury, diabetes and cancer. The ongoing pandemic coronavirus disease 19 (COVID-19) characterized by respiratory tract symptoms with different degrees of important organ and tissue damages has attracted global attention. Particularly, effective drugs are still lacking in the COVID-19 therapy. In this review, we find and summarize the effectiveness of magnesium supplementation on the disorders or diseases, and provide a reference to the possibility of magnesium supplementation for supportive treatment in patients with COVID-19.

Triiodo-L-Thyronine Promotes the Maturation of Cardiomyocytes Derived From Rat Bone Marrow Mesenchymal Stem Cells.

Bone marrow mesenchymal stem cells (BMMSCs) can differentiate into cardiomyocytes and be used in cardiac tissue engineering for heart regeneration. However, the effective clinical application of cardiomyocytes derived from BMMSCs is limited because of their immature phenotype. The aim of this study was to investigate the potential of triiodo-L-thyronine (T3) to drive cardiomyocytes derived from BMMSCs to a more mature state. BMMSCs were divided into 3 groups: untreated controls, differentiated, and T3 treated. The differentiation potential was evaluated by immunofluorescence microscopy and flow cytometry. Data were represented as the numbers of cells positive for the troponin I (cTnI), α-actinin, GATA4, and the connexin-43 (Cx-43). The mRNA levels of these specific markers of cardiomyocytes were determined by quantitative real-time polymerase chain reaction. The levels of cardiomyocytes markers protein and octamer-binding transcription factor 4 (Oct-4) were determined by Western blot analyses. Our data demonstrate that T3 treatment leads to a significant increase in cells positive for cTnI, GATA4, Cx-43, and α-actinin. The mRNA and protein expression levels of these specific markers of cardiomyocytes were also increased after T3 treatment. At the same time, the protein expression level of Oct-4 was substantially downregulated in T3-treated cells. These results demonstrate that T3 treatment increases the differentiation of BMMSCs induced to cardiomyocytes and promotes their maturation.

Rebuilding the balance of STAT1 and STAT3 signalings by fusaruside, a cerebroside compound, for the treatment of T-cell-mediated fulminant hepatitis in mice.

Dysregulation of signal transducer and activator of transcription (STAT) signaling is usually associated with intricate immune diseases and rebuilding the balance of STAT1 and STAT3 signaling is being explored as a useful approach for the treatment of these diseases. However, few chemicals have been reported to rebuild the balance of these two signalings for immune hepatitis therapy. In the present study, we found that fusaruside, a new kind of cerebroside isolated from an endophytic fungus Fusarium sp. IFB-121 in Quercus variabilis, significantly ameliorated concanavalin A (Con A)-induced T-cell-mediated fulminant hepatitis in mice, which was closely associated with the improvement of histopathological parameters, inhibition of activation of liver CD4(+) T cells and NKT cells, regulation of balance of Th1/Th2/Th17/Treg cytokines and protection of hepatocyte from apoptosis. Moreover, T-cell proliferation and activation was also notably inhibited by fusaruside in vitro. Furthermore, the protective effect of fusaruside was attributable to a novel regulatory mechanism through down-regulating STAT1 activation and T-bet expression in liver CD4(+) T cells and up-regulating STAT3 activation and Bcl-X(L) expression in hepatocytes. In conclusion, fusaruside exhibited its capability against T-cell-mediated liver injury in vivo, through rebuilding the balance of STAT1 and STAT3 signalings. These results suggest that fusaruside is potentially useful for the treatment of T-cell-mediated human liver disorders.

Cerebroside D, a glycoceramide compound, improves experimental colitis in mice with multiple targets against activated T lymphocytes.

In the present paper, we aimed to examine the novel effects of cerebroside D, a glycoceramide compound, on murine experimental colitis. Cerebroside D significantly reduced the weight loss, mortality rate and alleviated the macroscopic and microscopic appearances of colitis induced by dexran sulfate sodium. This compound also decreased the levels of TNF-α, IFN-γ and IL-1ß in intestinal tissue of mice with experimental colitis in a concentration-dependent manner, accompanied with markedly increased serum level of IL-10. Cerebroside D inhibited proliferation and induced apoptosis of T cells activated by concanavalin A or anti-CD3 plus anti-CD28 antibodies. The compound did not show an effect on naive lymphocytes but prevented cells from entering S phase and G2/M phase during T cells activation. Moreover, the treatment of cerebroside D led to apoptosis of activated T cells with the cleavage of caspase 3, 9, 12 and PARP. These results showed multiple effects of cerebroside D against activated T cells for a novel approach to treatment of colonic inflammation.

Cortex Dictamni extract induces apoptosis of activated hepatic stellate cells via STAT1 and attenuates liver fibrosis in mice.

ETHNOPHARMACOLOGICAL RELEVANCE: In traditional Chinese medicines, Cortex Dictamni is prescribed for the treatment of a variety of inflammatory diseases such as acute rheumatoid arthritis, skin inflammation and jaundice. AIM OF THE STUDY: This study was designed to investigate the effect of ethanol extract of Cortex Dictamni on treatment of hepatic fibrosis and its possible mechanisms. MATERIALS AND METHODS: The in vivo effect of Cortex Dictamni extract (CDE) was evaluated by measuring histological changes and collagen content in CCl(4)-indcued hepatic fibrosis mice. Viability, apoptosis and protein expression of hepatic stellate cells (HSC) were analyzed by MTT, Annexin V staining and Western blot respectively. RESULTS: CDE alleviated CCl(4)-induced hepatic fibrosis in mice and showed a much stronger inhibition of cell viability in activated HSC cell line HSC-T6 than that in normal hepatocyte L02 cells. Furthermore, CDE induced apoptosis of HSC-T6 cells associated with increased expressions of cleaved PARP and cleaved caspase-3. Interestingly, CDE activated STAT1 in HSC-T6 cells and the effect of CDE on apoptosis of HSC-T6 cells could be neutralized using JAK/STAT1 signaling inhibitor AG490. CONCLUSIONS: These findings suggest that CDE possesses anti-fibrosis activity with selectively induction of activated HSC apoptosis via activating STAT1, which might be a novel strategy for hepatic fibrosis therapy.

Novel immunomodulatory properties of cirsilineol through selective inhibition of IFN-gamma signaling in a murine model of inflammatory bowel disease.

Regulation of signal transducer and activator of transcription (STAT) 1 signaling is being explored as a new approach to the treatment of inflammatory bowel diseases. However, few chemicals have been reported to inhibit IFN-gamma/STAT1 signaling for Crohn's disease therapy. In the present study, we found that cirsilineol, a small natural compound isolated from Artemisia vestita, significantly ameliorated trinitro-benzene sulfonic acid (TNBS)-induced T-cell-mediated experimental colitis in mice, which was closely associated with reduced autoreactive T-cell proliferation and activation. Moreover, the regulatory action of pro-inflammatory and anti-inflammatory cytokine by cirsilineol treatment was found to decrease the activity of effector Th1 cells but increase the activity of regulatory T cells as characterized by down-regulation of IFN-gamma and corresponding up-regulation of IL-10 and TGF-beta. The therapeutic effect of cirsilineol was attributable to a novel regulatory mechanism with selective inhibiting IFN-gamma signaling in colonic lamina propria CD4(+) T cells, which was mediated through down-regulating STAT1 activation and T-bet expression. Furthermore, cirsilineol was found to down-regulate the activation of JAK2, a critical kinase for IFN-gamma/STAT1 signaling, and abrogate the expression of T-bet, resulting in markedly decreased proliferation and activation of T cells in vitro. Importantly, the inhibition of IFN-gamma/STAT1 signaling by cirsilineol was reversible in the presence of high level of IFN-gamma. These results strongly suggest that cirsilineol might be potentially useful for treating T-cell-mediated human inflammatory bowel diseases.

Anti-inflammatory and immunosuppressive effect of flavones isolated from Artemisia vestita.

AIM OF THE STUDY: Artemisia vestita is a common traditional Tibetan medicinal plant which has been used widely in China for treating various inflammatory diseases. Since little is known about its active components, the purpose of this study was to isolate and identify the immunosuppressive compounds from Artemisia vestita. MATERIALS AND METHODS: A bioassay-guided isolation was performed with picryl chloride-induced contact hypersensitivity in mice. MTT assay and Flow cytometric analysis were used for determining Con A-induced lymphocyte proliferation and CD25 expression in T cells, respectively. RESULTS: The ethanol extract of the Artemisia vestita was found to possess significant inhibitory activity against the picryl chloride-induced contact hypersensitivity in mice. Then 4 fractions were isolated by macroporous adsorption resin and one of these fractions (AV3), which showed the highest activity in in vivo test, was further subjected to column chromatography. Nine known flavones were isolated and identified as pectolinarigenin (1), jaceosidin (2), cirsilineol (3), cirsimaritin (4), hispidulin (5), quercetin (6), 6-methoxytricin (7), acacetin (8), and apigenin (9). The structures of the 9 flavones were elucidated by spectral techniques. All the compounds were evaluated for their inhibitory activity on the proliferation and activation of T cells in vitro. Among the 9 flavones, cirsilineol (3), 6-methoxytricin (7) and apigenin (9) significantly inhibited T cell proliferation and activation in the bioassays. CONCLUSION: The result suggests that cirsilineol, 6-methoxytricin and apigenin are the major active components in Artemisia vestita.

A novel synthetic oleanolic acid derivative (CPU-II2) attenuates liver fibrosis in mice through regulating the function of hepatic stellate cells.

UNLABELLED: Regulation on the function of the hepatic stellate cells (HSCs) is one of the proposed therapeutic approaches to liver fibrosis. In the present study, we examined the in vitro and in vivo effects of CPU-II2, a novel synthetic oleanolic acid (OLA) derivative with nitrate, on hepatic fibrosis. This compound alleviated CCl4-induced hepatic fibrosis in mice with a decrease in hepatic hydroxyproline (Hyp) content and histological changes. CPU-II2 also attenuated the mRNA expression of alpha-smooth muscle actin (alpha-SMA) and tissue inhibitor of metalloproteinase type 1 (TIMP-1) induced by CCl4 in mice and reduced both mRNA and protein levels of alpha-SMA in HSC-T6 cells. Interestingly, CPU-II2 did not affect the survival of HSC-T6 cells but decreased the expression of procollagen-alpha1 (I) in HSC-T6 cells through down-regulating the phosphorylation of p38 MAPK. CONCLUSION: CPU-II2 attenuates the development of liver fibrosis rather by regulating the function of HSCs through p38 MAPK pathway than by damaging the stellate cells.

Ethanol extract from Artemisia vestita, a traditional Tibetan medicine, exerts anti-sepsis action through down-regulating the MAPK and NF-kappaB pathways.

Artemisia vestita Wall., a traditional Tibetan medicine, has wide clinical application for inflammatory diseases. However, its molecular mechanism of anti-inflammatory effect is poorly understood. In the present study, we investigated the anti-inflammatory activity and underlying mechanism of the ethanol extract from Artemisia vestita (AV-ext) on lipopolysaccharide (LPS)-induced sepsis. Pretreatment with AV-ext significantly decreased the levels of tumor necrosis factor-alpha (TNF-alpha) in serum and liver and lung tissues, and improved the survival of mice with experimental sepsis. AV-ext also remarkably reduced the expression levels of TNF-alpha, interleukin-1beta and cyclooxygenase-2 in LPS-stimulated RAW 264.7 macrophages and dose dependently suppressed the activation of mitogen-activated protein kinases (MAPKs), such as p38, extracellular signal-regulated kinase (ERK1/2) and c-Jun NH2-terminal kinase (JNK). Furthermore, pretreatment with AV-ext dose dependently inhibited the activation of nuclear factor-kappaB (NF-kappaB), as well as the degradation and phosphorylation of inhibitory kappaB (IkappaB) in LPS-activated RAW 264.7 macrophages. These results collectively reveal that AV-ext inhibits TNF-alpha release from macrophages by suppressing MAPK and NF-kappaB signaling pathways and suggest that AV-ext may be beneficial for the treatment of endotoxin shock or sepsis.