A review for natural polysaccharides with anti-pulmonary fibrosis properties, which may benefit to patients infected by 2019-nCoV.

Pulmonary fibrosis (PF) is a lung disease with highly heterogeneous and mortality rate, but its therapeutic options are now still limited. Corona virus disease 2019 (COVID-19) has been characterized by WHO as a pandemic, and the global number of confirmed COVID-19 cases has been more than 8.0 million. It is strongly supported for that PF should be one of the major complications in COVID-19 patients by the evidences of epidemiology, viral immunology and current clinical researches. The anti-PF properties of naturally occurring polysaccharides have attracted increasing attention in last two decades, but is still lack of a comprehensively understanding. In present review, the resources, structural features, anti-PF activities, and underlying mechanisms of these polysaccharides are summarized and analyzed, which was expected to provide a scientific evidence supporting the application of polysaccharides for preventing or treating PF in COVID-19 patients.

Effects of Acupoint Application Therapy with TianGui Powder on Osteoporosis in Ovariectomized Rats through TGF-ß1 and Smad2/3 Signaling Pathway.

OBJECTIVES: To explore the effects of acupoint application therapy (AAT) with TianGui Powder (TGP) on the expressions of the transforming growth factor ß1 (TGF-ß1) and Smad-2/3 signaling pathway in ovariectomized osteoporosis rats. METHODS: Sixty rats were randomly divided into four groups: normal group (group A), model group (group B), TGP group (group C), and Western medicine group (group D). Group A had only the corresponding amount of adipose tissue around the ovary removed; rats in the other groups had bilateral ovariectomies. After 1 week, groups A and B were given 1 mL/100 mg normal saline solution by gavage, group C was treated with AAT with TGP on ShenQue acupoint (0.2 piece/rat, 6 h/time, 1 time/d) and group D was given calcium carbonate vitamin D3 (36 mg/kg/d) and alfacalcidol (0.05 µg/kg/d) tablet suspension. In this study, the bone mineral density (BMD) , the levels of BALP, TRAP-5b, and BGP in serum and the changes in bone histomorphology was detected. For acquiring lumbar experimental data, the expression of TGF-ß1, Smad-2/3 proteins and mRNA of TGF-ß1and Smad-2/3 were assessed. After 12 weeks, the data were collected for analysis. RESULTS: Compared with group A, the bone trabecula was thinner and significantly reduced in other groups. The result of BMD improved significantly in both groups C and D compared to group B after intervention (P < 0.05). In contrast, compared to group B, the levels of BALP, TRAP-5b, and BGP significantly declined in both groups C and D. In group C, the results of protein expressions in TGF-ß1, Smad-2/3 were 2.870 ± 0.270, 1.552 ± 0.111, and 1.420 ± 0.079, respectively. In groups C and D, those indications significantly declined compared to group B (P < 0.01). In group C, the level of mRNA expressions of TGF-ß1, Smad-2/3 were 1.872 ± 0.177, 1.672 ± 0.086, and 1.790 ± 0.136, respectively. Compared with group B, those indications had significant difference in groups C and D (P < 0.05). CONCLUSION: Acupoint application therapy with TGP could significantly improve the BMD. The TGF-ß1 and Smad-2/3 signaling pathway could be a therapeutic target of TGP in postmenopausal osteoporosis rats.

Is Growth Differentiation Factor 11 a Realistic Therapeutic for Aging-Dependent Muscle Defects?

This "Controversies in Cardiovascular Research" article evaluates the evidence for and against the hypothesis that the circulating blood level of growth differentiation factor 11 (GDF11) decreases in old age and that restoring normal GDF11 levels in old animals rejuvenates their skeletal muscle and reverses pathological cardiac hypertrophy and cardiac dysfunction. Studies supporting the original GDF11 hypothesis in skeletal and cardiac muscle have not been validated by several independent groups. These new studies have either found no effects of restoring normal GDF11 levels on cardiac structure and function or have shown that increasing GDF11 or its closely related family member growth differentiation factor 8 actually impairs skeletal muscle repair in old animals. One possible explanation for what seems to be mutually exclusive findings is that the original reagent used to measure GDF11 levels also detected many other molecules so that age-dependent changes in GDF11 are still not well known. The more important issue is whether increasing blood [GDF11] repairs old skeletal muscle and reverses age-related cardiac pathologies. There are substantial new and existing data showing that GDF8/11 can exacerbate rather than rejuvenate skeletal muscle injury in old animals. There is also new evidence disputing the idea that there is pathological hypertrophy in old C57bl6 mice and that GDF11 therapy can reverse cardiac pathologies. Finally, high [GDF11] causes reductions in body and heart weight in both young and old animals, suggestive of a cachexia effect. Our conclusion is that elevating blood levels of GDF11 in the aged might cause more harm than good.

A network pharmacology approach to discover active compounds and action mechanisms of San-Cao Granule for treatment of liver fibrosis.

ETHNOPHARMACOLOGICAL RELEVANCE: San-Cao Granule (SCG) has been used in patients with liver fibrosis for many years and has shown good effect. However, its mechanism of therapeutic action is not clear because of its complex chemical system. The purpose of our study is to establish a comprehensive and systemic method that can predict the mechanism of action of SCG in antihepatic fibrosis. MATERIALS AND METHODS: In this study, a "compound-target-disease" network was constructed by combining the SCG-specific and liver fibrosis-specific target proteins with protein-protein interactions, and network pharmacology was used to screen out the underlying targets and mechanisms of SCG for treatment of liver fibrosis. Then, some key molecules of the enriched pathway were chosen to verify the effects of SCG on liver fibrosis induced by thioacetamide (TAA). RESULTS: This systematic approach had successfully revealed that 16 targets related to 11 SCG compounds were closely associated with liver fibrosis therapy. The pathway-enrichment analysis of them showed that the TGF-ß1/Smad signaling pathway is relatively important. Animal experiments also proved that SCG could significantly ameliorate liver fibrosis by inhibiting the TGF-ß1/Smad pathway. CONCLUSION: SCG could alleviate liver fibrosis through the molecular mechanisms predicted by network pharmacology. Furthermore, network pharmacology could provide deep insight into the pharmacological mechanisms of Chinese herbal formulas.

Triptolide alleviates isoprenaline-induced cardiac remodeling in rats via TGF-ß1/Smad3 and p38 MAPK signaling pathway.

Triptolide (TPL) is a diterpene triepoxide with potent immunosuppressive and anti-inflammatory properties. It is the main effective component of the traditional Chinese herb Tripterygium wilfordii Hook F and has been used in China for centuries to treat immune-related disorders. The present study was conducted to investigate the effects of TPL on cardiac remodeling in rats. Age matched male Wistar rats were used in this study. Cardiac remodeling rat model was established by hypodermic injection of isoprenaline for ten days. The rats were treated with TPL (20 or 100 µg/kg/d) for six consecutive weeks. At the end of the study, the cardiac function, collagen volume fraction, perivascular collagen area and hydroxyproline concentration were studied. Echocardiography, Masson staining, immunohistochemistry, western blot and real-time polymerase chain reaction were performed. The protein and mRNA expression of transforming growth factor-ß1 (TGF-ß1), drosophila mothers against decapentaplegic protein 3 (Smad3) and p38 mitogen activated protein kinase (p38 MAPK) were analyzed. The results indicated that TPL treatment significantly reduced the collagen volume fraction, perivascular collagen area, ventricular weight/body weight ratio and hydroxyproline concentration in myocardial tissue compared with the model group. In addition, it also improved the cardiac function. TPL attenuated cardiac remodeling in rats by down-regulating the p38 MAPK and TGF-ß1/Smad3 signaling pathways. TPL treatment significantly attenuated cardiac fibrosis and improved cardiac function through suppressing the p38 MAPK and TGF-ß1/Smad3 signaling pathway in isoprenaline-induced cardiac remodeling rats. Our findings suggested that TPL might be a novel complementary medicine in the treatment of chronic heart failure.

[Effect of 1,25-(OH)2D3 supplementation during gestation and lactation on TGF-ß1 and Smad3 expression in lungs of rat offspring with asthma].

OBJECTIVE: To study the effect of 1,25-(OH)2D3 supplementation during gestation and lactation on TGF-ß1 and Smad3 expression in lungs of rat offspring with asthma. METHODS: Thirty-two female Wistar rats were randomly divided into four groups: low-, medium- and high-dose 1,25-(OH)2D3 supplementation and control groups (n=8 each). From the 7th day of gestation, the three 1,25-(OH)2D3 supplementation groups were administered with 2,10 and 20 µg/mL of 1,25-(OH)2D3 respectively every other day until weaning (rat offspring: 21 days old). The control group received normal saline instead. Then, bronchial asthma was induced in rat offspring from the 4 groups. The protein and mRNA expression of TGF-ß1 and Smad3 in the lung tissue was measured by immunochemistry and RT-PCR. RESULTS: Eosinophil cell infiltration and airway inflammation decreased in rat offspring from the low- and medium-dose 1,25-(OH)2D3 groups, but increased in rat offspring of the high-dose 1,25-(OH)2D3 group compared with the control group. Immunohistochemistry of lung tissues showed that the expression of TGF-ß1 protein and pSmad3 decreased in rat offspring from the low- and medium-dose 1,25-(OH)2D3 groups (P<0.05), but increased significantly in rat offspring from the high-dose 1,25-(OH)2D3 group compared with the control group (P<0.05). PCR showed that the expression of TGF-ß1 and Smad3 mRNA in the lung tissue decreased in rat offspring from the low- and medium-dose 1,25-(OH)2D3 groups (P<0.05), but increased significantly in rat offspring from the high-dose 1,25-(OH)2D3 group compared with the control group (P<0.05). CONCLUSIONS: 1,25-(OH)2D3 supplementation plays a role in regulating the immune system in asthmatic rats. Its mechanism may be associated with regulation of the expression of TGF-ß/Smad signal pathway-related proteins through the vitamin D receptor signal pathway.

Schisandrin B suppresses TGFß1 signaling by inhibiting Smad2/3 and MAPK pathways.

TGFß1 plays a crucial role in the pathogenesis of vascular fibrotic diseases. Schisandra chinensis (S. chinensis), which is used as an oriental herbal medicine, is effective in the treatment of vascular injuries that cause aberrant TGFß1 signaling. In this study, we investigated whether S. chinensis extract and its active ingredients inhibit TGFß1 signaling in A7r5 vascular smooth muscle cells. We found that S. chinensis extract suppressed TGFß1 signaling via inhibition of Smad2/3 phosphorylation and nuclear translocation. Among the active ingredients of S. chinensis extract, schisandrin B (SchB) most potently inhibited TGFß1 signaling. SchB inhibited sustained phosphorylation and nuclear translocation of Smad2/3. Moreover, SchB suppressed TGFß1-induced phosphorylation of p38 and JNK, which contributed to Smad2/3 inactivation. The present study is the first to demonstrate that S. chinensis extract and SchB inhibit TGFß1 signaling. Our results may help future investigations to understand vascular fibrosis pathogenesis and to develop novel therapeutic strategies for treatment of vascular fibrotic diseases.

In vitro models of TGF-beta-induced fibrosis suitable for high-throughput screening of antifibrotic agents.

Progressive fibrosis is a cause of progressive organ dysfunction. Lack of quantitative in vitro models of fibrosis accounts, at least partially, for the slow progress in developing effective antifibrotic drugs. Here, we report two complementary in vitro models of fibrosis suitable for high-throughput screening. We found that, in mesangial cells and renal fibroblasts grown in eight-well chamber slides, transforming growth factor-beta1 (TGF-beta1) disrupted the cell monolayer and induced cell migration into nodules in a dose-, time- and Smad3-dependent manner. The nodules contained increased interstitial collagens and showed an increased collagen I:IV ratio. Nodules are likely a biological consequence of TGF-beta1-induced matrix overexpression since they were mimicked by addition of collagen I to the cell culture medium. TGF-beta1-induced nodule formation was inhibited by vacuum ionized gas treatment of the plate surface. This blockage was further enhanced by precoating plates with matrix proteins but was prevented, at least in part, by poly-l-lysine (PLL). We have established two cell-based models of TGF-beta-induced fibrogenesis, using mesangial cells or fibroblasts cultured in matrix protein or PLL-coated 96-well plates, on which TGF-beta1-induced two-dimensional matrix accumulation, three-dimensional nodule formation, and monolayer disruption can be quantitated either spectrophotometrically or by using a colony counter, respectively. As a proof of principle, chemical inhibitors of Alk5 and the antifibrotic compound tranilast were shown to have inhibitory activities in both assays.