Taraxasterol mitigates Con A-induced hepatitis in mice by suppressing interleukin-2 expression and its signaling in T lymphocytes.

Discovery of anti-inflammatory drugs that can suppress T lymphocyte activation and proliferation by inhibiting TCR/CD3 and IL-2/IL-2R signaling is still needed in clinic, though rapamycin and other related reagents have made great success. Taraxasterol (TAS) is an active ingredient of dandelion, an anti-inflammatory medicinal herb with low in vivo toxicity that has long been used in China. Yet the action mechanism of TAS on lymphocytes remains elusive. The anti-inflammatory effects of TAS were evaluated in C57BL/6 mouse primary lymphocytes stimulated with concanavalin A (Con A) in vitro and in mouse model of Con A-induced acute hepatitis in vivo. Our results showed that TAS significantly suppressed Con A-induced acute hepatitis in a mouse model, reducing the hepatic necrosis areas, the release of aminotransferases, and the production of IL-2 and other inflammatory cytokines. Supporting this, in vitro study also showed that TAS reduced the production of IL-2 and the expression of IL-2 receptor subunit α (CD25) upon the stimulation of Con A, which was likely mediated by suppressing NF-κB activation. The downstream pathways of IL-2/IL-2R signaling, including the activation of PI3K/PDK1/mTOR, STAT3 and STAT5, were also suppressed by TAS. Consistently, Con A-induced T cell proliferation was also inhibited by TAS in vitro. Our data indicate that TAS can suppress both T lymphocyte activation and cell proliferation by down-regulating IL-2 expression and its signaling pathway thereby ameliorating Con A-induced acute hepatitis, highlighting TAS as a potential drug candidate for treating inflammatory diseases including autoimmune hepatitis.

The impact of recent chemotherapy on immunity in 2 COVID-19 cases with gastrointestinal tumors: A case report.

INTRODUCTION: Coronavirus disease 2019 (COVID-19) is a rapidly emerging infectious respiratory disease caused by severe acute respiratory syndrome coronavirus 2. Currently, more than 100 million cases of COVID-19 have been confirmed worldwide, with over 2.4 million mortalities. The pandemic affects people of all ages but older individuals and those with severe chronic illnesses, including cancer patients, are at higher risk. PATIENT CONCERNS: The impact of cancer treatment on the progression of COVID-19 is unclear. Therefore, we assessed the effects of chemotherapy on COVID-19 outcomes for 2 cancer patients. On January 24, 2020, a level I response to a major public health emergency was initiated in Hubei Province, China, which includes Enshi Autonomous Prefecture that has a population of 4.026 million people. As of April 30, 2020, 252 confirmed cases of COVID-19 and 11 asymptomatic carriers were identified in Enshi. DIAGNOSIS: Among the confirmed cases and asymptomatic carriers, 2 patients were identified who were previously diagnosed with malignant tumors, including one with hepatocellular carcinoma and the other with cardia carcinoma. INTERVENTIONS: These 2 patients were receiving or just completed chemotherapy at the time of their COVID-19 diagnosis. OUTCOMES: Both patients were followed and presented favorable outcomes. The positive outcomes for these 2 patients could be partially explained by their recent chemotherapy that impacted their immune status. Also, their relatively younger ages and lack of comorbidities were likely factors in their successful recovery from COVID-19. CONCLUSIONS: Anticancer treatment might enhance a patient's ability to respond favorably to COVID-19 infection. However, anticancer treatment is likely to impact immune function differently in different individuals, which can influence disease outcomes.

Inhibition of NLRP3 Inflammasome Activation and Pyroptosis in Macrophages by Taraxasterol Is Associated With Its Regulation on mTOR Signaling.

Taraxasterol (TAS) is an active ingredient of Dandelion (Taraxacum mongolicum Hand. -Mazz.), a medicinal plant that has long been used in China for treatment of inflammatory disorders. But the underlying mechanism for its therapeutic effects on inflammatory disorders is not completely clear. Inflammasome activation is a critical step of innate immune response to infection and aseptic inflammation. Among the various types of inflammasome sensors that has been reported, NLR family pyrin domain containing 3 (NLRP3) is implicated in various inflammatory diseases and therefore has been most extensively studied. In this study, we aimed to explore whether TAS could influence NLPR3 inflammasome activation in macrophages. The results showed that TAS dose-dependently suppressed the activation of caspase-1 in lipopolysaccharide (LPS)-primed murine primary macrophages upon nigericin treatment, resulting in reduced mature interleukin-1ß (IL-1ß) release and gasdermin D (GSDMD) cleavage. TAS greatly reduced ASC speck formation upon the stimulation of nigericin or extracellular ATP. Consistent with reduced cleavage of GSDMD, nigericin-induced pyroptosis was alleviated by TAS. Interestingly, TAS time-dependently suppressed the mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) and mTORC2 signaling induced by LPS priming. Like TAS, both INK-128 (inhibiting both mTORC1 and mTORC2) and rapamycin (inhibiting mTORC1 only) also inhibited NLRP3 inflammasome activation, though their effects on mTOR signaling were different. Moreover, TAS treatment alleviated mitochondrial damage by nigericin and improved mouse survival from bacterial infection, accompanied by reduced IL-1ß levels in vivo. Collectively, by inhibiting the NLRP3 inflammasome activation, TAS displayed anti-inflammatory effects likely through regulation of the mTOR signaling in macrophages, highlighting a potential action mechanism for the anti-inflammatory activity of Dandelion in treating inflammation-related disorders, which warrants further clinical investigation.

Dietary betaine prevents obesity through gut microbiota-drived microRNA-378a family.

Betaine is a natural compound present in commonly consumed foods and may have a potential role in the regulation of glucose and lipids metabolism. However, the underlying molecular mechanism of its action remains largely unknown. Here, we show that supplementation with betaine contributes to improved high-fat diet (HFD)-induced gut microbiota dysbiosis and increases anti-obesity strains such as Akkermansia muciniphila, Lactobacillus, and Bifidobacterium. In mice lacking gut microbiota, the functional role of betaine in preventing HFD-induced obesity, metabolic syndrome, and inactivation of brown adipose tissues are significantly reduced. Akkermansia muciniphila is an important regulator of betaine in improving microbiome ecology and increasing strains that produce short-chain fatty acids (SCFAs). Increasing two main members of SCFAs including acetate and butyrate can significantly regulate the levels of DNA methylation at host miR-378a promoter, thus preventing the development of obesity and glucose intolerance. However, these beneficial effects are partially abolished by Yin yang (YY1), a common target gene of the miR-378a family. Taken together, our findings demonstrate that betaine can improve obesity and associated MS via the gut microbiota-derived miR-378a/YY1 regulatory axis, and reveal a novel mechanism by which gut microbiota improve host health.

Berberine augments hypertrophy of colonic patches in mice with intraperitoneal bacterial infection.

Colonic patches, the counterparts of Peyer's patches in the small intestine, are dynamically regulated lymphoid tissues in the colon that have an important role in defensing against microbial infections. Berberine is an isoquinoline alkaloid extracted from medicinal herbs including Rhizoma coptidis and has long been used for the treatment of infectious gastroenteritis, but its impact on the colonic lymphoid tissues (such as colonic patches) is unknown. In this study, we aimed to investigate whether berberine had any influences on the colonic patches in mice with bacterial infection. The results showed that oral berberine administration in bacterial infected mice substantially enhanced the hypertrophy of colonic patches, which usually possessed the features of two large B-cell follicles with a separate T-cell area. Moreover, the colonic patches displayed follicular dendritic cell networks within the B-cell follicles, indicative of mature colonic patches containing germinal centers. Concomitant with enlarged colonic patches, the cultured colon of infected mice treated with berberine secreted significantly higher levels of interleukin-1ß (IL-1ß), IL-6, TNF-α, and CCL-2, while NLRP3 inhibitor MMC950 or knockout of NLRP3 gene abrogated berberine-induced hypertrophy of colonic patches, suggesting the involvement of the NLRP3 signaling pathway in this process. Functionally, oral administration of berberine ameliorated liver inflammation and improved formed feces in the colon. Altogether, these results indicated that berberine was able to augment the hypertrophy of colonic patches in mice with bacterial infection probably through enhancing local inflammatory responses in the colon.

A wetland plant, Phalaris arundinacea, accumulates nitrogen and phosphorus during senescence.

Secondary pollution resulting from shoot death is a difficult problem that complicated the application of wetland plants for water purification in northern wetlands. Phalaris arundinacea, a perennial herb with an obviously declining stage, or senescence, is a species that is often selected for water purification in Northern China; however, whether it reduces the secondary pollution risk via nitrogen (N) and phosphorus (P) accumulation during senescence or not remains unclear. To investigate this question, an experiment was conducted with containerized plants during the winter of 2016, after roughly half the leaves on the plants had withered. The experimental observations and analyses were conducted within 0, 2, 4, 6, and 8 weeks of the initiation of senescence. Results revealed that leaves continued to wither and shoot death occurred during weeks 4 to 6 and 8 to 10, respectively. However, no significant differences occurred in fresh biomass or in N and P accumulations of a single plant during senescence. The root biomass, root weight per volume, and total N content increased significantly, while total P content remained stable when leaves withered, respectively. H+-ATPase, a key enzyme for ion transportation, decreased after the leaves withered. However, root activity, evaluated by absorption surface per root volume, remained stable, and percentage of fine root length (diameter < 1 mm) increased significantly during senescence. In conclusion, the root activity and morphology enables P. arundinacea to accumulate N and P during senescence, which makes it a good choice for water purification in northern wetlands.

The Use of RNAi Technology to Interfere with Zfx Gene Increases the Male Rates of Red Deer (Cervus elaphus) Offspring.

Zinc finger protein X-linked (Zfx) was regarded to be a sex determination factor and plays a critical role in spermatogenesis. RNAi is an effective method of silencing Zfx mRNA expression. However, there has been little research on the use of RNAi technology to control the sex of the offspring of red deer (Cervus elaphus). The objective of this study was first to explore an efficient method to alter the red deer offspring sex-ratio by silencing the gene Zfx during spermatogenesis. Three recombinant expression vectors pLL3.7/A, pLL3.7/B, and pLL3.7/C were constructed to interrupt the Zfx gene. The results showed that the expression of Zfx mRNA was significantly silenced by pLL3.7/A (P < 0.01), compared with the control group. The group injected with pLL3.7/A produced 94 red deer, including 68 males and 26 females. The male rates (72.34%) were significantly higher than the control groups (P < 0.01). Our result suggests that Zfx siRNA is a useful approach to control offspring sex in red deer. This study further confirms that the Zfx gene plays a significant role in the process of X spermatogenesis.

Two-Dimensional Device with Light-Controlled Capability for Treatment of Cancer-Relevant Infection Diseases.

Concurrent infection in cancer treatment is the leading cause of high cancer mortality that requires urgent action. Currently developed diagnostic methods are hindered by the difficulty of rapidly and reliably screening small amounts of pathogens in the blood and then release pathogens for downstream analysis, limiting the advance of cancer concurrent infection diseases diagnosis and targeted treatment. Herein, we present a near-infrared (NIR) light-responsive black phosphorus (BP)-based device that effectively captures and releases pathogen for downstream drug-resistance analysis. The aptamer-modified BP nanostructures exhibit enhanced topographical interactions and binding capabilities with pathogen, enabling highly efficient and selective capture of pathogen in serum. NIR light irradiation induces BP nanostructure to generate a local thermal effect, which regulates the three-dimensional structure of the aptamer and causes efficient release of pathogen from the substrate surface. The released pathogen is resistant to ampicillin as demonstrated by downstream genetic analysis. The design of the functionalized light-controlled device for monitoring pathogen behavior shows great potential for assisting in cancer therapy and promoting personalized healthcare.

[Study on medication regularity of chronic atrophic gastritis in Beijing-Tianjin-Hebei region based on latent structure model].

To explore the etiology, pathogenesis, distribution of syndromes and the rule of medication of chronic atrophic gastritis(CAG) in Beijing-Tianjin-Hebei region based on the latent structure model. Chronic atrophic gastritis of 279 cases in Beijing-Tianjin-Hebei region were extracted from the established database of spleen and stomach diseases of famous veteran Chinese medicine experts. The latent structure models of symptoms and drugs of chronic atrophic gastritis were constructed by using Lantern 3.1.2 software, and the latent structure models were interpreted. SAS 10.0 software was used to mine association rules of drugs and symptoms. The constitutional characteristics of patients with chronic atrophic gastritis in Beijing-Tianjin-Hebei region were "turbid toxin and damaging Yin". The common syndromes were turbid toxin, deficiency of stomach Yin, stagnation of liver and stomach, stagnation of liver and stomach Qi, obstruction of stomach collaterals and blood stasis, and weakness of spleen and stomach. Common medicines are Lobeliae Chinensis Herba, Scutellariae Barbatae Herba, Amomi Fructus Rotundus, Amomi Fructus, Poria, Isatidis Radix, Artemisiae Scopariae Herba, Scorpio, Coptidis Rhizoma, Lilii Bulbus, Linderae Radix, Phragmitis Rhizoma, Ophiopogonis Radix, Pogostemonis Herba, Eupatorii Herba, Magnoliae Officinalis Cortex, Aurantii Fructus Immaturus. Common prescriptions are Baihe Wuyao Powder, Danggui Shaoyao Powder, Xiaoyao Pills, Xiangsu Powder, Dachengqi Decoction, Zuojin Pills, Qingzhong Decoction, Zhishi Daozhi Pills, etc. The application of latent structure model and correlation analysis in the empirical study of famous and veteran Chinese medicine experts is in line with the research direction of modern Chinese medicine "traditional Chinese medicine + X". The conclusions obtained effectively tap the experience of famous and veteran TCM experts, and provide a data and visual clinical reference and prescription compatibility for young TCM physicians in the treatment of chronic atrophic gastritis based on syndrome differentiation.

Intercrops can mitigate pollen-mediated gene flow from transgenic cotton while simultaneously reducing pest densities.

Genetically modified (GM) cotton, engineered to express Bt toxins that protect it from insect damage, has become the most successfully commercialized GM crop in China since its authorization in 1997. In light of the potential ecological consequences of pollen-mediated gene flow (PGF) from GM plants, a two year field trial was conducted to test the effects on PGF of sunflower, Helianthus annuus, buckwheat, Fagopyrum esculentum, and soybean, Glycine max, as intercrops in non-GM cotton fields during 2017 and 2018. DNA tests for hybridized seed were used to estimate rates of PGF in intercrop treatments. PGF was the lowest in cotton intercropped with either buckwheat or sunflower, likely due to the trapping of pollen in these flowers, and/or the diversion of pollinators away from cotton flowers. PGF declined as an exponential function of distance from the GM cotton; Y = -lnx was the model of best fit for estimating pollen dispersal potential. A sunflower intercrop reduced the peak abundance of Aphis gossypii, (Hemiptera: Aphididae), Bemisia tabaci (Hemiptera: Aleyrodidae), and Nysius ericae (Hemiptera: Lygaeidae) on cotton plants, although densities of Tetranychus cinnabarinus (Acari: Tetranychidae), were increased. A buckwheat intercrop had very similar effects on these pests, likely due to attraction of their natural enemies. We conclude that sunflower and buckwheat are suitable intercrops for reducing PGF from GM cotton, and may be useful for reducing PGF from other insect-pollinated GM crops in the agricultural landscape, while simultaneously contributing to control of specific pests. This is the first demonstration, to our knowledge, that intercrops can be used to reduce PGF from transgenic plants.

Conservation implications of primate trade in China over 18 years based on web news reports of confiscations.

Primate species have been increasingly threatened by legal and illegal trade in China, mainly for biomedical research or as pets and traditional medicine, yet most reports on trade from China regard international trade. To assess a proxy for amount of national primate trades, we quantified the number of reports of native primate species featuring in unique web news reports from 2000 to 2017, including accuracy of their identification, location where they were confiscated or rescued, and their condition upon rescue. To measure temporal trends across these categories, the time span was divided into three sections: 2000-2005, 2006-2011 and 2012-2017. A total of 735 individuals of 14 species were reported in 372 news reports, mostly rhesus macaques (n = 165, 22.5%, Macaca mulatta) and two species of slow lorises (n = 487, 66.3%, Nycticebus spp.). During the same period, live individuals of rhesus macaques were recorded 206 times (70,949 individuals) in the Convention on International Trade in Endangered Species of Wild Fauna and Flora Trade Database, whereas slow lorises were only recorded four times (nine individuals), indicating that the species originated illegally from China or were illegally imported into China. Due to their rescued locations in residential areas (n = 211, 56.7%), most primates appeared to be housed privately as pets. A higher proportion of 'market' rescues during 2006-2011 (χ2 = 8.485, df = 2, p = 0.014), could be partly attributed to an intensive management on wildlife markets since the outbreak of severe acute respiratory syndrome (SARS) in 2003. More than half (68.3%, 502 individuals) of the primate individuals were unhealthy, injured or dead when rescued. Thus, identification and welfare training and capacity-building should be provided to husbandry and veterinary professionals, as well as education to the public through awareness initiatives. The increase in presence of some species, especially slow lorises, with a declining population in restricted areas, also suggests the urgent need for public awareness about the illegal nature of keeping these taxa as pets.

Metabolic engineering of Saccharomyces cerevisiae for 7-dehydrocholesterol overproduction.

BACKGROUND: 7-Dehydrocholesterol (7-DHC) has attracted increasing attentions due to its great medical value and the enlarging market demand of its ultraviolet-catalyzed product vitamin D3. Microbial production of 7-DHC from simple carbon has been recognized as an attractive complement to the traditional sources. Even though our previous work realized 7-DHC biosynthesis in Saccharomyces cerevisiae, the current productivity of 7-DHC is still too low to satisfy the demand of following industrialization. As increasing the compatibility between heterologous pathway and host cell is crucial to realize microbial overproduction of natural products with complex structure and relative long pathway, in this study, combined efforts in tuning the heterologous Δ24-dehydrocholesterol reductase (DHCR24) and manipulating host cell were applied to promote 7-DHC accumulation. RESULTS: In order to decouple 7-DHC production with cell growth, inducible GAL promoters was employed to control 7-DHC synthesis. Meanwhile, the precursor pool was increased via overexpressing all the mevalonate (MVA) pathway genes (ERG10, ERG13, tHMG1, ERG12, ERG8, ERG19, IDI1, ERG20). Through screening DHCR24s from eleven tested sources, it was found that DHCR24 from Gallus gallus (Gg_DHCR24) achieved the highest 7-DHC production. Then 7-DHC accumulation was increased by 27.5% through stepwise fine-tuning the transcription level of Gg_DHCR24 in terms of altering its induction strategy, integration position, and the used promoter. By blocking the competitive path (ΔERG6) and supplementing another copy of Gg_DHCR24 in locus ERG6, 7-DHC accumulation was further enhanced by 1.07-fold. Afterward, 7-DHC production was improved by 48.3% (to 250.8 mg/L) by means of deleting NEM1 that was involved in lipids metabolism. Eventually, 7-DHC production reached to 1.07 g/L in 5-L bioreactor, which is the highest reported microbial titer as yet known. CONCLUSIONS: Combined engineering of the pathway and the host cell was adopted in this study to boost 7-DHC output in the yeast. 7-DHC titer was stepwise improved by 26.9-fold compared with the starting strain. This work not only opens large opportunities to realize downstream de novo synthesis of other steroids, but also highlights the importance of the combinatorial engineering of heterologous pathway and host to obtain microbial overproduction of many other natural products.

Effects of water level regulation on the seed germination and production of annual plant Xanthium sibiricum in the water-level-fluctuating-zone of Three Gorges Reservoir.

Vegetation effectively slows down the deterioration rate of the ecosystem in the water-level fluctuation zone (WLFZ). In this study, we investigated the impact of impoundment on the germination of seeds from Xanthium sibiricum fruits with various degrees of maturity and produced by X. sibiricum plants growing at different elevations in the WLFZ. Seed production by X. sibiricum under the current water level regulation mode was also investigated. Seeds were collected from seven elevations of the WLFZ of Three Gorges Reservoir (TGR) and exposed at these elevations to submergence. Seed production of the plants germinated from X. sibiricum seeds was observed. The maturity degree of X. sibiricum fruits from different elevations has no influence on the seed production by the plants that are produced from the fruits. Under the present water-level regulation mode, X. sibiricum growing above 155 m are able to generate mature seeds and thus provide seed sources for population maintenance, although the plants growing at an elevation below 165 m failed to produce fruits in 2010 due to unusual flooding. This study is useful for the vegetation recovery and reconstruction in other regions with hydrological characteristics similar to that of the TGR.

Divalent copper is a potent extracellular blocker for TRPM2 channel.

Transient receptor potential melastatin 2 (TRPM2) is a Ca(2+)-permeable cationic channel in the TRP channel family. The channel activity can be regulated by reactive oxygen species (ROS) and cellular acidification, which has been implicated to the pathogenesis of diabetes and some neuronal disorders. However, little is known about the effect of redox-active metal ions, such as copper, on TRPM2 channels. Here we investigated the effect of divalent copper on TRPM2. TRPM2 channel was over-expressed in HEK-293 cells and the whole-cell current was recorded by patch clamp. We found the whole-cell current evoked by intracellular ADP-ribose was potently inhibited by Cu(2+) with a half maximal inhibitory concentration (IC(50)) of 2.59 µM. The inhibitory effect was irreversible. The single channel activity was abolished in the outside-out patches, and intracellular application of Cu(2+) did not prevent the channel activation, suggesting that the action site of Cu(2+) is located in the extracellular domains of the channel. TRPM2 current was also blocked by Hg(2+), Pb(2+), Fe(2+) and Se(2+). We concluded that Cu(2+) is a potent TRPM2 channel blocker. The sensitivity of TRPM2 channel to heavy metal ions could be a new mechanism for the pathogenesis of some metal ion-related diseases.

Green tea polyphenols produce antidepressant-like effects in adult mice.

Recent studies have shown that a higher consumption of green tea leads to a lower prevalence of depressive symptoms in elderly individuals. However, no studies have explored the antidepressant-like effect of green tea in preclinical models of depression. The aim of this study was to investigate the antidepressant-like effects and the possible mechanism of action of green tea in widely used mouse models of depression. Mice were orally administered green tea polyphenols (GTP; 5, 10 and 20mg/kg) for 7days and assessed in the forced swimming test (FST) and tail suspension test (TST) 60min after the last GTP administration. Serum corticosterone and adrenocorticotrophic hormone (ACTH) levels were also determined immediately after the FST. Green tea polyphenols significantly reduced immobility in both the FST and TST but did not alter locomotor activity in the open field test, suggesting that GTP has antidepressant-like effects, and this action did not induce nonspecific motor changes in mice. Green tea polyphenols also reduced serum corticosterone and ACTH levels in mice exposed to the FST. The present study demonstrated that GTP exerts antidepressant-like effects in a mouse behavioral models of depression, and the mechanism may involve inhibition of the hypothalamic-pituitary-adrenal axis.

Effects of alkyl polyglycoside, a nonionic surfactant, and forage-to-concentrate ratio on rumen fermentation, amino acid composition of rumen content, bacteria and plasma in goats.

In the present study, the effects of different forage-to-concentrate ratios (F:C) and an alkyl polyglycoside (APG) supplementation on parameters of rumen and blood metabolism were investigated in goats. A 2 x 2 factorial experiment was arranged within a 4 x 4 Latin square design (four 22-day periods), using four wether goats equipped with permanent ruminal cannulas. The experimental diets included two F:C levels (40:60 vs. 60:40), and two APG supplementation levels (None or 13 ml APG daily per animal). Rumen contents and blood samples were collected at the end of each period. Dietary F:C alteration affected plasma urea and influenced the proportions of leucine, histidine, arginine, glycine, proline, alanine, valine, phenylalanine, cysteine and tyrosine in rumen content, and the proportions of methionine, threonine and proline in solid-associated bacteria (SAB) significantly. Dietary APG decreased the proportions of valine and phenylalanine in rumen content, and the histidine content of liquid-associated bacteria. The interaction between dietary F:C and APG was significant for the proportions of glycine and alanine in rumen content, and the proportions of lysine and threonine in SAB. The proportion of lysine was greater, but the proportion of threonine was less in SAB for goats fed high F:C diet without APG supplementation. The proportions of plasma free amino acids and glucose concentration were not affected by experimental treatments. These results indicated that dietary APG addition affected the amino acid composition of the rumen content and ruminal bacteria, but this depended on the dietary F:C ratio. It is necessary to validate the effectiveness of dietary APG supplementation in further studies with more animals.