The spleen is a secondary lymphoid organ which can influence the progression of multiple diseases, notably liver cirrhosis. In chronic liver diseases, splenomegaly and hypersplenism can manifest ...following the development of portal hypertension. These splenic abnormalities correlate with and have been postulated to facilitate the progression of liver fibrosis to cirrhosis, although precise mechanisms remain poorly understood. In this review, we summarize the literature to highlight the mechanistic contributions of splenomegaly and hypersplenism to the development of liver cirrhosis, focusing on three key aspects: hepatic fibrogenesis, hepatic immune microenvironment dysregulation and liver regeneration. We conclude with a discussion of the possible therapeutic strategies for modulating splenic abnormalities, including the novel potential usage of nanomedicine in non-surgically targetting splenic disorders for the treatment of liver cirrhosis.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Recent studies have revealed robust metabolic changes during cell differentiation. Mitochondria, the organelles where many vital metabolic reactions occur, may play an important role. Here, we report ...the involvement of SIRT3-regulated mitochondrial stress in osteoblast differentiation and bone formation. In both the osteoblast cell line MC3T3-E1 and primary calvarial osteoblasts, robust mitochondrial biogenesis and supercomplex formation were observed during differentiation, accompanied by increased ATP production and decreased mitochondrial stress. Inhibition of mitochondrial activity or an increase in mitochondrial superoxide production significantly suppressed osteoblast differentiation. During differentiation, SOD2 was specifically induced to eliminate excess mitochondrial superoxide and protein oxidation, whereas SIRT3 expression was increased to enhance SOD2 activity through deacetylation of K68. Both SOD2 and SIRT3 knockdown resulted in suppression of differentiation. Meanwhile, mice deficient in SIRT3 exhibited obvious osteopenia accompanied by osteoblast dysfunction, whereas overexpression of SOD2 or SIRT3 improved the differentiation capability of primary osteoblasts derived from SIRT3-deficient mice. These results suggest that SIRT3/SOD2 is required for regulating mitochondrial stress and plays a vital role in osteoblast differentiation and bone formation.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
•Baicalein possesses potent anti-HCC activity both in vitro and in vivo.•Baicalein exerts its anti-HCC effect via several cancer-related signaling or molecules.•Baicalein may be developed as a ...potential, novel anti-cancer drug for HCC treatment.
Baicalein (5,6,7-trihydroxy-2-phenyl-4H-1-benzopyran-4-one) is a flavonoid compound derived from the roots of Scutellaria baicalensis. It has historically been used in anti-oxidant, anti-virus, anti-bacteria, anti-inflammatory and anti-allergic therapies. Recently, baicalein has been found to possess anti-cancer activities via its effect on a variety of biological processes involving cell proliferation, metastasis, apoptosis and autophagy and so on. Hepatocellular carcinoma (HCC) is one of the most prevalent malignancies and high fatality rate worldwide. Noteworthy, treatment protocols of HCC include conventional resection and chemotherapy, all of which may result in enormous mortality rate. Therefore, there is extreme interest to find a relatively non-toxic medicine which may reduce side effects without compromising therapeutic efficacy. Many studies have showed that baicalein is one such potential candidate. In this review, we summarized the various anti-cancer effects of baicalein on HCC and their underlying molecular mechanisms based on in vitro and in vivo experimental evidences discovered so far. Taken together, baicalein may be developed as a potential, novel anticancer drug for HCC treatment.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Background/Aims: Baicalein has been shown to possess significant anti-hepatoma activity by inhibiting cell proliferation. Whether the anti-proliferative effect of baicalein is related to its ...modulation of miRNA expression in hepatocellular carcinoma (HCC) is still unknown. Methods: The anti-proliferative effects of baicalein on HCC cell line Bel-7402 was assessed by detecting the proliferation activity, cell cycle distribution, expression changes of p21/CDKN1A, P27/CDKN1B, total Akt and phosphoryted AKT. Microarray analysis was conducted to determine the miRNA expression profiles in baicalein-treated or untreated Bel-7402 cells and then validated by qRT-PCR in two HCC cell lines (Bel-7402 and Hep3B). The gain-of-function of miR-3127-5p was performed by detecting anti-proliferative effects after transfecting miRNA mimics in cells. Finally, the expression level of miR-3127-5p in different HCC cell lines was determined by qRT-PCR. Results: Baicalein was able to inhibit the proliferation of Bel-7402 cells by inducing cell cycle arrest at the S and G2/M phase via up-regulating the expression of p21/CDKN1A and P27/CDKN1B and suppressing the PI3K/Akt pathway. Baicalein could alter the miRNA expression profiles in Bel-7402 cells. Putative target genes for differentially expressed miRNAs could be enriched in terms of cell proliferation regulation, cell cycle arrest and were mainly involved in MAPK, PI3K-Akt, Wnt, Hippo and mTOR signaling pathways. MiR- 3127-5p, one of up-regulated miRNAs, exhibits low expression level in several HCC cell lines and its overexpression could inhibit cell growth of Bel-7402 and Hep3B cell lines by inducing S phase arrest by up-regulating the expression of p21and P27 and repressing the PI3K/Akt pathway. Conclusions: Modulation of miRNA expression may be an important mechanism underlying the anti-hepatoma effects of baicalein.
Hepatitis B virus (HBV) and hepatitis C virus (HCV) infection were known to be risk factors for HCC, they were suspected to promote its development by eliciting epigenetic changes. However, the ...precise gene targets and underlying mechanisms have not been elucidated. Epigenetic regulation of gene expression has emerged as a fundamental aspect of cancer development and progression. The molecular mechanisms of carcinogenesis in hepatocellular carcinoma involve a complex interplay of both genetic and epigenetic factors. DNA methylation, post-translational modifications of histone proteins, chromatin remodeling, and noncoding RNAs are four major types of mechanistic layers in the field of epigenetics. HBV infection could affect methylation on p16(INK4A), GSTP1, CDH1(E-cadherin), RASSF1A, p21(WAF1/CIP1) genes, which may play important roles in the development of HCC. HCV infection was related to aberrant methylation on SOCS-1, Gadd45β, MGMT, STAT1 and APC. Other epigenetic alterations included histone proteins, chromatin remodeling, and noncoding RNAs were described in literature. Uncovering the epigenetic alterations of HBV/HCV-induced HCC carcinogenesis could highlight a new strategy for deciphering the mechanism of HCC tumorigenesis and development, as well as a potential diagnostic advantage.
Baicalein, a widely used Chinese herbal medicine, has historically been used in anti-inflammatory and anti-cancer therapies. However, the anti-metastatic effect and molecular mechanism(s) of ...baicalein on hepatocellular carcinoma (HCC) remain poorly understood. Therefore, the purpose of this study was to assess the anti-metastatic effects of baicalein and related mechanism(s) on HCC. Based on assays utilized in both HCC cell lines and in an animal model, we found that baicalein inhibited tumor cell metastasis in vivo and in vitro. Furthermore, after treatment with baicalein for 24 hours, there was a decrease in the levels of matrix metalloproteinase-2 (MMP-2), MMP-9 and urokinase-type plasminogen activator (u-PA) expression as well as proteinase activity in hepatocellular carcinoma MHCC97H cells. Meanwhile, the expression of tissue inhibitor of metalloproteinase-1 (TIMP-1) and TIMP-2 were increased in a dose-dependent fashion. Moreover, baicalein treatment dramatically decreased the levels of the phosphorylated forms of MEK1 and ERK1/2. MEK1 overexpression partially blocked the anti-metastatic effects of baicalein. Combined treatment with an ERK inhibitor (U0126) and baicalein resulted in a synergistic reduction in MMP-2, MMP-9 and u-PA expression and an increase in TIMP-1 and TIMP-2 expression; the invasive capabilities of MHCC97H cells were also inhibited. In conclusion, baicalein inhibits tumor cell invasion and metastasis by reducing cell motility and migration via the suppression of the ERK pathway, suggesting that baicalein is a potential therapeutic agent for HCC.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The excessive use of chemical herbicides has resulted in evolution of herbicide-resistant weeds. Cytochrome P450 monooxygenases (P450s) are vital detoxification enzymes for herbicide-resistant weeds. ...Herein, we confirmed a resistant (R) Polypogon fugax population showing resistance to quizalofop-p-ethyl, acetolactate synthase (ALS)-inhibiting herbicide pyroxsulam, and several other ACCase (acetyl-CoA carboxylase)-inhibiting herbicides. Molecular analysis revealed no target-site gene mutations in the R population. Foliar spraying with malathion clearly reversed the quizalofop-p-ethyl phytotoxicity. Higher level of quizalofop-p-ethyl degradation was confirmed in the R population using HPLC analysis. Subsequently, RNA-Seq transcriptome analysis indicated that the overexpression of CYP89A2 gene appeared to be responsible for reducing quizalofop-p-ethyl phytotoxicity. The molecular docking results supported a metabolic effect of CYP89A2 protein on most herbicides tested. Furthermore, we found that low doses of herbicides stimulated the rhizosphere enzyme activities in P. fugax and the increase of rhizosphere dehydrogenase of R population may be related to its resistance mechanism. In summary, our research has shown that metabolic herbicide resistance mediated by CYP89A2, contributes to quizalofop-p-ethyl resistance in P. fugax.
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•Polypogon fugax has evolved cross-resistance to herbicide in China.•P450s-mediated metabolism was responsible for reducing herbicide accumulation.•Malathion can remediate the phytotoxicity of herbicide to the herbicide-resistant plant.•P. fugax CYP89A2 gene played significant role in herbicide metabolism and detoxification.•Rhizosphere enzyme activities may be related to the herbicide resistance mechanism.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The liver is a site of complex immune activity. The hepatic immune system tolerates harmless immunogenic loads in homeostasis status, shelters liver function, while maintaining vigilance against ...possible infectious agents or tissue damage and providing immune surveillance at the same time. Activation of the hepatic immunity is initiated by a diverse repertoire of hepatic resident immune cells as well as non-hematopoietic cells, which can sense “danger signals” and trigger robust immune response. Factors that mediate the regulation of hepatic immunity are elicited not only in liver, but also in other organs, given the dual blood supply of the liver
via
both portal vein blood and arterial blood. Emerging evidence indicates that inter-organ crosstalk between the liver and other organs such as spleen, gut, lung, adipose tissue, and brain is involved in the pathogenesis of liver diseases. In this review, we present the features of hepatic immune regulation, with particular attention to the correlation with factors from extrahepatic organ. We describe the mechanisms by which other organs establish an immune association with the liver and then modulate the hepatic immune response. We discuss their roles and distinct mechanisms in liver homeostasis and pathological conditions from the cellular and molecular perspective, highlighting their potential for liver disease intervention. Moreover, we review the available animal models and methods for revealing the regulatory mechanisms of these extrahepatic factors. With the increasing understanding of the mechanisms by which extrahepatic factors regulate liver immunity, we believe that this will provide promising targets for liver disease therapy.
Similar to two other lethal coronaviruses, SARS‐CoV and MERS‐CoV, SARS‐CoV‐2 induces excessive and aberrant host immune responses that are always accompanied by cytokine storms (CS) and subsequent ...ALI or even ARDS, resulting in multiple organ failure and death. 2 Even in patients who were treated in intensive care units for CS, persistent inflammation led to serious sequelae of lung fibrosis, causing lung dysfunction and reduced quality of life. 3 Although corticosteroid given to reverse catabolism in critical illness decreased the mortality after SARS and MERS infection, the clinical application of corticosteroid has been restricted in COVID‐19, considering its delay in virus clearance and complications in survivors. To alleviate acute respiratory disease and reverse pulmonary fibrosis in intensive‐care SARS‐CoV‐2‐infected patients, three curative properties of MSCs have emerged (Figure 1): (a) directly inducing the apoptosis of activated T cells to relieve the aberrant and excessive immune responses, (b) homing toward specific injuries of lung to maintain homeostasis as well as promote regeneration, and (c) releasing cytokines to diminish inflammation and extracellular vesicles (EVs) to stimulate tissue reparation. 1 Notably, it has been proved that MSC‐released cytokines can potently inhibit neutrophil intravasation and enhance the differentiation of macrophages. 5,6 Moreover, these MSC‐released EVs can deliver microRNA, mRNA, DNA, proteins, and metabolites into host cells in specific injuries of the lung to promote lung repair as well as regeneration and restore lung function. 1 1 FIGURE. Potential mechanism of MSCs in the treatment of severe COVID‐19 As the continuing epidemic threat of SARS‐CoV‐2 to global health and the fast‐growing number of fatalities, advancing new therapeutic development becomes central or primary to minimize the death and sequelae from SARS‐CoV‐2 infection. ...MSCs should be considered as a potential treatment for these critical patients.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Due to the urgency caused by the COVID-19 pandemic worldwide, vaccine manufacturers have to shorten and parallel the development steps to accelerate COVID-19 vaccine production. Although all usual ...safety and efficacy monitoring mechanisms remain in place, varied attitudes toward the new vaccines have arisen among different population groups.
This study aimed to discern the evolution and disparities of attitudes toward COVID-19 vaccines among various population groups through the study of large-scale tweets spanning over a whole year.
We collected over 1.4 billion tweets from June 2020 to July 2021, which cover some critical phases concerning the development and inoculation of COVID-19 vaccines worldwide. We first developed a data mining model that incorporates a series of deep learning algorithms for inferring a range of individual characteristics, both in reality and in cyberspace, as well as sentiments and emotions expressed in tweets. We further conducted an observational study, including an overall analysis, a longitudinal study, and a cross-sectional study, to collectively explore the attitudes of major population groups.
Our study derived 3 main findings. First, the whole population's attentiveness toward vaccines was strongly correlated (Pearson r=0.9512) with official COVID-19 statistics, including confirmed cases and deaths. Such attentiveness was also noticeably influenced by major vaccine-related events. Second, after the beginning of large-scale vaccine inoculation, the sentiments of all population groups stabilized, followed by a considerably pessimistic trend after June 2021. Third, attitude disparities toward vaccines existed among population groups defined by 8 different demographic characteristics. By crossing the 2 dimensions of attitude, we found that among population groups carrying low sentiments, some had high attentiveness ratios, such as males and individuals aged ≥40 years, while some had low attentiveness ratios, such as individuals aged ≤18 years, those with occupations of the 3rd category, those with account age <5 years, and those with follower number <500. These findings can be used as a guide in deciding who should be given more attention and what kinds of help to give to alleviate the concerns about vaccines.
This study tracked the year-long evolution of attitudes toward COVID-19 vaccines among various population groups defined by 8 demographic characteristics, through which significant disparities in attitudes along multiple dimensions were revealed. According to these findings, it is suggested that governments and public health organizations should provide targeted interventions to address different concerns, especially among males, older people, and other individuals with low levels of education, low awareness of news, low income, and light use of social media. Moreover, public health authorities may consider cooperating with Twitter users having high levels of social influence to promote the acceptance of COVID-19 vaccines among all population groups.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
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