Single-cell RNA sequencing reveals that MYBL2 in malignant epithelial cells is involved in the development and progression of ovarian cancer.

Background: Ovarian carcinoma (OC) is a prevalent gynecological malignancy associated with high recurrence rates and mortality, often diagnosed at advanced stages. Despite advances in immunotherapy, immune exhaustion remains a significant challenge in achieving optimal tumor control. However, the exploration of intratumoral heterogeneity of malignant epithelial cells and the ovarian cancer tumor microenvironment is still limited, hindering our comprehensive understanding of the disease. Materials and methods: Utilizing single-cell RNA sequencing (scRNA-seq), we comprehensively investigated the cellular composition across six ovarian cancer patients with omental metastasis. Our focus centered on analysis of the malignant epithelial cells. Employing CytoTRACE and slingshot pseudotime analyses, we identified critical subpopulations and explored associated transcription factors (TFs) influencing ovarian cancer progression. Furthermore, by integrating clinical factors from a large cohort of bulk RNA sequencing data, we have established a novel prognostic model to investigate the impact of the tumor immune microenvironment on ovarian cancer patients. Furthermore, we have investigated the condition of immunological exhaustion. Results: Our study identified a distinct and highly proliferative subgroup of malignant epithelial cells, known as C2 TOP2A+ TCs. This subgroup primarily consisted of patients who hadn't received neoadjuvant chemotherapy. Ovarian cancer patients with elevated TOP2A expression exhibited heightened sensitivity to neoadjuvant chemotherapy (NACT). Moreover, the transcription factor MYBL2 in this subgroup played a critical role in ovarian cancer development. Additionally, we developed an independent prognostic indicator, the TOP2A TCs Risk Score (TTRS), which revealed a correlation between the High TTRS Group and unfavorable outcomes. Furthermore, immune infiltration and drug sensitivity analyses demonstrated increased responsiveness to Paclitaxel, Cisplatin, and Gemcitabine in the Low TTRS Group. Conclusion: This research deepens our understanding of malignant epithelial cells in ovarian cancer and enhances our knowledge of the ovarian cancer immune microenvironment and immune exhaustion. We have revealed the heightened susceptibility of the C2 TOP2A+ TCs subgroup to neoadjuvant chemotherapy and emphasized the role of MYBL2 within the C2 subgroup in promoting the occurrence and progression of ovarian cancer. These insights provide valuable guidance for the management of ovarian cancer treatment.

V-set and immunoglobulin domain containing 4 inhibits oxidative stress, mitochondrial dysfunction, and inflammation to attenuate Parkinson's disease progression by activating the JAK2/STAT3 pathway.

OBJECTIVE: V-set and immunoglobulin domain containing 4 (VSIG4) inhibits neurological dysfunction, microglial M1 polarization, and inflammation to participate in the progression of neurological disorders, but evidence regarding Parkinson's disease (PD) is scarce. The present study intended to investigate the engagement of VSIG4 in PD progression, and the potential mechanism. METHODS: BV-2 cells were treated with 1-Methyl-4-phenylpyridinium (MPP+) to establish PD model. MPP+ treated BV-2 cells were infected with VSIG4 overexpression adenovirus-associated virus (AAV) (oeVSIG4) and negative control AAV (oeNC), and AZD1480 (JAK2 inhibitor) was added to these cells. RESULTS: MPP+ reduced VSIG4 mRNA (P < 0.05) and protein (P < 0.05) in BV-2 cells. Interestingly, VSIG4 reduced malondialdehyde (P < 0.01), reactive oxygen species (P < 0.01), NOD-like receptor family pyrin domain containing 3 (P < 0.05), cleaved-caspase1 (P < 0.05), tumor necrosis factor-α (P < 0.05), and interleukin-1ß (P < 0.05), but increased glutathione (P < 0.05), mitochondrial membrane potential (P < 0.05), phosphorylation (p)-JAK2 (P < 0.05), and p-STAT3 (P < 0.01) in MPP+ treated BV-2 cells, which indicated that VSIG4 inhibited oxidative stress, mitochondrial dysfunction, and inflammation, as well as activated the JAK2/STAT3 pathway in PD model. Moreover, AZD1480 inhibited the JAK2/STAT3 pathway and aggravated oxidative stress, mitochondrial dysfunction, and inflammation in PD model (all P < 0.05). Importantly, AZD1480 attenuated the influence of VSIG4 on oxidative stress, mitochondrial dysfunction, inflammation, and the JAK2/STAT3 pathway in PD model (all P < 0.05). CONCLUSION: VSIG4 suppresses oxidative stress, mitochondrial dysfunction, and inflammation by activating the JAK2/STAT3 pathway, which may be helpful in attenuating PD progression.

Ipsilateral restriction of chromosome movement along a centrosome, and apical-basal axis during the cell cycle.

Little is known about how distance between homologous chromosomes are controlled during the cell cycle. Here, we show that the distribution of centromere components display two discrete clusters placed to either side of the centrosome and apical/basal axis from prophase to G 1 interphase. 4-Dimensional live cell imaging analysis of centromere and centrosome tracking reveals that centromeres oscillate largely within one cluster, but do not cross over to the other cluster. We propose a model of an axis-dependent ipsilateral restriction of chromosome oscillations throughout mitosis.

Comparison of the efficacy and safety of a 730 nm picosecond titanium sapphire laser and a 755 nm picosecond alexandrite laser for the treatment of freckles in Asian patients: A two-center randomized, split-face, controlled trial.

OBJECTIVE: The 730 nm picosecond titanium sapphire laser is a novel laser that shows promising results in treating freckles. This study aimed to further investigate the efficacy and safety of the 730 nm picosecond titanium sapphire laser for treating freckles in Asian patients compared with those of the 755 nm picosecond alexandrite laser. METHODS: Each face of 86 participants was split into two parts and randomly assigned either one session of 730 or 755 nm picosecond-laser treatment each. Efficacy and safety were determined based on blinded visual evaluations and self-reports at each follow-up visit. RESULTS: The treatment outcomes of the 730 nm picosecond laser for the treatment of freckles were comparable to those of the 755 nm picosecond laser, with 68.99 ± 7.42% and 69.27 ± 7.75% clearance, respectively (p > 0.05). Participants achieved similar Global Aesthetic Improvement Scale scores (4.04 ± 0.31 vs. 4.02 ± 0.30, respectively [p > 0.05]). Additionally, the 730 nm picosecond laser was perceived to be less painful than the 755 nm picosecond laser (4.69 ± 1.63 vs. 5.65 ± 1.80 nm, p < 0.0001). CONCLUSION: The 730 nm picosecond laser is safe and effective for the treatment of freckles in Asian patients. Besides, the 730 nm picosecond laser is less painful than the 755 nm picosecond laser.

Recent advances in Chinese patent medicines entering the international market.

As an indispensable part of Traditional Chinese medicine (TCM), Chinese patent medicines have played an important role in preventing and treating diseases in China. Since they are easy to use, easy to store, and cost-effective, Chinese patent medicines have been generally accepted and widely used in Chinese clinical practice as a vital medical resource. In recent years, as TCM has developed and it has been accepted around the world, many Chinese patent medicine companies have gained international market access and successfully registered several Chinese patent medicines as over-the-counter (OTC) or prescription drugs in regions and countries that primarily use Western medicine such as the EU, Russia, Canada, Singapore, and Vietnam. Moreover, several Chinese patent medicines have been obtained the US Food and Drug Administration (FDA) approval conducting phase II or III clinical trials in the US. The current work has focused on several Chinese patent medicines that have been successfully registered or that have been submitted for registration abroad. Summarized here are recent advances in the efficacy and molecular mechanisms of these Chinese patent medicines to treat respiratory infectious diseases (Lianhua Qingwen capsules, Jinhua Qinggan granules, and Shufeng Jiedu Capsules), cardiovascular and cerebrovascular diseases (Compound Danshen Dripping Pills, Huatuo Zaizao pills, and Tongxinluo Capsules), cancers (a Kanglaite injection and a Shenqi Fuzheng Injection), and gynecological diseases (Guizhi Fuling Capsules). The hope is that this review will contribute to a better understanding of Chinese patent medicines by people around the world.

Fibroblast growth factor receptor 2 promotes the proliferation, migration, and invasion of ectopic stromal cells via activation of extracellular-signal-regulated kinase signaling pathway in endometriosis.

Endometriosis is defined as the presence of endometrial tissues with cancer-like features in extrauterine locations. Fibroblast growth factor receptor 2 (FGFR2) is a tyrosine kinase that is involved in cancer pathogenesis. This study aimed to determine the role of FGFR2 in endometriosis. A total of 29 pairs of ectopic and eutopic endometrial tissues were collected from women with endometriosis. Endometrial tissues from women with hysteromyomas were considered as normal controls. Primary ectopic stromal cells (ESCs) were isolated from the ectopic endometrium. The role of FGFR2 in ESCs was assessed using immunohistochemistry, polymerase chain reaction, cell counting kit-8 assay, EdU staining, flow cytometry, transwell assay, and western blotting. The following signaling pathways were detected using bioinformatic analysis and confirmed in vitro. By searching the GSE171154, GSE86543, and GSE77182 datasets, FGFR2 was identified as an upregulated overlapping gene in endometriosis. Compared to eutopic and normal endometria, FGFR2 was highly expressed in ectopic tissues. Transfection of primary ESCs with FGFR2 small interfering RNA (siRNA) repressed the viability and proliferation of cells and induced apoptosis. FGFR2 siRNA inhibited the migration, invasion, and transforming growth factor-ß1-triggered epithelial-mesenchymal transition (EMT). Extracellular signal-regulated kinase (ERK) signaling was found to be a downstream signaling pathway for FGFR2. The ERK1/2 inhibitor PD98059 was found to reverse the promoting effects of FGFR2 on ESC proliferation and invasion. FGFR2 silencing effectively inhibited the growth, migration, invasion, and EMT of ESCs. The effects of FGFR2 on endometriosis might be mediated via the activation of ERK signaling.

The positive role of traditional Chinese medicine as an adjunctive therapy for cancer.

Traditional Chinese medicine (TCM), especially Chinese herbal medicines and acupuncture, has been traditionally used to treat patients with cancers in China and other East Asian countries. Numerous studies have indicated that TCM not only alleviates the symptoms (e.g., fatigue, chronic pain, anorexia/cachexia, and insomnia) of patients with cancer and improves their quality of life (QOL) but also diminishes adverse reactions and complications caused by chemotherapy, radiotherapy, or targeted-therapy. Therefore, Chinese herbal medicines and acupuncture and other alternative therapies need to be understood by TCM physicians and other health care providers. This review mainly summarizes the experimental results and conclusions from literature published since 2010, and a search of the literature as been performed in the PubMed, MEDLINE, Web of Science, Scopus, Springer, ScienceDirect, and China Hospital Knowledge Database (CHKD) databases. Some Chinese herbal medicines (e.g., Panax ginseng, Panax quinquefolius, Astragali radix, Bu-zhong-yi-qi-tang (TJ-41), Liu-jun-zi-tang (TJ-43), Shi-quan-da-bu-tang (TJ-48), and Ban-xia-xie-xin-tang (TJ-14)) and some acupuncture points (e.g., Zusanli (ST36), Zhongwan (CV12), Neiguan (PC6) and Baihui (GV20)) that are commonly used to treat cancer-related symptoms and/or to reduce the toxicity of chemotherapy, radiotherapy, or targeted-therapy are highlighted and summarized. Through a review of literature, we conclude that TCM can effectively alleviate adverse gastrointestinal reactions (including diarrhea, nausea, and vomiting) to these anti-cancer therapies, decrease the incidence of bone marrow suppression, alleviate cardiotoxicity, and protect against chemotherapy-induced peripheral neuropathy and radiation-induced pneumonitis. Moreover, TCM can alleviate epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI)-related acneiform eruptions, diarrhea, and other adverse reactions. The hope is that this review can contribute to an understanding of TCM as an adjuvant therapy for cancer and that it can provide useful information for the development of more effective anti-cancer therapies. However, more rigorously designed trials involving cancer treatment must be conducted in the future, including complete quality control and standardized models at the cellular, organic, animal and clinical levels, in order to study TCM in multiple forms and at multiple levels.

The role of the MAP kinase-kinase protein StMKK1 in potato immunity to different pathogens.

Mitogen-activated protein kinase (MAPK) cascades play important roles in plant immunity. Previously, we reported that the potato StMKK1 protein negatively regulates Nicotiana benthamiana resistance to Phytophthora infestans. However, the functions of StMKK1 in potato immunity are unknown. To investigate the roles of StMKK1 in potato resistance to different pathogens, such as the potato late-blight pathogen P. infestans, the bacterial wilt pathogen Ralstonia solanacearum, and the gray-mold fungal pathogen Botrytis cinerea, we generated StMKK1 transgenic lines and investigated the response of potato transformants to destructive oomycete, bacterial, and fungal pathogens. The results showed that overexpression and silencing of StMKK1 do not alter plant growth and development. Interestingly, we found that StMKK1 negatively regulated potato resistance to the hemibiotrophic/biotrophic pathogens P. infestans and R. solanacearum, while it positively regulated potato resistance to the necrotrophic pathogen B. cinerea. Further investigation showed that overexpression of StMKK1 suppressed potato pathogen-associated molecular pattern (PAMP)-triggered immunity (PTI) and salicylic acid (SA)-related responses, while silencing of StMKK1 enhanced PTI and SA-related immune responses. Taken together, our results showed that StMKK1 plays dual roles in potato defense against different plant pathogens via negative regulation of PTI and SA-related signaling pathways.

Hematoporphyrin monomethyl ether photodynamic therapy for the treatment of facial port-wine stains resistant to pulsed dye laser.

BACKGROUND: Pulsed dye laser is the first treatment choice for port-wine stains. However, as some facial port-wine stains are resistant to this modality, we evaluated the efficacy and safety of hematoporphyrin monomethyl ether (hemoporfin) photodynamic therapy for the treatment of such resistant port-wine stains. METHODS: Patients were treated with two sessions of hemoporfin photodynamic therapy in our department. Patients received an intravenous injection of hematoporphyrin monomethyl ether (5 mg/kg) followed by 532 nm LED green light therapy. Three physicians graded the improvement in the port-wine stain, using a 4-level scale. Patients' satisfaction, reaction to treatment, and adverse effects were evaluated. RESULTS: Thirty-one patients (mean age, 23.9 ± 11.9 years, range, 3-48 years) were enrolled in this study. Hypertrophic lesions accounted for 48.4% of port-wine stain, with 80.6% of lesions being larger than 40 cm2. With regard to location, 41.9% were located on the central face and 32.3% involved a mix of the central and peripheral face. After one session, a treatment response was identified in 87.1% of cases, with the response deemed 'significant' in 29.0%. After two sessions, these rates increased to 100.0% and 61.3%, respectively. The clinical effect after two sessions was significantly greater than that after one session. Treatment reactions and adverse effects were well tolerated, and included pruritus, burning sensation, pain, edema, purpura-like change, blister, crust, and hyperpigmentation. CONCLUSIONS: Hemoporfin photodynamic therapy is a promising treatment for port-wine stains resistant to pulsed dye laser therapy.

Targeting MicroRNA-125b Promotes Neurite Outgrowth but Represses Cell Apoptosis and Inflammation via Blocking PTGS2 and CDK5 in a FOXQ1-Dependent Way in Alzheimer Disease.

This study aimed to explore the molecular regulatory network among microRNA-125b (miR-125b), forkhead box Q1 (FOXQ1), prostaglandin-endoperoxide synthase 2 (PTGS2), and cyclin-dependent kinase 5 (CDK5), as well as their effects on cell apoptosis, neurite outgrowth, and inflammation in Alzheimer disease (AD). Rat embryo cerebral cortex neurons and nerve growth factor-stimulated PC12 cells were insulted by Aß1-42 to construct two AD cellular models. Negative control (NC) inhibitor, miR-125b inhibitor, NC siRNA, FOXQ1 siRNA, PTGS2 siRNA, and CDK5 siRNA were transferred into the two AD cellular models alone or combined. Then, cell apoptosis, neurite outgrowth, proinflammatory cytokines, miR-125b, FOXQ1, PTGS2, and CDK5 expressions were detected. MiR-125b inhibition facilitated neurite outgrowth but suppressed cell apoptosis and proinflammatory cytokines (tumor necrosis factor-α, interleukin 1ß, and interleukin 6); meanwhile, it upregulated FOXQ1 but downregulated PTGS2 and CDK5. Furthermore, FOXQ1 inhibition promoted cell apoptosis and proinflammatory cytokines but repressed neurite outgrowth; PTGS2 inhibition achieved the opposite effects; CDK5 inhibition attenuated cell apoptosis, whereas it less affected neurite outgrowth and inflammation. Notably, FOXQ1 inhibition attenuated, whereas PTGS2 inhibition elevated the effect of miR-125b inhibition on regulating neurite outgrowth, cell apoptosis, and proinflammatory cytokines. As for CDK5 inhibition, it enhanced the effect of miR-125b inhibition on regulating cell apoptosis, but less impacted the neurite outgrowth and proinflammatory cytokines. Additionally, PTGS2 inhibition and CDK5 inhibition both reversed the effect of FOXQ1 inhibition on regulating cell apoptosis, neurite outgrowth, and proinflammatory cytokines. In conclusion, targeting miR-125b alleviates AD progression via blocking PTGS2 and CDK5 in a FOXQ1-dependent way.

The toxicity and safety of traditional Chinese medicines: Please treat with rationality.

For a long time, many people have believed that traditional Chinese medicines (TCMs) are safe because they derive from natural products. However, this belief has been greatly challenged in recent years especially after some reports on aristolochic acid involved in the genesis of cancer. According to the Chinese pharmacopoeia, many TCMs are known to be toxic, causing damage to the nervous, liver, renal, respiratory, and reproductive system. How to reduce the toxicity of TCMs and how to avoid abuse of TCMs in daily practice is the question? Here, we will give a brief summary and some tips on these issues. First, the accurate differentiation of a specific syndrome is the foundation of an effective and individualized treatment strategy, as well as the key to applying TCMs. Second, through standard processing, proper compatibility, rational decoction, and appropriate dose for TCMs, the harm of TCMs can be effectively avoided. Third, it should be remembered that Chinese herbs cannot be taken continuously as dietary supplements. Finally, Chinese patent medicines should be used with caution. In addition, the dosage of TCMs should not exceed the limit prescribed by the current China Pharmacopoeia, which will ensure the balance of efficacy and toxicity. Taken together, it is necessary to treat the toxicity and safety of TCMs with rationality. The more toxicity we can find, the more safety patients will have.

[Microbial Community Distributions in Soils of an Oil Exploitation Site].

To design a reasonable and effective remediation scheme for soil in contaminated sites, it is necessary to understand the microbial communities in the soil. Samples were collected at different depths (0 cm to 400 cm) in four locations: one that was persistently contaminated and near an oil well, one that was historically contaminated in the middle of the site, one in a mud pit, and one in farmland. High-throughput sequencing of the V4 region of 16S rRNA in these samples was performed. In addition to physico-chemical properties of the soil, the α-diversity, species composition, and differences in species between groups of microorganisms were analyzed, and a principal coordinate analysis and canonical correlation analysis were conducted. Results showed that oil and salt contents in soils were the dominant factors affecting microbial community structure. Hydrocarbon-degrading microorganisms were abundant in oil-contaminated soils, whereas halophilic hydrocarbon-degrading microorganisms were present in soils with high salt contents. Therefore, hydrocarbon-degrading microorganisms might be useful in remediation of oil-contaminated sites.

An update on Chinese herbal medicines as adjuvant treatment of anticancer therapeutics.

Numerous studies have indicated that in cancer treatment Chinese herbal medicines in combination with chemo-, radio-, or targeted-therapy can be used to enhance the efficacy of and diminish the side effects and complications caused by these therapies. Therefore, an understanding of Chinese herbal medicines is needed by physicians and other health care providers. This review provides an update on Chinese herbal medicines as adjuvant treatment of anticancer therapeutics. First, some Chinese herbal medicines (e.g. Astragalus, Ginseng, Scutellaria barbata, TJ-41, TJ-48, PHY906, Huachansu injection, and Kanglaite injection) that are commonly used for treating the cancer and/or reducing the toxicity induced by chemo-, radio-, or targeted-therapy are discussed. These Chinese herbal medicines have been shown to possess great advantages in terms of suppressing tumor progression, increasing the sensitivity of chemo-, radio-, or targeted-therapeutics, improving an organism's immune system function, and lessening the damage caused by these therapeutics. Second, some clinical trials using Chinese herbal medicines as adjuvant improving cancer treatment related side effects and complications are reviewed. Some Chinese herbal medicines have a significant effect on reducing cancer-related fatigue and pain, improving peripheral neuropathy and gastrointestinal side effects including diarrhea, nausea, and vomiting, decrease the incidence of bone marrow suppression, protecting anthracycline-induced cardiotoxicity and radiation-induced pneumonitis, and relieving EGFR-TKIs related acneiform eruptions and other side effects. This review of those medicines should contribute to an understanding of Chinese herbal medicines as adjuvant treatment for cancer and provide useful information for the development of more effective anti-cancer drugs. However, rigorously designed trials on potential Chinese herbal medicine must be further examined involving cancer treatment especially molecular targeted-therapy in the future.

Cinobufacini inhibits epithelial-mesenchymal transition of human hepatocellular carcinoma cells through c-Met/ERK signaling pathway.

Cinobufacini, an aqueous extract from the skins and parotid venom glands of the toad Bufo bufo gargarizans Cantor, is a well known traditional Chinese medicine widely used in clinical cancer therapy in China. Its therapeutic effect is especially pronounced in liver cancer. However, the precise mechanisms induced by cinobufacini in human hepatocellular carcinoma (HCC) cells are still not very clear. Here, we investigated the effects and mechanisms of cinobufacini on inhibiting HepG2 cells invasion and metastasis. Epithelial-mesenchymal transition (EMT) is identified as an important initiation step for HCC metastasis. After the HepG2 cells were treated with different concentrations of cinobufacini, the expression of EMT related E-cadherin was increased while N-cadherin and Vimentin were decreased, and the expression of EMT related transcription factors Snail and Twist were decreased. Moreover, the phosphorylation of c-Met was inhibited by cinobufacini, and the expression of MEK1/2 and ERK1/2, the downstream kinase of the signal transduction pathway activated by c-Met, also decreased in a dose-dependent manner with cinobufacini. In addition, after the cells were treated with different concentrations of cinobufacini, there was a significant decrease in MMP-2 and MMP-9 expression in HepG2 cells. In conclusion, the current study suggested cinobufacini could prevent HepG2 cells migration and invasion via inhibiting EMT through c-Met/ERK signaling pathway, which might provide experimental evidence for cinobufacini treatment of HCC.

Adenovirus-mediated P311 ameliorates renal fibrosis through inhibition of epithelial-mesenchymal transition via TGF-ß1-Smad-ILK pathway in unilateral ureteral obstruction rats.

Epithelial-mesenchymal transition (EMT) is a critical step and key factor during renal fibrosis. Preventing renal tubular EMT is important for delaying the progression of chronic kidney disease (CKD). P311, a highly conserved 8-kDa intracellular protein, has been indicated as an important factor in myofibroblast transformation and in the progression of fibrosis. However, the related studies on P311 on renal fibrosis are limited and the mechanisms of P311 in the progression of renal tubulointerstitial fibrosis remain largely unknown. In the present study, we examined the effect of P311 on transforming growth factor-ß1 (TGF-ß1)-mediated EMT in a rat model of unilateral ureteral occlusion (UUO) renal fibrosis. The recombinant adenovirus p311 (also called Ad-P311) was constructed and transferred it into UUO rats, the preventive effect and possible mechanism of P311 on TGF-ß1-mediated EMT were explored. The UUO model was established successfully and Ad-P311 was administered into UUO rats each week for 4 weeks, then the serum levels of Cr, blood urea nitrogen (BUN) and albumin (ALB) were evaluated. H&E staining and Masson staining were performed to observe the pathological changes of kidneys. Immunohistochemical staining and western blot analysis were used to examine the EMT markers [E-cadherin and α-smooth muscle actin (α-SMA)], and signal transducers (p-Smad2/3 and Smad7). Integrin linked kinase (ILK) as a keyintracellular mediator that controls TGF-ß1-mediated-EMT was also assayed by western blot analysis. The results showed that P311 could alleviate renal tubular damage and interstitial fibrosis improving Cr, BUN and ALB serum levels in UUO kidneys. Furthermore, P311 attenuated TGF-ß1-mediated EMT through Smad-ILK signaling pathway with an increase in α-SMA, pSmad2/3 and ILK expression, and a decrease in E-cadherin and Smad7 expression in UUO kidneys. In conclusion, P311 may be involved in the pathogenesis of renal fibrosis by blocking TGF-ß1-mediated EMT via TGF-ß1-Smad-ILK pathway in UUO kidneys. P311 may be a novel target for the control of renal fibrosis and the progression of CKD.

Shenqi detoxification granule combined with P311 inhibits epithelial-mesenchymal transition in renal fibrosis via TGF-ß1-Smad-ILK pathway.

Shenqi detoxification granule (SDG), a traditional Chinese herbal formula, has been shown to have nephroprotective and anti-fibrotic activities in patients with chronic kidney disease (CKD). However, its mechanisms in renal fibrosis and the progression of CKD remain largely unknown. P311, a highly conserved 8-kDa intracellular protein, plays a key role in renal fibrosis by regulating epithelial-mesenchymal transition (EMT). Previously, we found P311 might be involved in the pathogenesis of renal fibrosis by inhibiting EMT via the TGF-ß1-Smad-ILK pathway. We also found SDG combined with P311 could ameliorate renal fibrosis by regulating the expression of EMT markers. Here we further examined the effect and mechanism of SDG combined with P311 on TGF-ß1-mediated EMT in a rat model of unilateral ureteral occlusion (UUO) renal fibrosis. After establishment of the UUO model successfully, the rats were gavaged with SDG daily and/or injected with recombinant adenovirus p311 (also called Ad-P311) through the tail vein each week for 4 weeks. Serum creatinine (Cr), blood urea nitrogen (BUN) and albumin (ALB) levels were tested to observe renal function, and hematoxylin eosin (HE) and Masson staining were performed to observe kidney histopathology. Furthermore, the expression of EMT markers (E-cadherin and α-smooth muscle actin (α-SMA)) and EMT-related molecules TGF-ß1, pSmad2/3, Smad7 and ILK were observed using immunohistochemical staining and Western blot analysis. Treatment with SDG and P311 improved renal function and histopathological abnormalities, as well as reversing the changes of EMT markers and EMT-related molecules, which indicated SDG combined with P311 could attenuate renal fibrosis in UUO rats, and the underlying mechanism might involve TGF-ß1-mediated EMT and the TGF-ß1-Smad-ILK signaling pathway. Therefore, SDG might be a novel alternative therapy for treating renal fibrosis and delaying the progression of CKD. Furthermore, SDG combined with P311 might have a synergistic effect on attenuating renal fibrosis.

[Relationship between hepatitis B virus X protein and hepatic cellular cancer].

Hepatic cellular cancer (HCC) is one of the most common cancers in the world, which is a serious threat to human health and life quality. More than 700,000 people die of HCC each year on average, and its incidence increases in many countries. Chronic hepatitis B virus (HBV) infection has been identified as a dominant risk factor for HCC. The pathogenesis of HBV-induced hepatocarcinogenesis is, however, incompletely understood. Evidence currently available supports a key role of the HBV X protein (HBx) in the cancer transformation and malignant tumor metastasis. HBx is a multifunctional regulator that may cooperate with the host factors to exert its effects on transcription, signal transduction, cell cycle progression, apoptosis, protein degradation, expression of oncogene and anti-oncogene. This review presents the current knowledge in the molecular pathogenesis of HBx in the induction of HCC.

Adenovirus-mediated P311 inhibits TGF-ß1-induced epithelial-mesenchymal transition in NRK-52E cells via TGF-ß1-Smad-ILK pathway.

P311, a highly conserved 8-kDa intracellular protein, has been indicated as an important factor in myofibroblast transformation and in the progression of fibrosis. In the present study, we constructed a recombinant adenovirus vector of p311 (called Ad-P311) and transferred it into rat renal proximal tubular epithelial cells (NRK-52E) to explore the effect of P311 on epithelial-mesenchymal transition (EMT) of NRK-52E cells induced by TGF-ß1 and to elucidate its underlying mechanism against EMT. After successfully construction of Ad-P311 and transfer into NRK-52E cells, the proliferation and growth of P311-expressing cells was detected by MTT assay. TGF-ß1 was used to induce NRK-52E cells and Western blot analysis was used to examine the EMT markers (E-cadherin and α-smooth muscle actin (α-SMA)), signal transducers (p-Smad2/3 and Smad7). Integrin Linked Kinase (ILK) as a key intracellular mediator that controls TGF-ß1-induced-EMT was also assayed by Western blot analysis. The results showed that P311 transfection could significantly inhibit the proliferation and growth of TGF-ß1 induced NRK-52E cells. The results also showed that TGF-ß1 could induce EMT in NRK-52E cells through Smad-ILK signaling pathway with an increase in α-SMA, pSmad2/3 and ILK expression, and a decrease in E-cadherin and Smad7 expression. However, P311 efficiently blocked Smad-ILK pathway activation and attenuated all these EMT changes induced by TGF-ß1. These findings suggest that P311 might be involved in the pathogenesis of renal fibrosis by inhibiting the EMT process via TGF-ß1-Smad-ILK pathway. P311 might be a novel target for the control of renal fibrosis and the progression of CKD.

Chinese herbal medicine Shenqi Detoxification Granule inhibits fibrosis in adenine induced chronic renal failure rats.

BACKGROUND: Progressive fibrosis accompanies all chronic renal disease, connective tissue growth factor (CTGF,) and platelet-derived growth factor-B, (PDGF-B,) play important roles in extra-cellular matrix abnormal accumulation, while endothelin-1 (ET-1) nitric oxide (NO,) are related to endothelial dysfunction, which mediates the progression of renal fibrosis. Shenqi Detoxification Granule (SDG), a traditional Chinese herbal formula, has been used for treatment of chronic renal failure in clinic for many years. MATERIALS AND METHODS: In order to evaluate the efficacy, and explore the mechanism of SDG to inhibit the progression of renal fibrosis, study was carried out using the adenine-induced Wister rats as the CRF model, and losartan as postive control drug. Levels of serum creatinine [Scr], and blood urea nitrogen (BUN), albumin (ALB), 24hrs, urine protein (24hUP), triacylglycerol (TG), and cholesterol (CHO), together with ET-1, and NO were detected. Pathological changes of renal tissues were observed by HE, staining. In addition, CTGF and PDGF-B expression were analyzed by immuno-histo-chemistry. RESULTS: The results indicated that SDG can effectively reduce Scr, BUN, 24hUP, TG, and CHO levels, increase ALB levels, inhibit renal tissue damage in CRF rats, and the mechanism maybe reduce PDGF-B, CTGF expression and ET-1/NO. CONCLUSION: Shenqi Detoxification Granule is a beneficial treatment for chronic renal failure.