MDSCs in bone metastasis: Mechanisms and therapeutic potential.

Bone metastasis (BM) is a frequent complication associated with advanced cancer that significantly increases patient mortality. Myeloid-derived suppressor cells (MDSCs) play a pivotal role in BM progression by promoting angiogenesis, inhibiting immune responses, and inducing osteoclastogenesis. MDSCs induce immunosuppression through diverse mechanisms, including the generation of reactive oxygen species, nitric oxide, and immunosuppressive cytokines. Within the bone metastasis niche (BMN), MDSCs engage in intricate interactions with tumor, stromal, and bone cells, thereby establishing a complex regulatory network. The biological activities and functions of MDSCs are regulated by the microenvironment within BMN. Conversely, MDSCs actively contribute to microenvironmental regulation, thereby promoting BM development. A comprehensive understanding of the indispensable role played by MDSCs in BM is imperative for the development of novel therapeutic strategies. This review highlights the involvement of MDSCs in BM development, their regulatory mechanisms, and their potential as viable therapeutic targets.

Global trends in bufalin application research for cancer from 2003 to 2022: A bibliometric and visualised analysis.

Background: Bufalin, the main active ingredient of the traditional Chinese medicine huachansu, is used in the clinical treatment of colorectal cancer and has multiple effects, including the inhibition of migratory invasion, reversal of multi-drug resistance, induction of apoptosis and differentiation, and inhibition of angiogenesis. Methods: We collected relevant articles on bufalin from 2003 to 2022 using the Web Science platform, and analysed the information using VOSviewer, CiteSpace, and Microsoft Excel to categorise and summarise the publications over the past 20 years. Results: We collected 371 papers, with a steady increase in the number of articles published globally. China has the highest number of published articles, whereas Japan has the highest number of citations. Currently, there is considerable enthusiasm for investigating the anti-tumour mechanism of bufalin and optimising drug delivery systems for its administration. Conclusion: For the first time, we present a comprehensive overview of papers published worldwide on bufalin over the past two decades and the progress of its application in tumour therapy. We summarised the key authors, institutions, and countries that have contributed to the field and the potential of bufalin for the treatment of cancer. This will help other researchers obtain an overview of progress in the field, enhance collaboration and knowledge sharing, and promote future research on bufalin.

PGE2-JNK signaling axis non-canonically promotes Gli activation by protecting Gli2 from ubiquitin-proteasomal degradation.

Both bench and bedside investigations have challenged the supportive role of Hedgehog (Hh) activity in the progression of colorectal cancers, thus raising a critical need to further deeply determine the contribution of Hh to the growth of colorectal cancer. Combining multiple complementary means, including in vitro and in vivo inflammatory colorectal cancer models, and pathological analysis of clinical colorectal cancer patients samples. We report that colorectal cancer cells hijack prostaglandin E2 (PGE2) to non-canonically promote Hh transcriptional factor Gli activity and Gli-dependent proliferation of colorectal cancer cells in a Smo-independent manner. Mechanistically, PGE2 activates c-Jun N-terminal kinase (JNK), which in turn enables Gli2 to evade ubiquitin-proteasomal degradation by phosphorylating Gli2 at Thr1546. This study not only presents evidence for understanding the contribution of Hh to colorectal cancers, but also provides a novel molecular portrait underlying how PGE2-activated JNK fine-tunes the evasion of Gli2 from ubiquitin-proteasomal degradation. Therefore, it proposes a rationale for the future evaluation of chemopreventive and selective therapeutic strategies for colorectal cancers by targeting PGE2-JNK-Gli signaling route.

The Anti-Tumor Effect and Mechanism of Triterpenoids in Rhus chinensis Mill. on Reversing Effector CD8+ T-cells Dysfunction by Targeting Glycolysis Pathways in Colorectal Cancer.

Rhus chinensis Mill. is a traditional Chinese medicine (TCM) which is commonly used for cancer treatments. Our previous work had proven that triterpenoids of Rhus chinensis (TER) could effectively regulate glycolysis involved in colorectal cancer (CRC) and play an important role in the prevention of T-cells dysfunction. This study aimed to systematically investigate the effects and mechanisms of TER on glucose metabolism in CRC, while the regulatory mechanisms of TER on restoring T-cells function and activity in CRC were explored as well. The extract of triterpenoids from Rhus chinensis was obtained, and production of lactic acid and glucose uptake were assayed. Also, the expression of CD8+ T-cells surface markers, cytokines secreted by CD8+ T cells, and the expression of key glycolytic enzymes and glucose deprivation induced by tumor cells were further examined. Notably, results showed that TER prevented the dysfunction in CD8+ T cells by enhancing mTOR activity and subsequent cellular metabolism. Furthermore, our findings also demonstrated that TER promoted glycolytic gene expression in CD8+ T cells in vivo, and significantly inhibited tumor growth. Altogether, our studies suggested that TER not only reversed effector CD8+ T-cells dysfunction and enhanced T-cells recognition, but also improved tumor microenvironment, thereby providing new insight into the prevention and treatment of CRC with TCM.

Effects and mechanisms of fatty acid metabolism­mediated glycolysis regulated by betulinic acid­loaded nanoliposomes in colorectal cancer.

Although previous studies have demonstrated that triterpenoids, such as betulinic acid (BA), can inhibit tumor cell growth, their potential targets in colorectal cancer (CRC) metabolism have not been systematically investigated. In the present study, BA­loaded nanoliposomes (BA­NLs) were prepared, and their effects on CRC cell lines were evaluated. The aim of the present study was to determine the anticancer mechanisms of action of BA­NLs in fatty acid metabolism­mediated glycolysis, and investigate the role of key targets, such as acyl­CoA synthetase (ACSL), carnitine palmitoyltransferase (CPT) and acetyl CoA, in promoting glycolysis, which is activated by inducing hexokinase (HK), phosphofructokinase­1 (PFK­1), phosphoenolpyruvate (PEP) and pyruvate kinase (PK) expression. The results demonstrated that BA­NLs significantly suppressed the proliferation and glucose uptake of CRC cells by regulating potential glycolysis and fatty acid metabolism targets and pathways, which forms the basis of the anti­CRC function of BA­NLs. Moreover, the effects of BA­NLs were further validated by demonstrating that the key targets of HK2, PFK­1, PEP and PK isoenzyme M2 (PKM2) in glycolysis, and of ACSL1, CPT1a and PEP in fatty acid metabolism, were blocked by BA­NLs, which play key roles in the inhibition of glycolysis and fatty acid­mediated production of pyruvate and lactate. The results of the present study may provide a deeper understanding supporting the hypothesis that liposomal BA may regulate alternative metabolic pathways implicated in CRC adjuvant therapy.

Cinobufacini Inhibits Colon Cancer Invasion and Metastasis via Suppressing Wnt/ß-Catenin Signaling Pathway and EMT.

Cinobufacini is a well-known Chinese medicine extracted from Venenum Bufonis, also called Chan Su. It has been used clinically for various cancers, including colon cancer. However, the function of Cinobufacini on colon cancer invasion and metastasis, and its underlying molecular mechanism, is still not clear. In this study, we investigated the function and mechanism of Cinobufacini on colon cancer invasion and metastasis both in vitro and in vivo studies. Human colon cancer cells were cultured. CCK assay was used to detect the effect of Cinobufacini on colon cancer cells proliferation. The invasion and migration abilities were observed by transwell assays, and the expression of invasion and migration related genes MMP2, MMP9, and epithelial-to-mesenchymal transition (EMT) relate genes were observed by Western blot assays. An orthotopic xenograft model in nude mice was established using colon cancer HCT116 cells, and the function of Cinobufacini on colon cancer invasion and metastasis were observed in vivo. We found Cinobufacini significantly inhibited colon cancer cell proliferation in a dose/time-dependent manner; the invasion and migration abilities of colon cancer were decreased after treated with Cinobufacini. The metastasis and EMT related genes MMP9, MMP2, N-cadherin and Snail were obviously down-regulated, while the expression of E-cadherin was up-regulated after treatment with Cinobufacini. The Wnt/ß-catenin signaling pathway related genes were observed using WB,and results show that the expression of ß-catenin, wnt3a, c-myc, cyclin D1, and MMP7 were all down-regulated after being treated with cinobufacini, while the expression of APC was up-regulated. In vivo studies of the volume and weight of orthotopic xenograft tumors showed significantly shrinkage in the Cinobufacini group compared to the control group. The enterocoelia and liver metastasis tumors were significantly decreased, and the expression of MMP9, MMP2, and ß-catenin were also down-regulated, while E-cadherin was up-regulated in vivo after the treatment with Cinobufacini. Our data proves that Cinobufacini can inhibit colon cancer invasion and metastasis both in vitro and in vivo; the mechanism is related by suppressing the Wnt/ß-catenin signaling pathway and then inhibiting the EMT of CRC.

Effect and Molecular Mechanisms of Traditional Chinese Medicine on Tumor Targeting Tumor-Associated Macrophages.

Traditional Chinese medicine (TCM) has been used as a significant cancer treatment method for many years in China. It has been demonstrated that TCM could assist in inhibiting the growth of tumors and prolonging the survival rates of cancer patients. Although the mechanism of TCM are still not clear, accumulating evidence has shown that they may be related to the tumor microenvironment (TME). Tumor-associated macrophages (TAMs) play a significant role in TME and are polarized to two phenotypes, M1 (classically activated) and M2 (alternatively activated) TAMs. The two different phenotypes of TAMs play converse roles in the TME and M2-polarized tumor-associated macrophages (M2-TAMs) always lead to poor prognosis in cancer patients compared to M1-polarized tumor-associated macrophages (M1-TAMs). In this review, the potential correlation between TCM and TAMs (especially the M2 phenotype) in tumor progression and promising TCM strategies targeting TAMs in cancer are discussed.

Triterpenoids Extracted from Rhus chinensis Mill Act Against Colorectal Cancer by Inhibiting Enzymes in Glycolysis and Glutaminolysis: Network Analysis and Experimental Validation.

Background: Rhus chinensis Mill is a traditional Chinese medicine (TCM) mostly used to treat several cancer types. Although previous studies have found that certain ingredients of R. chinensis such as flavonoids can inhibit tumor cell proliferation [e.g. colorectal cancer (CRC)], systematic research on the mechanism underlying anticancer effect of active compounds like triterpenoids (TER) is lacking.Study Design: Herein, the concept of "network pharmacology primarily based on active compounds" was applied to explore the anticancer mechanisms of TER extract from R. chinensis. In this regard, potential targets and pathways of glycolysis and glutaminolysis form the basis for the anti-CRC effect of triterpenoids. Network pharmacology was used to predict several key proteins in the metabolic pathways, which were further verified via western blot and metabolomics methods.Results: Our results showed that the total TER in R. chinensis remarkably inhibited the proliferation and apoptosis of SW620 cells. The top 4 compounds of TER (viz., betulinic acid-BTA, betulonic acid-BTOA, betulin-BT, and semialactic acid-SA) were confirmed through the detection of UPLC-MS and analysis of cell proliferation assays. Mechanistically, this study revealed that TER plays an anti-CRC role through key targets, such as ENO1, ALDOA, PFKFB3, PKM2, and LDHA, as well as key glycolytic and glutaminolytic pathways.Conclusion: Collectively, these results have provided new insights into the mechanism underlying anti-CRC effect of triterpenoids extract obtained from R. chinensis, mainly through combination of compositional quantitative analysis, network pharmacology, and experimental verification.

cRGD-Conjugated Fe3O4@PDA-DOX Multifunctional Nanocomposites for MRI and Antitumor Chemo-Photothermal Therapy.

BACKGROUND: Photothermal therapy (PTT) has great potential in the clinical treatment of tumors. However, most photothermal materials are difficult to apply due to their insufficient photothermal conversion efficiencies (PCEs), poor photostabilities and short circulation times. Furthermore, tumor recurrence is likely to occur using PTT only. In the present study, we prepared cyclo (Arg-Gly-Asp-d-Phe-Cys) [c(RGD)] conjugated doxorubicin (DOX)-loaded Fe3O4@polydopamine (PDA) nanoparticles to develop a multifunctional-targeted nanocomplex for integrated tumor diagnosis and treatment. MATERIALS AND METHODS: Cytotoxicity of Fe3O4@PDA-PEG-cRGD-DOX against HCT-116 cells was determined by cck-8 assay. Cellular uptake was measured by confocal laser scanning microscope (CLSM). Pharmacokinetic performance of DOX was evaluated to compare the differences between free DOX and DOX in nanocarrier. Performance in magnetic resonance imaging (MRI) and antitumor activity of complex nanoparticles were evaluated in tumor-bearing nude mice. RESULTS: Fe3O4@PDA-PEG-cRGD-DOX has a particle size of 200-300 nm and a zeta potential of 22.7 mV. Further studies in vitro and in vivo demonstrated their excellent capacity to target tumor cells and promote drug internalization, and significantly higher cytotoxicity with respect to that seen in a control group was shown for the nanoparticles. In addition, they have good thermal stability, photothermal conversion efficiencies (PCEs) and pH responsiveness, releasing more DOX in a mildly acidic environment, which is very conducive to their chemotherapeutic effectiveness in the tumor microenvironment. Fe3O4@PDA-PEG-cRGD-DOX NPs were used in a subcutaneous xenograft tumor model of nude mouse HCT-116 cells showed clear signal contrast in T2-weighted images and effective anti-tumor chemo-photothermal therapy under NIR irradiation. CONCLUSION: According to our results, Fe3O4@PDA-PEG-cRGD-DOX had a satisfactory antitumor effect on colon cancer in nude mice and could be further developed as a potential integrated platform for the diagnosis and treatment of cancer to improve its antitumor activity against colon cancer.

Bufalin inhibits gastric cancer invasion and metastasis by down-regulating Wnt/ASCL2 expression.

Achaete-scute-like 2 (ASCL2) is a transcription factor containing a basic helix-loop-helix (bHLH) domain and is a downstream target of Wnt signaling in intestinal stem cells. Bufalin is the primary active ingredient in Chan Su, a traditional Chinese medicine obtained from the skin and parotid venom glands of toads. The purpose of this study was to research the anti-invasion and anti-metastasis activity of bufalin in gastric cancer and to identify the potential mechanism. Bufalin inhibited gastric cancer cell invasion and metastasis, suppressed cancer cell colony formation, and inhibited the growth of subcutaneous xenografted tumors in nude mice. Furthermore, bufalin inhibited ASCL2 expression and down-regulated the expression of invasion-related genes such as MMP2, MMP9, and vimentin, thereby suppressing epithelial-mesenchymal transition (EMT) in gastric cancer. A Wnt signaling inhibitor (XAV939) down-regulated invasion and the expression of ASCL2, ß-catenin, and vimentin but up-regulated E-cadherin expression. In nude mice, bufalin inhibited the tumorigenic behavior of gastric cancer cells, induced cancer cell apoptosis, and regulated invasion-related gene expression. Together, our results suggest that bufalin arrests invasion and metastasis and that its mechanism of action may involve down-regulating Wnt/ASCL2 expression.

Bufalin reverses acquired drug resistance by inhibiting stemness in colorectal cancer cells.

Drug resistance is an obstacle to chemotherapy in tumor patients. Recent studies have shown that the high stemness of cancer cells may be induced by chemotherapeutic drugs, which is correlated with drug resistance. In the present study, we investigated the effects of bufalin on the stemness of colorectal cancer. We found that cisplatin could induce high stemness through the tumorsphere formation assay in vitro and in vivo in the colorectal cancer cell lines HCT116 and LoVo. In addition, cisplatin-treated tumorsphere cells showed drug­resistant properties. These results suggested that acquired drug resistance induced by cisplatin in colorectal cancer cells occurred via high stemness. On assessing the effects of bufalin, a traditional Chinese medicine monomer, we found that it could reverse the high stemness and drug resistance induced by cisplatin in colorectal cancer. These findings suggest that bufalin plays an adjuvant role in colorectal cancer chemotherapy and may help reverse acquired drug resistance. These findings may aid in the development of new therapeutic strategies.

Bufalin reverses ABCB1-mediated drug resistance in colorectal cancer.

Multidrug resistance (MDR), mainly mediated by ABCB1 transporter, is a major cause for chemotherapy failure. Bufalin (BU), an active component of the traditional Chinese medicine chan'su, has been reported to have antitumor effects on various types of cancer cells. The purpose of this present study was to investigate the reversal effect of BU on ABCB1-mediated multidrug resistance in colorectal cancer. BU at safe concentration (5, 10, 20 nM) could reverse chemosensitivity of ABCB1-overexpression HCT8/ADR, LoVo/ADR and HCT8/ABCB1 nearly back to their parental cells level. In addition, results from the drug accumulation studies revealed that BU was able to enhance intracellular accumulation of doxorubicin (DOX) and Rhodamine 123 (Rho-123) in a dose-dependent manner. Furthermore, Western blot assays showed that BU significantly inhibited the expression level of ABCB1 protein. Meanwhile, BU stimulated the ATPase activity of ABCB1, which suggested that BU might be a substrate of ABCB1. More interestingly, docking analysis predicted that BU could be docked into the large hydrophobic drug-binding cavity of human ABCB1. Importantly, BU remarkable increased the effect of DOX against the ABCB1 resistant HCT8/ADR colorectal cell xenografts in nude mice, without inducing any obvious toxicity. Overall, we concluded that BU efficiently reversed ABCB1-mediated MDR through not only inhibited the efflux function of ABCB1, but also down-regulate its protein expression, which might represent a potential and superior ABCB1 modulator in colorectal cancer.

Folate receptor targeted bufalin/ß-cyclodextrin supramolecular inclusion complex for enhanced solubility and anti-tumor efficiency of bufalin.

Bufalin (BF), a traditional Chinese medicine, exhibited inhibitory activities against a broad spectrum of tumor cells. The present study elaborates that bufalin was successfully encapsulated into the cavity of ß-cyclodextrin (ß-CD), which was determined by Fourier transform infrared spectroscopy (FT-IR), proton nuclear magnetic resonance spectroscopy (1H NMR), differential scanning calorimetry (DSC) and scanning electron microscopy (SEM). The best reaction mole ratio of BF/ß-CD was 1:5. The solubilities of bufalin in water and phosphate buffer solution (pH=7.4) were increased up to 24 and 34 times after encapsulated into the cavity of ß-CD respectively. The inclusion efficiency (IE) and drug loading (DL) of bufalin in the inclusion complex were (94.22±0.85)% and (14.11±0.20)%, respectively. Then ß-CD conjugated with folic acid (FA) were further prepared and employed to improve the anti-tumor efficacy of inclusion complex. The in vitro dissolution and solubility study showed better values of inclusion complex and FA targeted inclusion complex than that of pure BF. Cytotoxicity experiments by using HCT116 cell line revealed that the antitumor efficiency of bufalin were enhanced more than two folds in the presence of ß-CD and folate conjugated ß-CD (FA-PEI-ß-CD), which demonstrated the potential application of ß-CD (FA-PEI-ß-CD) as delivery vehicles of bufalin for antitumor therapy.

The Zuo Jin Wan Formula Induces Mitochondrial Apoptosis of Cisplatin-Resistant Gastric Cancer Cells via Cofilin-1.

Despite the status of cisplatin (DDP) as a classical chemotherapeutic agent in the treatment of cancer, the development of multidrug resistance often leads to a failure of DDP therapy. Here we found that phosphorylated cofilin-1 (p-cofilin-1) was overexpressed in the DDP-resistant human gastric cancer cell lines SGC7901/DDP and BGC823/DDP, relative to the respective parent cell lines (SGC7901 and BGC823), and that DDP induced the dephosphorylation of p-cofilin-1 in both parent lines but not in the DDP-resistant lines. However, we noted that the traditional Chinese medicine formula Zuo Jin Wan (ZJW) could induce the dephosphorylation of p-cofilin-1 and promote cofilin-1 translocation from the cytoplasm into the mitochondria in both SGC7901/DDP and BGC823/DDP cells. This mitochondrial translocation of cofilin-1 was found to induce the conversion of filamentous actin to globular-actin, activate mitochondrial damage and calcium overloading, and induce the mitochondrial apoptosis pathway. We further observed that these effects of ZJW on DDP-resistant human gastric cancer cell lines could be reversed via transfection with cofilin-1-specific siRNA, or treatment with a PP1 and PP2A inhibitor. These results suggest that ZJW is an effective drug therapy for patients with DDP-resistant gastric cancer.

Sinomenine, a COX-2 inhibitor, induces cell cycle arrest and inhibits growth of human colon carcinoma cells in vitro and in vivo.

Certain non-steroidal anti-inflammatory drugs may possess anti-tumorigenic effects in certain cancer cell types. Sinomenine (SIN) is an alkaloid from Sinomenium acutum, a Chinese medicinal plant that inhibits inflammatory reactions and that has been used in the treatment of neuralgia and rheumatic diseases. In this study, we investigated the anticancer effects of SIN against colorectal cancer in vitro and in vivo, as well as the underlying mechanisms. The effects of SIN on proliferation, cell cycle progression and cyclooxygenase (COX)-2 expression were examined in human colorectal cancer-derived SW1116 cells. The in vivo effects of SIN were examined in a model of SW1116 tumor xenograft growth in athymic nude mice. Changes in COX-2 expression induced by the biological effects of SIN were analyzed by western blot analysis. The effects of SIN treatment on G1 phase cell cycle regulators in xenografts were analyzed by immunohistochemistry. Our findings demonstrate that SIN inhibits the proliferation of SW1116 cells by promoting their accumulation in the G1 phase, with concomitant suppression of COX-2 expression. Time- and dose-dependent inhibition of tumor growth and reduced toxicity were observed in nude mice administered daily intraperitoneal injections of SIN at doses of 25, 50 and 100 mg/kg. SIN-treated tumors also exhibited reduced COX-2 expression, a marked increase in Cip1/p21 protein levels and a decrease in the levels of cyclin D1 and cyclin E. SIN may be an effective chemopreventive agent against colorectal cancer. The growth inhibitory properties of SIN against colorectal cancer may be mediated via a COX-2 inhibitory effect and cell cycle arrest in the G1 phase.

Effect of Auricular Acupressure on Uremic Pruritus in Patients Receiving Hemodialysis Treatment: A Randomized Controlled Trial.

Background. Uremic pruritus (UP) is a common symptom in patients undergoing maintenance hemodialysis for end-stage renal disease (ESRD). Objective. To determine the clinical efficacy of auricular acupressure therapy on pruritus in hemodialysis patients and to explore possible underlying mechanisms. Methods. Patients receiving maintenance hemodialysis at a referral medical center were recruited and assigned to intervention (n = 32) and control (n = 30) groups. The intervention group underwent auricular acupressure treatment three times a week for six weeks. Auricular acupressure was not applied to patients in the control group. However, tape without Vaccaria seeds was applied to the same six auricular acupoints as the intervention group. Pruritus scores were assessed using VAS scores, and enzyme-linked immunosorbent assays (ELISA) were used to measure levels of other possible contributory biochemical factors. Results. There was a significant difference in mean VAS scores between the postintervention and control groups during follow-up (3.844 ± 1.687 versus 5.567 ± 2.285, F = 22.32, P < 0.0001). Compared to the control group, serum histamine levels in the postintervention group at the six-week follow-up had decreased significantly (F = 5.01, P = 0.0290). Conclusion. Our findings suggest that auricular acupressure may be a useful treatment in the multidisciplinary management of UP in ESRD patients.

You-gui Pill ameliorates renal tubulointerstitial fibrosis via inhibition of TGF-ß/Smad signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: You-gui Pill (YGP), a traditional Chinese medicinal prescription, was widely used to warm and recuperate "kidney-yang" clinically for hundreds of years in China. Recent studies found that YGP had a potential benefit for renoprotection. AIM OF THE STUDY: The present study aimed to elucidate the in vivo and in vitro efficacy of YGP on renal tubulointerstitial fibrosis, and the molecular mechanism is also investigated. MATERIALS AND METHODS: Rat renal tubulointerstitial fibrosis model was elicited by unilateral ureteral obstruction (UUO). Sprague-Dawley rats underwent UUO and were studied after 14 days. Animals were randomly subjected to six groups: sham, UUO, UUO/YGP (0.14, 0.42, 1.26g/kg/d), and UUO/enalapril (10mg/kg/d). HE, Masson and ELISA were used for evaluate renal injury and function. Immunohistochemical analysis and western blot were used to detect the expressions of α-SMA, fibronectin, collagen matrix and Smads. In vitro studies were investigated in TGF-ß1-stiumlated NRK-49F cell line. RESULTS: Oral administration of YGP significantly decreased UUO-induced inflammatory cell infiltration, tubular atrophy and interstitial fibrosis, and there was no significant difference between YGP at 1.26g/kg and enalapril at 10mg/kg treatment (P>0.05). Meanwhile, serum creatinine and blood urea nitrogen levels were reduced dramatically (P<0.01). In coincide with the decreased of TGF-ß1, α-SMA, fibronectin and collagen matrix expressions were also declined with YGP treatment in both UUO kidneys and TGF-ß1-stimulated NRK-49F cell line. Additionally, nuclear translocation of p-Smad2/3 was markedly down-regulated by YGP (P<0.001), with a relative mild up-regulated expression of Smad7 (P<0.05). CONCLUSIONS: Our findings demonstrate that YGP had a renoprotective effect in ameliorating renal tubulointerstitial fibrosis, and this activity possibly via suppression of the TGF-ß and its downstream regulatory signaling pathway, including Smad2/3.

ERK1/2-Egr-1 Signaling Pathway-Mediated Protective Effects of Electroacupuncture in a Mouse Model of Myocardial Ischemia-Reperfusion.

Early growth response- (Egr-) 1 is an upstream master switch in controlling inflammatory responses following myocardial ischemia-reperfusion (I/R). Activation of extracellular signal-regulated protein kinase-1 and kinase-2 (ERK1/2) signaling is known to upregulate Egr-1. ERK1/2 pathway has been previously shown to mediate the therapeutic action of electroacupucture (EA). Thus, we hypothesized that EA would reduce myocardial I/R injury and inflammatory responses through inhibiting Egr-1 expression via the ERK1/2 pathway. Mice were pretreated with EA, U0126, or combination of EA and U0126 and then underwent 1 h myocardial ischemia and 3 h reperfusion. We investigated that EA significantly attenuated the I/R-induced upregulation of both Egr-1 and phosporylated-ERK1/2 (p-ERK1/2), decreased myocardial inflammatory cytokines including tumor necrosis factor- α (TNF- α ) and interleukin-1 ß (IL-1 ß ), and reduced the infarct size and the release of cardiac troponin I (cTnI). U0126 treatment also exhibited the same effect as EA on Egr-1 level and subsequent cardioprotective effects. There was no additive effect of cotreatment with EA and U0126 on the expression of Egr-1 and its downstream target genes (TNF- α , IL-1 ß ) or serum cTnI level. Collectively, these observations suggested that EA attenuates myocardial I/R injury, possibly through inhibiting the ERK1/2-Egr-1 signaling pathway and reducing the release of proinflammatory cytokines.

Synergistic Effect of Zuo Jin Wan on DDP-Induced Apoptosis in Human Gastric Cancer SGC-7901/DDP Cells.

A traditional Chinese medicine (TCM) formula, Zuo Jin Wan (ZJW), has been found as an anticancer drug in human cancer. In this study, we investigated the synergistic effect of ZJW extracts on DDP-induced apoptosis in human gastric cancer SGC-7901/DDP cells. Our results demonstrated that ZJW extracts could increase the sensitivity of SGC-7901/DDP cells to DDP by increasing the concentration of DDP in cytoplasm and enhance the proapoptosis of DDP by upregulating the JNK and Bax expression, downregulating the Bcl-2 expression, increasing the accumulation of Cytochrome C in cytoplasm, and promoting the activities of caspase-3 and caspase-9. In vivo, ZJW extracts enhanced the inhibiting effect of DDP on tumor growth in SGC-7901/DDP xenograft model and upregulated the expression of p-JNK and Bax but downregulated the Bcl-2 expression in xenograft tumors. In conclusion, in vitro and in vivo, ZJW extracts could enhance the proapoptotic effect of DDP by promoting the activation of JNK and the expression of Bcl-2, inhibiting the Bax expression, followed by increasing the release of Cytochrome C from mitochondria to cytoplasm, and finally activating the caspase cade reaction. Our results implied that ZJW might serve as a synergistic drug with chemotherapeutic drugs DDP in the treatment of gastric cancer.

Mitochondrial translocation of cofilin-1 promotes apoptosis of gastric cancer BGC-823 cells induced by ursolic acid.

The pathogenesis of gastric cancer is characterized by excessive proliferation, abnormal differentiation, and reduced apoptosis. Ursolic acid, extracted from traditional Chinese medicine bearberry, inhibits cell growth and induces apoptosis in gastric cancer. However, the mechanism of the proapoptotic effect of ursolic acid on gastric cancer cells needs further investigation. In our present study, we found in apoptotic gastric cancer BGC-823 cells induced by ursolic acid that a translocation of cofilin-1 protein from the cytoplasm to the mitochondria promoted the release of cytochrome c from the mitochondria to the cytoplasm, thereby activating the caspase cascade and finally inducing gastric cancer cell apoptosis. These results implied that the mitochondrial translocation of cofilin-1 might play a crucial role in the promotion of apoptosis and might be a key target for future treatment of human gastric cancer.