Peptide Transporter 1-Mediated Dipeptide Transport Promotes Hepatocellular Carcinoma Metastasis by Activating MAP4K4/G3BP2 Signaling Axis.

Cancer metastasis is the leading cause of mortality in patients with hepatocellular carcinoma (HCC). To meet the rapid malignant growth and transformation, tumor cells dramatically increase the consumption of nutrients, such as amino acids. Peptide transporter 1 (PEPT1), a key transporter for small peptides, has been found to be an effective and energy-saving intracellular source of amino acids that are required for the growth of tumor cells. Here, the role of PEPT1 in HCC metastasis and its underlying mechanisms is explored. PEPT1 is upregulated in HCC cells and tissues, and high PEPT1 expression is associated with poor prognosis in patients with HCC. PEPT1 overexpression dramatically promoted HCC cell migration, invasion, and lung metastasis, whereas its knockdown abolished these effects both in vitro and in vivo. Mechanistic analysis revealed that high PEPT1 expression increased cellular dipeptides in HCC cells that are responsible for activating the MAP4K4/G3BP2 signaling pathway, ultimately facilitating the phosphorylation of G3BP2 at Thr227 and enhancing HCC metastasis. Taken together, these findings suggest that PEPT1 acts as an oncogene in promoting HCC metastasis through dipeptide-induced MAP4K4/G3BP2 signaling and that the PEPT1/MAP4K4/G3BP2 axis can serve as a promising therapeutic target for metastatic HCC.

Role of sodium taurocholate cotransporting polypeptide (NTCP) in HBV-induced hepatitis: Opportunities for developing novel therapeutics.

Hepatitis B is an infectious disease caused by the HBV virus. It presents a significant challenge for treatment due to its chronic nature and the potential for developing severe complications, including hepatocirrhosis and hepatocellular carcinoma. These complications not only cause physical and psychological distress to patients but also impose substantial economic and social burdens on both individuals and society as a whole. The internalization of HBV relies on endocytosis and necessitates the involvement of various proteins, including heparin sulfate proteoglycans, epidermal growth factor receptors, and NTCP. Among these proteins, NTCP is pivotal in HBV internalization and is primarily located in the liver's basement membrane. As a transporter of bile acids, NTCP also serves as a receptor facilitating HBV entry into cells. Numerous molecules have been identified to thwart HBV infection by stifling NTCP activity, although only a handful exhibit low IC50 values. In this systematic review, our primary focus dwells on the structure and regulation of NTCP, as well as the mechanism involved in HBV internalization. We underscore recent drug breakthroughs that specifically target NTCP to combat HBV infection. By shedding light on these advances, this review contributes novel insights into developing effective anti-HBV medications.

Immunological characteristics of immunogenic cell death genes and malignant progression driving roles of TLR4 in anaplastic thyroid carcinoma.

Anaplastic thyroid carcinoma (ATC) was a rare malignancy featured with the weak immunotherapeutic response. So far, disorders of immunogenic cell death genes (ICDGs) were identified as the driving factors in cancer progression, while their roles in ATC remained poorly clear. Datasets analysis identified that most ICDGs were high expressed in ATC, while DE-ICDGs were located in module c1_112, which was mainly enriched in Toll-like receptor signalings. Subsequently, the ICD score was established to classify ATC samples into the high and low ICD score groups, and function analysis indicated that high ICD score was associated with the immune characteristics. The high ICD score group had higher proportions of specific immune and stromal cells, as well as increased expression of immune checkpoints. Additionally, TLR4, ENTPD1, LY96, CASP1 and PDIA3 were identified as the dynamic signature in the malignant progression of ATC. Notably, TLR4 was significantly upregulated in ATC tissues, associated with poor prognosis. Silence of TLR4 inhibited the proliferation, metastasis and clone formation of ATC cells. Eventually, silence of TLR4 synergistically enhanced paclitaxel-induced proliferation inhibition, apoptosis, CALR exposure and release of ATP. Our findings highlighted that the aberrant expression of TLR4 drove the malignant progression of ATC, which contributed to our understanding of the roles of ICDGs in ATC.

Rab11-FIP4 interacts with ARF5 to promote cancer stemness in hepatocellular carcinoma

Recent studies suggest that Rab11-family interacting proteins (Rab11-FIPs) play an important role in tumorigenesis and progression. Among the Rab11-FIPs, Rab11-FIP4 has been reported to be significantly upregulated in various cancers, including hepatocellular carcinoma (HCC). However, the possible effect on HCC stemness and the underlying mechanism has never been characterized. Here, we found that Rab11-FIP4 was dramatically increased in HCC cell lines and tissues, and had a positive correlation with cancer stemness. Functional studies revealed that elevated expression of Rab11-FIP4 in HCC cells significantly promoted sphere formation, and enhanced the mRNA and protein levels of stemness-associated markers, ALDH1A1, CD133, NANOG, and OCT4. Conversely, the knockdown of Rab11-FIP4 suppressed the cancer stem cell (CSC)-like characteristics of HCC cells. Moreover, silencing of Rab11-FIP4 obviously increased the sensitivity of HCC cells to sorafenib. Mechanistically, Rab11-FIP4 was shown to interact with ADP-ribosylation factor 5 (ARF5) to influence cell cycle-related proteins, CDK1/cyclin B, thereby promoting HCC stemness. Taken together, our results uncovered an essential role for Rab11-FIP4 in regulating CSC-like features of HCC cells and identified Rab11-FIP4 as a potential target for HCC therapy. (AU)

Effects of the CYP3A inhibitors, voriconazole, itraconazole, and fluconazole on the pharmacokinetics of osimertinib in rats.

Background: Osimertinib, as third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), is the first-line treatment approved to treat advanced T790M mutation-positive tumors. Triazole antifungals are therapeutic drugs for cancer patients to reduce the risk of opportunistic fungal infections. Our objective was to investigate whether three triazole antifungals (voriconazole, itraconazole, and fluconazole) could change the pharmacokinetics of osimertinib in rats. Methods: The adult male Sprague-Dawley rats were randomly divided into four groups (n = 6): control (0.3% CMC-Na), and voriconazole (20 mg/kg), itraconazole (20 mg/kg), or fluconazole (20 mg/kg) combined with osimertinib (10 mg/kg) group. Tail vein blood samples were collected into heparin tubes at various time points within 0-48 h after osimertinib administration. Osimrtinib's plasma concentration was detected using HPLC-MS/MS system equipped with a Waters XBridge C18 column, with the mobile phase consisting of acetonitrile and 0.2% formic acid water at a flow rate of 0.5 mL/min. Results: Co-administration with voriconazole or fluconazole increased the Cmax of osimertinib by 58.04% and 53.45%, respectively; the AUC0-t increased by 62.56% and 100.98%, respectively. However, when co-administered with itraconazole, the Cmax and AUC0-t of osimertinib only increased by 13.91% and 34.80%, respectively. Conclusions: Our results revealed that the pharmacokinetics of osimertinib were significantly changed by voriconazole and fluconazole in rats, whereas it was slightly affected by itraconazole. This work will contribute to a more comprehensive understanding of the pharmacokinetic properties of osimertinib when co-administered with triazole antifungals.

Identification of potential pseudogenes for predicting the prognosis of hepatocellular carcinoma.

PURPOSE: Hepatocellular carcinoma (HCC) remains a highly deadly malignant tumor with high recurrence and metastasis rates. Cancer stem cells (CSCs) are involved in tumor metastasis, recurrence, and resistance to drugs, which have attracted widespread attention in recent years. Research has shown that pseudogenes may regulate stemness to promote the progression of HCC, but its specific mechanisms and impact on prognosis remain unclear. METHODS: In this study, clinical prognosis information of HCC was first downloaded from The Cancer Genome Atlas (TCGA) database. Then we calculated the mRNA expression-based stemness index (mRNAsi) of HCC. We also screened the differentially expressed pseudogene (DEPs) and conducted univariate Cox regression analysis to investigate their effect on the prognosis of HCC. Further, genomic mutation frequency analysis and weighted gene co-expression network analysis (WGCNA) were performed to compare the role of pseudogenes and stemness in promoting the progression of HCC. Finally, we conducted the correlation analysis to examine the potential mechanism of pseudogenes regulating stemness to promote the progression of HCC and detected the possible pathways through the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. RESULTS: Herein, we revealed that the high stemness of HCC correlated with an unfavorable prognosis. We obtained 31 up-regulated and 8 down-regulated DEPs in HCC and screened CTB-63M22.1, a poor prognostic indicator of HCC. In addition, CTB-63M22.1 had a mutation frequency similar to mRNAsi and acted in a module similar to that of mRNAsi on HCC. We then screened two RNA-binding proteins (RBPs) LIN28B and NOP56 with the highest correlation with stemness. We also discovered that they were primarily enriched in the biological process as examples of mitotic nuclear division and cell cycle. CONCLUSIONS: Collectively, these results revealed that pseudogenes CTB-63M22.1 may regulate cancer stemness by regulating RBPs, suggesting that CTB-63M22.1 may serve as an innovative therapeutic target and a reliable prognostic marker for HCC.

ISG15 and ISGylation modulates cancer stem cell-like characteristics in promoting tumor growth of anaplastic thyroid carcinoma.

BACKGROUND: Anaplastic thyroid carcinoma (ATC) was a rare and extremely malignant endocrine cancer with the distinct hallmark of high proportion of cancer stem cell-like characteristics. Therapies aiming to cancer stem-like cells (CSCs) were emerging as a new direction in cancer treatment, but targeting ATC CSCs remained challenging, mainly due to incomplete insights of the regulatory mechanism of CSCs. Here, we unveiled a novel role of ISG15 in the modulation of ATC CSCs. METHODS: The expression of ubiquitin-like proteins were detected by bioinformatics and immunohistochemistry. The correlation between ISG15 expression and tumor stem cells and malignant progression of ATC was analyzed by single-cell RNA sequence from the Gene Expression Omnibus. Flow cytometry combined with immunofluorescence were used to verify the enrichment of ISG15 and ISGyaltion in cancer stem cells. The effect and mechanism of ISG15 and KPNA2 on cancer stem cell-like characteristics of ATC cells were determined by molecular biology experiments. Mass spectrometry combined with immunoprecipitation to screen the substrates of ISG15 and validate its ISGylation modification. Nude mice and zebrafish xenograft models were utilized to demonstrate that ISG15 regulates stem cell characteristics and promotes malignant progression of ATC. RESULTS: We found that among several ubiquitin proteins, only ISG15 was aberrantly expressed in ATC and enriched in CSCs. Single-cell sequencing analysis revealed that abnormal expression of ISG15 were intensely associated with stemness and malignant cells in ATC. Inhibition of ISG15 expression dramatically attenuated clone and sphere formation of ATC cells, and facilitated its sensitivity to doxorubicin. Notably, overexpression of ISGylation, but not the non-ISGylation mutant, effectively reinforced cancer stem cell-like characteristics. Mechanistically, ISG15 mediated the ISGylation of KPNA2 and impeded its ubiquitination to promote stability, further maintaining cancer stem cell-like characteristics. Finally, depletion of ISG15 inhibited ATC growth and metastasis in xenografted mouse and zebrafish models. CONCLUSION: Our studies not only provided new insights into potential intervention strategies targeting ATC CSCs, but also uncovered the novel biological functions and mechanisms of ISG15 and ISGylation for maintaining ATC cancer stem cell-like characteristics.

Rab11-FIP4 interacts with ARF5 to promote cancer stemness in hepatocellular carcinoma.

Recent studies suggest that Rab11-family interacting proteins (Rab11-FIPs) play an important role in tumorigenesis and progression. Among the Rab11-FIPs, Rab11-FIP4 has been reported to be significantly upregulated in various cancers, including hepatocellular carcinoma (HCC). However, the possible effect on HCC stemness and the underlying mechanism has never been characterized. Here, we found that Rab11-FIP4 was dramatically increased in HCC cell lines and tissues, and had a positive correlation with cancer stemness. Functional studies revealed that elevated expression of Rab11-FIP4 in HCC cells significantly promoted sphere formation, and enhanced the mRNA and protein levels of stemness-associated markers, ALDH1A1, CD133, NANOG, and OCT4. Conversely, the knockdown of Rab11-FIP4 suppressed the cancer stem cell (CSC)-like characteristics of HCC cells. Moreover, silencing of Rab11-FIP4 obviously increased the sensitivity of HCC cells to sorafenib. Mechanistically, Rab11-FIP4 was shown to interact with ADP-ribosylation factor 5 (ARF5) to influence cell cycle-related proteins, CDK1/cyclin B, thereby promoting HCC stemness. Taken together, our results uncovered an essential role for Rab11-FIP4 in regulating CSC-like features of HCC cells and identified Rab11-FIP4 as a potential target for HCC therapy.

Single-cell sequencing analysis fibrosis provides insights into the pathobiological cell types and cytokines of radiation-induced pulmonary fibrosis.

BACKGROUND: Radiotherapy is an essential treatment for chest cancer. Radiation-induced pulmonary fibrosis (RIPF) is an almost irreversible interstitial lung disease; however, its pathogenesis remains unclear. METHODS: We analyzed specific changes in cell populations and potential markers by using single-cell sequencing datasets from the Sequence Read Archive database, PERFORMED from control (0 Gy) and thoracic irradiated (20 Gy) mouse lungs at day 150 post-radiation. We performed IHC and ELISA on lung tissue and cells to validate the potential marker cytokines identified by the analysis on rat thoracic irradiated molds (30 Gy). RESULTS: Single-cell sequencing analysis showed changes in abundance across cell types and at the single-cell level, with B and T cells showing the most significant changes in abundance. And four cytokines, CCL5, ICAM1, PF4, and TNF, were significantly upregulated in lung tissues of RIPF rats and cell supernatants after ionizing radiation. CONCLUSION: Cytokines CCL5, ICAM1, PF4, and TNF may play essential roles in radiation pulmonary fibrosis. They are potential targets for the treatment of radiation pulmonary fibrosis.

Research progress on non-protein-targeted drugs for cancer therapy.

Non-protein target drugs, especially RNA-based gene therapies for treating hereditary diseases, have been recognized worldwide. As cancer is an insurmountable challenge, no miracle drug is currently available. With the advancements in the field of biopharmaceuticals, research on cancer therapy has gradually focused on non-protein target-targeted drugs, especially RNA therapeutics, including oligonucleotide drugs and mRNA vaccines. This review mainly summarizes the clinical research progress in RNA therapeutics and highlights that appropriate target selection and optimized delivery vehicles are key factors in increasing the effectiveness of cancer treatment in vivo.

A review on the role of long non-coding RNA and microRNA network in clear cell renal cell carcinoma and its tumor microenvironment.

Renal cell carcinoma (RCC) is the second lethal urogenital malignancy with the increasing incidence and mortality in the world. Clear cell renal cell carcinoma (ccRCC) is one major subtype of RCC, which accounts for about 70 to 80% of all RCC cases. Although many innovative therapeutic options have emerged during the last few decades, the efficacy of these treatments for ccRCC patients is very limited. To date, the prognosis of patients with advanced or metastatic ccRCC is still poor. The 5-year survival rate of these patients remains less than 10%, which mainly attributes to the complexity and heterogeneity of the tumor microenvironment (TME). It has been demonstrated that long non-coding RNAs (lncRNAs) perform an indispensable role in the initiation and progression of various tumors. They mostly function as sponges for microRNAs (miRNAs) to regulate the expression of target genes, finally influence the growth, metastasis, apoptosis, drug resistance and TME of tumor cells. However, the role of lncRNA/miRNA/mRNA axis in the TME of ccRCC remains poorly understood. In this review, we summarized the biological function of lncRNA/miRNA/mRNA axis in the pathogenesis of ccRCC, then discussed how lncRNA/miRNA/mRNA axis regulate the TME, finally highlighted their potential application as novel biomarkers and therapeutic targets for ccRCC.

CREB3L1 promotes tumor growth and metastasis of anaplastic thyroid carcinoma by remodeling the tumor microenvironment.

Anaplastic thyroid carcinoma (ATC) is an extremely malignant type of endocrine cancer frequently accompanied by extrathyroidal extension or metastasis through mechanisms that remain elusive. We screened for the CREB3 transcription-factor family in a large cohort, consisting of four microarray datasets. This revealed that CREB3L1 was specifically up regulated in ATC tissues and negatively associated with overall survival of patients with thyroid cancer. Consistently, high expression of CREB3L1 was negatively correlated with progression-free survival in an independent cohort. CREB3L1 knockdown dramatically attenuated invasion of ATC cells, whereas overexpression of CREB3L1 facilitated the invasion of papillary thyroid carcinoma (PTC) cells. Loss of CREB3L1 inhibited metastasis and tumor growth of ATC xenografts in zebrafish and nude mouse model. Single-cell RNA-sequencing analysis revealed that CREB3L1 expression gradually increased during the neoplastic progression of a thyroid follicular epithelial cell to an ATC cell, accompanied by the activation of the extracellular matrix (ECM) signaling. CREB3L1 knockdown significantly decreased the expression of collagen subtypes in ATC cells and the fibrillar collagen in xenografts. Due to the loss of CREB3L1, ATC cells were unable to activate alpha-smooth muscle actin (α-SMA)-positive cancer-associated fibroblasts (CAFs). After CREB3L1 knockdown, the presence of CAFs inhibited the growth of ATC spheroids and the metastasis of ATC cells. Further cytokine array screening showed that ATC cells activated α-SMA-positive CAFs through CREB3L1-mediated IL-1α production. Moreover, KPNA2 mediated the nuclear translocation of CREB3L1, thus allowing it to activate downstream ECM signaling. These results demonstrate that CREB3L1 maintains the CAF-like property of ATC cells by activating the ECM signaling, which remodels the tumor stromal microenvironment and drives the malignancy of ATC.

Efficacy of Qingfei oral liquid for idiopathic pulmonary fibrosis in rats and related network pharmacology study.

To investigate the therapeutic effect and mechanism of Qingfei oral liquid in idiopathic pulmonary fibrosis. Seventy-two male SD rats were divided into control group, model group, pirofenidone group and Qingfei group with 18 animals in each group. The idiopathic pulmonary fibrosis was induced in last three groups by intratracheal injection of bleomycin; pirofenidone group was given oral administration of pirofenidone b.i.d for 21 d, and Qingfei group was given Qingfei oral liquid 3.6 mL/kg q.d for Lung tissues were obtained for HE staining, Masson staining and transforming growth factor (TGF)-ß immunohistochemical staining. Superoxide dismutase (SOD), malondialdehyde (MDA) and glutathione (GSH) were detected in tissue homogenates. The BATMAN-TCM database was used to retrieve the chemical components and their corresponding targets of Qingfei oral solution by network pharmacology method, and then the component-target-disease network diagram was constructed. Finally, the pathway enrichment analysis was carried out to explore the molecular mechanism of Qingfei oral liquid against idiopathic fibrosis. Histopathology results showed that Qingfei oral liquid had a similar relieving effect on pulmonary fibrosis as the positive drug pirfenidone; TGF-ß secretion had a significant reduction in lung tissues of Qingfei group; and Qingfei oral liquid had better regulatory effect on SOD, MDA and GSH than pirfenidone. The results of component-target-disease network and pathway enrichment analysis showed that the related molecular pathways were concentrated in inflammation, extracellular matrix and cytokines. Qingfei oral liquid has a good therapeutic effect on idiopathic pulmonary fibrosis in rats via regulation of inflammation, extracellular matrix and cytokines.

Overview of PROTACs Targeting the Estrogen Receptor: Achievements for Biological and Drug Discovery.

Estrogen receptors (ERs) are steroid hormone receptors, which belong to a large nuclear receptor family. Endocrine diseases correlate strongly with dysregulated ER signaling. Traditional therapies continue to rely on small molecule inhibitors, including aromatase inhibitors (AIs) and selective estrogen receptor modulators (SERMs), all of which permit acquired resistance to endocrine therapy. Proteolytic targeting chimeras (PROTACs) offer unprecedented potential for solving acquired endocrine resistance. ARV-471, an ER-targeting PROTAC developed by Arvinas, was designated as an Investigational New Drug by the US FDA in 2019, and a phase I trial in patients suffering from locally advanced or metastatic ER-positive/HER2- negative breast cancer was initiated. In this review, we will focus on progress in developing ER-targeting PROTACs from publications and patents aimed at the treatment of endocrine diseases.

Obstructive sleep apnea-hypopnea syndrome complicated with idiopathic intracranial hypertension: a case report.

BACKGROUND: Obstructive sleep apnea-hypopnea syndrome (OSAHS) is characterized by repetitive episodes of hypopnea or apnea during sleep. With the improved living conditions of the population and the increased number of obese individuals, the incidence of OSAHS is rising. Hypopnea in OSAHS patients can cause and aggravate cerebrocardiovascular diseases and metabolic disorders However, OSAHS patients with idiopathic intracranial hypertension is rare and we just have searched one paper so far. CASE DESCRIPTION: In this paper, we report the case of an OSAHS patient with idiopathic intracranial hypertension (IIH) as a prominent symptom. The patient was suffering weakness and fatigue lasting about half a year without the headache symptom. The IIH was diagnosed by lumbar puncture and the results showed that the cerebrospinal fluid (CSF) pressure was higher than 400 mmH2O. After treatment with non-invasive positive pressure ventilation, the symptoms were completely resolved and the quality of life of the patient was significantly improved. The CSF pressure was 200 mmH2O in the last lumbar puncture. CONCLUSIONS: For patients with unexplained IIH, the possibility of OSAHS should be warned. Lumbar puncture is easy to perform and obtain the results. Regular ventilator treatment is important and necessary to these patients. The symptoms of some OSAHS patients is atypical that we may need new insights into this disease.

Identification of novel key genes associated with the metastasis of prostate cancer based on bioinformatics prediction and validation.

BACKGROUND: Metastatic prostate cancer (PCa) is a lethal tumor. However, the molecular mechanisms underlying PCa progression have not been fully elucidated. METHODS: Transcriptome expression profiling and clinical information on primary and metastatic PCa samples were obtained from TCGA. R software was used to screen the DEGs, and LASSO logistical regression method was utilized to identify the pivotal PCa metastasis-related DEGs. The transcriptional expression levels of the key genes were analyzed using the UALCAN database, and the corresponding protein expression were validated by Immunohistochemistry (IHC). Survival analysis of the key genes was performed using the GEPIA database. Wound healing assay and Transwell assay were conducted to determine whether knockdown of the key genes influence the migration and invasion abilities of PCa cells (22Rv1 and PC3). GSEA was performed to predict key genes-mediated signaling pathways for the development of PCa. Western blotting was used to evaluate the expression changes of E-cadherin, Twist1, and Vimentin in PCa cells with the key genes silencing. An in vivo mouse metastatic model for PCa was also generated to verify the important role of ISG15 and CST2 in PCa metastasis. RESULTS: A comparison between primary and metastatic PCa tissues was conducted, and 19 DEGs were screened. Among these, three key genes were identified that might be closely associated with PCa progression according to the LASSO logistical analysis, namely ISG15, DNAH8, and CST2. Further functional experiments revealed that knockdown of ISG15 and CST2 suppressed wound healing, migration, and invasion of PCa cells. To explore the molecular mechanism of ISG15 and CST2 in the development of PCa, GSEA was performed, and it was found that both genes play crucial roles in cell adhesion molecules, extracellular matrix-receptor interaction, and focal adhesion. Western blotting results exhibited that inhibiting ISG15 and CST2 led to increase the expression of E-cadherin and decrease the expression of Twist1 and Vimentin. Additionally, the metastatic in vivo study demonstrated that both PC3 and 22Rv1 cells expressing with luciferase-shISG15 and luciferase-shCST2 had significantly lower detectable bioluminescence than that in the control PCa cells. CONCLUSION: ISG15 and CST2 may participate in PCa metastasis by regulating the epithelial-mesenchymal transition (EMT) signaling pathway. These findings may help to better understand the pathogenetic mechanisms governing PCa and provide promising therapeutic targets for metastatic PCa therapy.

L-tetrahydropalmatine reduces oxaliplatin accumulation in the dorsal root ganglion and mitochondria through selectively inhibiting the transporter-mediated uptake thereby attenuates peripheral neurotoxicity.

Oxaliplatin (OXA) is a third-generation platinum drug; however, its application is greatly limited due to the severe peripheral neurotoxicity. This study aims to confirm the transport mechanism of OXA and to explore whether L-tetrahydropalmatine (L-THP) would alleviate OXA-induced peripheral neurotoxicity by selectively inhibiting these uptake transporters in vitro and in vivo. Our results revealed that organic cation transporter 2 (OCT2), organic cation/carnitine transporter 1 (OCTN1) and organic cation/carnitine transporter 2 (OCTN2) were involved in the uptake of OXA in dorsal root ganglion (DRG) neurons and mitochondria, respectively. L-THP (1-100 µM) reduced OXA (40 µM) induced cytotoxicity in MDCK-hOCT2 (Madin-Darby canine kidney, MDCK), MDCK-hOCTN1, MDCK-hOCTN2, and rat primary DRG cells, and decreased the accumulation of OXA in above cells and rat DRG mitochondria, but did not affect its efflux from MDCK-hMRP2 cells. Furthermore, Co-administration of L-THP (5-20 mg/kg for mice, 10-40 mg/kg for rats; twice a week, iv or ig) attenuated OXA (8 mg/kg for mice, 4 mg/kg for rats; twice a week, iv) induced peripheral neurotoxicity and reduced the platinum concentration in the DRG. Whereas, L-THP (1-100 µM for cells; 10-20 mg/kg for mice) did not impair the antitumour efficacy of OXA (40 µM for cells; 8 mg/kg for mice) in HT29 tumour-bearing nude mice nor in tumour cells (HT29 and SW620 cells). In conclusion, OCT2, OCTN1 and OCTN2 contribute to OXA uptake in the DRG and mitochondria. L-THP attenuates OXA-induced peripheral neurotoxicity via inhibiting OXA uptake but without impairing the antitumour efficacy of OXA. L-THP is a potential candidate drug to attenuate OXA-induced peripheral neurotoxicity.

The role of alcohol dehydrogenase 1C in regulating inflammatory responses in ulcerative colitis.

Ulcerative colitis (UC) is a chronic relapsing inflammatory bowel disease caused by an interaction of genetics, immune responses, and environmental factors. However, the precise pathogenesis of UC remains poorly understood. The aim of the present study was to explore the potential target genes implicated in UC and to elucidate its underlying pathogenic mechanism. Firstly, three UC-associated microarray datasets (GSE75214, GSE87466, and GSE92517) were obtained to screen the differentially expressed genes (DEGs). As a result, alcohol dehydrogenase 1C (ADH1C) was the most significantly downregulated DEG in UC. We confirmed that ADH1C was downregulated in colonic tissue taken from patients with UC and colitis mice. Moreover, ADH1C expression was also decreased in colonic cell lines (NCM460 and HT29) treated with mixed proinflammatory cytokines (TNF-α, IFN-γ, IL-1ß). Interestingly, we found that overexpression of ADH1C could distinctly decrease the production of IL-6 and IL-8. To elucidate the molecular mechanism of ADH1C in UC, gene set enrichment analysis (GSEA) was performed and demonstrated that immune-related pathways were mainly enriched in the low ADH1C group. Further studies displayed that STAT1/NF-κB pathway was activated in colitis mice and inflammatory cell model. Importantly, overexpression of ADH1C could suppress the phosphorylation of STAT1 and IκB. Therefore, ADH1C might regulate inflammatory responses through STAT1/NF-κB pathway. In conclusion, ADH1C was downregulated during inflammation, and its increased expression could inhibit the activation of STAT1/NF-κB pathway, thereby alleviating the secretion of IL-6 and IL-8. These findings indicate that ADH1C may be a potential therapeutic target for UC therapy.

Low curcumin concentration enhances the anticancer effect of 5-fluorouracil against colorectal cancer.

BACKGROUND: Colon cancer treatments include surgery, radiotherapy, and chemotherapy. Chemotherapy using 5-fluorouracil (5-FU) has been widely applied to treat colorectal cancer (CRC). However, it is important to explore the use of chemotherapy drugs in combination with other agents to decrease severe adverse effects. PURPOSE: This study aimed to investigate the effects of curcumin in combination with 5-FU on the proliferation, migration, and apoptosis of CRC SW620 cell line both in vitro and in vivo. METHODS: Flow cytometry was used to study the effect of curcumin on chemotherapy-induced apoptosis in CRC cells. The mechanism of curcumin's enhanced antitumor effect in vivo was investigated using gene knockdown, TUNEL, western blot, qRT-PCR and immunohistochemistry. RESULTS: The results showed a synergistic effect of the two compounds on CRC cells. Considerable reduction in the proliferation and migration of SW620 cells was observed in the combination treatment group. Significantly increased apoptosis rate extended the survival of immunodeficient mice in the combination group as compared to that of the 5-FU group (p < 0.05). The results showed that curcumin significantly inhibited pERK signaling and downregulated L1 expression in SW620 cells. CONCLUSIONS: We conclude that curcumin promotes chemosensitivity of CRC cells to 5-FU by downregulating L1 expression. Our findings provide experimental evidence for the synergism between curcumin and 5-FU, which can be utilized in clinical applications for reducing the toxicity and adverse effects of 5-FU.

Analysis of dynamic molecular networks: the progression from colorectal adenoma to cancer.

BACKGROUND: Colorectal cancer (CRC) is one of the deadliest cancers worldwide. It is the fourth most deadly cancer in the world with nearly 900,000 people die every year, the progression of polyps into cancer as one of its most common developmental pathways. METHODS: This study obtained gene chip data collections from the Gene Expression Omnibus for colorectal adenoma (GSE8671) and colorectal cancer (GSE32323). Differentially expressed genes (DEGs) in normal tissue and different stages of CRC were analyzed for clustering, comparison, and visualization using R software. The Cytoscape plugin DyNetViewer was used to construct a dynamic protein-protein interaction network. Subsequently, through the Database for Annotation, Visualization and Integrated Discovery, the DEGs were functionally annotated and path enriched. RESULTS: Our study found that the matrix metalloprotein family and chemokines were the key regulatory genes that drove CRC progression. The Wnt signaling pathway, chemokine signaling pathway, and CRC pathway were the pathological pathways for CRC. Maintenance played an important role in this process. In addition, the related nodes and pathways at various stages may be potential mechanisms for promoting dynamic CRC progression. CONCLUSIONS: Our study provides a better understanding of the dynamic pattern of molecular interaction networks during CRC progression and provides relevant markers for more accurate screening of cancer in polyps.