Current molecular pharmacology最新文献

Background: Nasopharyngeal carcinoma (NPC) is a usual head and neck malignancy. Guggulsterone (GS) has potential in cancer chemoprophylaxis and treatment, but its therapeutic effect on NPC is unknown. We aimed to explore whether GS could promote the secretion of exosomal circFIP1L1 from NPC cells and its regulatory mechanism.

Methods: NPC tissues and adjacent tissues were collected from NPC patients. Human nasopharyngeal epithelial cell lines (NP69) and NPC lines (5-8F, CNE1, and HNE1) were used for in vitro experiments. HNE1 cells were treated with GS (20, 40, 60 μmol/L). The expressions of miR-125a-5p and circFIP1L1 were evaluated by qRT-PCR. Cell proliferation and apoptosis abilities were measured by CCK-8 and flow cytometry. HNE1 cell exosomes were extracted and identified, and the levels of VEGFA and VEGFR2 were detected by ELISA. Then miR-125a-5p was knocked down and overexpressed. HUVECs angiogenesis was determined by the tube formation assay. qRT-PCR and Western blot were utilized to evaluate the expressions of VEGFA, MMP-2, MMP-9, and ICAM-1 in HUVECs.

Results: miR-125a-5p was highly expressed in NPC tissues and cells. GS promoted the secretion of exosomal circFIP1L1 from HNE1 cells to affect HUVECs proliferation and angiogenesis. Overexpression of miR-125a-5p accelerated HUVECs proliferation and angiogenesis. Knocking down miR-125a- 5p inhibited VEGFA expression. In addition, exosomal circFIP1L1 sponged miR-125a-5p, inhibiting the VEGFA pathway to repress HUVECs angiogenesis.

Conclusions: GS promoted exosomal circFIP1L1 in NPC cells to mediate miR-125a-5p/VEGFA axis affecting tumor angiogenesis.

Background: Fatty acid synthase (FASN) is generally over-expressed in human tumor tissues and catalyzes de novo synthesis of fatty acids on which tumor cells depend. Bestatin, an inhibitor of aminopeptidase/CD13, is one of the dipeptide substrates for the human oligopeptide transporter 1 (PEPT1).

Objectives: In the current study, we aimed to uncover the role of FASN inhibitors in bestatininduced tumor cell apoptosis and the underlying mechanism, extending our understanding of the correlations between FASN and PEPT1 in cancer and providing a new strategy for tumor targeted treatment.

Methods: Cerulenin, orlistat and siRNAs were applied to inhibit FASN. The cell viability and apoptosis were assessed with MTT (thiazolyl blue tetrazolium bromide) assays and annexin VFITC/ PI staining with flow cytometry analysis. Western blot and qRT-PCR analysis were used to detect the protein levels and mRNA levels of the indicated genes in tumor cells, respectively. Protein degradation or stability was examined with cycloheximide chase assays. CD13 activity was detected by gelatin zymography. The HT1080 and C26 xenografts models were conducted to assess the efficacy in vivo.

Results: In the current study, we found that inhibiting FASN by cerulenin and orlistat both augmented the effects of bestatin in decreasing tumor cell viability. Cerulenin increased the apoptosis rates and enhanced the cleavage of PARP caused by bestatin. Furthermore, cerulenin, orlistat and siFASNs markedly elevated PEPT1 protein levels. Indeed, cerulenin induced the upregulation of PEPT1 mRNA expression rather than affecting the protein level after the cells were treated with CHX. And Gly-Sar, a typical competitive substrate of PEPT1, could attenuate the augment of bestatin-induced cell killing by cerulenin. Moreover, synergistic restrain of tumor growth accompanied by a reduction of Ki-67 and increment of TUNEL was significantly achieved in the xenograft models. Interestingly, no clear correlation was observed between the CD13 with FASN and/or PEPT1 in tumor cells.

Conclusion: FASN inhibitors facilitate tumor cells susceptible to bestatin-induced apoptosis involving the up-regulation of PEPT1 at the mRNA translation level and the transport of bestatin by PEPT1, emerging as a promising strategy for tumor targeted therapy.

Sodiun Oxybate (SO) has a number of attributes that may mitigate the metabolic stress on the substantia nigra pars compacta (SNpc) dopaminergic (DA) neurons in Parkinson's disease (PD). These neurons function at the borderline of energy sufficiency. SO is metabolized to succinate and supplies energy to the cell by generating ATP. SO is a GABAB agonist and, as such, also arrests the high energy requiring calcium pace-making activity of these neurons. In addition, blocking calcium entry impedes the synaptic release and subsequent neurotransmission of aggregated synuclein species. As DA neurons degenerate, a homeostatic failure exposes these neurons to glutamate excitotoxicity, which in turn accelerates the damage. SO inhibits the neuronal release of glutamate and blocks its agonistic actions. Most important, SO generates NADPH, the cell's major antioxidant cofactor. Excessive free radical production within DA neurons and even more so within activated microglia are early and key features of the degenerative process that are present long before the onset of motor symptoms. NADPH maintains cell glutathione levels and alleviates oxidative stress and its toxic consequences. SO, a histone deacetylase inhibitor also suppresses the expression of microglial NADPH oxidase, the major source of free radicals in Parkinson brain. The acute clinical use of SO at night has been shown to reduce daytime sleepiness and fatigue in patients with PD. With long-term use, its capacity to supply energy to DA neurons, impede synuclein transmission, block excitotoxicity and maintain an anti-oxidative redox environment throughout the night may delay the onset of PD and slow its progress.

Background: Melanoma, a highly malignant skin cancer, is a hot topic in oncology treatment research. Nowadays, tumor immunotherapy, especially immunotherapy combined with other therapies, has attracted more and more attention. Indoleamine 2,3-dioxygenase 2 (IDO2), a ratelimiting enzyme of the tryptophan metabolism pathway in the urine of dogs with immunosuppression, is highly expressed in melanoma tissue. Additionally, IDO2 significantly inhibits the anti-tumor immunity of the body and has become a novel target of melanoma treatment. Nifuroxazide, as an intestinal antibacterial agent, was found to be able to inhibit Stat3 expression and exert an anti-tumor effect. Therefore, the present study aimed to examine the therapeutic effect of a self-designed IDO2-small interfering RNA (siRNA) delivered by attenuated Salmonella combined with nifuroxazide on melanoma- bearing mice, as well as determine its underlying mechanism.

Methods: The effect of nifuroxazide on melanoma was detected by flow cytometry, CCK-8 and colony- forming ability assays, respectively, in vitro. The plasmid of siRNA-IDO2 was constructed, and the mice-bearing melanoma model was established. After the treatment, the tumor growth and survival rate were monitored, and the morphological changes of tumor tissue were detected by HE staining. The expression of related proteins was detected by Western blotting, and the expression of CD4 and CD8 positive T cells in tumor tissue was detected by IHC and IF, and the proportion of CD4 and CD8 positive T cells in spleen was detected by flow cytometry.

Results: The results demonstrated that the combination therapy effectively inhibited the phosphorylation of Stat3 and the expression level of IDO2 in melanoma cells, which effectively inhibited tumor growth and prolonged the survival time of tumor-bearing mice. The mechanistic study revealed that, compared with control groups and monotherapy groups, the combination treatment group reduced the atypia of tumor cells, increased the apoptotic rate, enhanced the infiltration of T lymphocytes in tumor tissue and increased the CD4⁺ and CD8⁺ T lymphocytes in the spleen, suggesting that the mechanism may be associated with the inhibition of tumor cell proliferation, the increase of apoptosis and the enhancement of the cellular immunity.

Conclusion: In conclusion, IDO2-siRNA combined with nifuroxazide therapy could serve a significant role in the treatment of melanoma-bearing mice, enhance the tumor immunity and provide an experimental basis for identifying a novel combination method for the treatment of melanoma clinically.

Modafinil (MOD, 2-diphenyl-methyl-sulphinil-2-acetamide) is a stimulant-like medicine used to treat narcolepsy. Off-label uses include improving cognitive ability in the course of other diseases. This review aims to discuss findings demonstrating the memory and learningenhancing activity of MOD in experimental and clinical studies. We included behavioral evaluations alongside the effects of MOD at the cellular and molecular level. MOD in different animal disease models exerted beneficial effects on induced memory and learning impairment, which in some cases were accompanied by modulation of neurotransmitter pathways or neuroplastic capabilities, reducing oxidative stress, or expression of synaptic proteins. Individuals treated with MOD showed improved memory and learning skills in different conditions. These effects were associated with regulating brain activity in some participants, confirmed by functional magnetic resonance imaging. Presented herein, data support the use of MOD in treating memory and learning deficits in various disease conditions.

Background: Breviscapine is a flavonoid extracted from Erigeron breviscapus (Vant.) Hand.-Mazz., and mainly contains scutellarin. Nuclear receptors play important roles in regulating transporter and drug metabolic enzymes.

Objective: To investigate the regulatory effects of scutellarin on CYP3A4 and 2C19 in HepG2 and Caco-2 cells based on nuclear receptors PXR and CAR.

Methods: The proteins and mRNA levels of CYP3A4 and CYP2C19 treated with scutellarin were detected by Western Blot and RT-qPCR. Using assays of the dual-luciferase reporter, promoter sequences containing hPXR and hCAR protein recognition and binding regulatory elements CYP3A4 and CYP2C19 were inserted upstream of the reporter gene, and the expression vector and the reporter vector were cotransfected into HepG2 and Caco-2 cells.

Results: Scutellarin inhibited mRNA of CYP3A4 and PXR, and promoted mRNA expression of CYP2C19 and CAR in RT-qPCR results. Western-blot results showed scutellarin inhibited the expression of CYP3A4 and promoted the expression of CYP2C19. The dual-luciferase reporter genes showed that scutellarin enhanced the expression level of CYP2C19, and when its concentration was 40 and 80μmol/L, CYP3A4 was significantly increased.

Conclusion: Scutellarin down-regulates CYP3A4 through PXR, and its mechanism may work by up-regulating CAR, binding to PXR to inhibit PXR-mediated expression of CYP3A4. Scutellarin up-regulates CYP2C19 through CAR.

Background: MicroRNAs (miRNA) are small non-coding RNAs that regulate the function of mRNA post-transcriptionally in a tissue-specific manner. miRNA expressions are heavily dysregulated in human cancer cells through various mechanisms, including epigenetic changes, karyotype abnormalities, and miRNA biogenesis defects. miRNAs may act as either oncogenes or tumor suppressors under different conditions. Epicatechin is a natural compound found in green tea which possesses antioxidant and antitumor properties.

Objective: The objective of this study is to investigate the effect of epicatechin treatment on the expression level of several oncogenic and tumor suppressor miRNAs in breast and colorectal cancer cell lines (MCF7 and HT-29) and identify its mechanism of action.

Methods: The MCF-7 and HT29 cells were treated with epicatechin for 24 hours and untreated cells were considered control cultures. miRNA was isolated and qRT-PCR was used to measure the expression profile changes of different oncogenic and tumor suppressor miRNAs. Furthermore, the mRNA expression profile was also screened at different concentrations of epicatechin.

Results: Our results showed several-fold changes in miRNAs expression level, which is cell line specific. Also, epicatechin at different concentrations induces biphasic changes in mRNA expression levels in both cell lines.

Conclusion: Our findings first time demonstrated that epicatechin can reverse the expression of these miRNAs and may trigger the cytostatic effect at a lower concentration.

The most prevalent primary bone malignancy among children and adolescents is osteosarcoma. The high mortality rate of osteosarcoma is due to lung metastasis. Despite the development of multi-agent chemotherapy and surgical resection, patients with osteosarcoma have a high metastasis rate and poor prognosis. Thus, it is necessary to identify novel therapeutic agents to improve the 5-year survival rate of these patients. Curcumin, a phytochemical compound derived from Curcuma longa, has been employed in treating several types of cancers through various mechanisms. Also, in vitro studies have demonstrated that curcumin could inhibit cell proliferation and induce apoptosis in osteosarcoma cells. Development in identifying signaling pathways involved in the pathogenesis of osteosarcoma has provided insight into finding new therapeutic targets for the treatment of this cancer. Targeting MAPK/ERK, PI3k/AKT, Wnt/β-catenin, Notch, and MircoRNA by curcumin has been evaluated to improve outcomes in patients with osteosarcoma. Although curcumin is a potent anti-cancer compound, it has rarely been studied in clinical settings due to its congenital properties such as hydrophobicity and poor bioavailability. In this review, we recapitulate and describe the effect of curcumin in regulating signaling pathways involved in osteosarcoma.

Cancer is a leading cause of death and a severe threat to global public health. Organoid, as a novel 3D in vitro model, has been applied in various tumor related studies due to its apparent advantages. The organoid is mainly constructed by Matrigel-depended 3D culture system, Air-Liquid Interface (ALI) culture, and Microfluidic culture or Organ-on-chips platform. For the application in carcinogenesis studies, the organoid model may favor depicting initiative hallmarks and identifying potential intervening targets, investigating driver genes of carcinogenesis, and identifying known or unknown risk or protective factors. In this review, we discussed different organoid construction methods and their properties. We also noted that tumor organoids can portray initiative hallmarks and identify possible intervening targets, as well as explore carcinogenesis driver genes and uncover known or unknown risks or protective factors. Organoid systems have been used to identify tumor-preventive drugs such as oligomeric proanthocyanidins, Vitamin D, n-3 PUFAs, and pomegranate. The current evidence underscores the organoid model's potential importance in developing innovative tumorprevention techniques.

COVID-19 is caused by the SARS-CoV-2 virus, which has afflicted more than 245.37 million individuals worldwide and resulted in more than 4.9 million deaths as of today, with a mortality rate of 2.1%. Diabetes mellitus (DM) and its secondary complications are the major serious global health concerns today due to its growth rate, and it is the fastest-growing non-communicable disease. According to International Diabetes Federation (IDF) data, one out of 11 adults is diabetic, and the projection says that the figure will reach 642 million by 2040 globally. The occurrence of DM and its secondary complications is also associated with the severity of COVID-19 and high mortality. People with DM have a weakened immune system owing to innate immunity defects affecting phagocytosis, neutrophil chemotaxis, and cellmediated immunity; however, the high prevalence of diabetes in serious cases of COVID-19 may reflect the higher prevalence of type 2 DM (T2DM) in older people. Moreover, DM is linked to cardiovascular illness in older people, which could underlie the correlation between COVID-19 and fatal outcomes. SARS-CoV-2 infects via the angiotensin-converting enzyme 2 (ACE2), which is found in pancreatic islets, and infection with SARS-CoV-1 has been linked to hyperglycemia in individuals who do not have DM. And hence diabetic patients need to take more precautions and maintain their blood glucose levels. Many pieces of research say that COVID-19 and DM, especially its secondary complications are interlinked. But it also needs more elaborative evidence on whether the anti-diabetic drugs can manage only blood glucose or SARS-CoV-2.