Current molecular pharmacology最新文献

Background: Carbamazepine (CBZ) is widely used as an anti-epileptic drug. Vitamin B12 has been shown to protect against DNA damage caused by several mutagenic agents.

Objective: This study aimed to investigate the effect of vitamin B12 on CBZ-induced genotoxicity in cultured human lymphocytes.

Methods: Sister chromatid exchanges (SCEs) and chromosomal aberrations (CAs) genotoxic assays were utilized to achieve the study objective.

Results: The results showed significantly higher frequencies of CAs and SCEs in the CBZ-treated cultures (12 μg/mL) compared to the control group (P<0.01). The genotoxic effects of CBZ were reduced by pre-treatment of cultures with vitamin B12 (13.5μg/ml, P<0.05). Neither CBZ nor vitamin B-12 showed any effects on mitotic and proliferative indices.

Conclusion: CBZ is genotoxic to lymphocyte cells, and this genotoxicity can be reduced by vitamin B12.

Background: Acute and chronic sleep deprivation present many health-related problems in modern societies, mainly concerning the immune system. Immune factors, particularly the interleukins, regulate sleep and, therefore, may be altered by sleep deprivation (SD).

Objectives: We aimed to investigate the possible effects of acute and chronic sleep deprivation on selected cytokines, including interleukins (IL-1β, IL-9, IL-17, and IL-23) and tumor necrosis factor- alpha (TNF-α).

Methods: The animals were grouped into acute sleep-deprived (SD; for 24 hours) and chronic sleep-deprived (8 hours a day for 10, 20, and 30-days). The SD was induced using the multipleplatforms model. The serum levels of cytokines were measured using commercially available ELISA.

Results: The serum levels of IL-1β were significantly reduced after acute SD, whereas they were increased after 20-days of chronic SD. The IL-9 levels were reduced after acute SD, increased after 10-days of SD, and reduced again after 30-days of SD. Conversely, the levels of IL-23 were not changed after acute SD, reduced after 10 days of SD, and increased after 30-days of SD. Levels of TNF-α were not changed after acute SD, whereas they were increased after 20 and 30- days of SD.

Conclusion: In conclusion, both acute and chronic SD distinctly disturb the immune profile, which might result in the emergence of various pathologies presented during sleep deprivation.

Backgrounds: Hypertensive nephropathy (HN) is a kind of renal disease caused by essential hypertension that eventually worsens into end-stage renal disease (ESRD). HN could damage the renal tubules, induce kidney damage and renal failure, and increase the risk of stroke, heart disease or death, but there are few ideal drugs for HN treatment.

Methods: In this study, we explored the therapeutic effect of bajijiasu (a compound from Morinda officinalis how and a common traditional Chinese medicine for tonifying the kidney) on the HN rat model. Biochemical analysis, HE staining, and PAS staining were used to assess the effects of bajijiasu on HN rat model. Western blotting was used to analyze the potential mechanisms.

Results: The results of HE staining and PAS staining showed that bajijiasu could alleviate the pathological changes in HN rat models; biochemical analysis found that the concentration of Malondialdehyde (MDA), total protein (TP), albumin (ALB), microalbuminuria (MALB), blood urea nitrogen (BUN), creatinine (Cr), triglyceride (TG), and low-density lipoprotein-cholesterol (LDL-C) were significantly decreased compared with the model group after bajijiasu treatment; and bajijiasu could regulate the expression of TNF-α, IL-6, MDA, SOD1 and AGEs in HN rats; the result of western blotting demonstrated that bajijiasu could down-regulate the expression of TGFβ1, NOX4, JNK, p- JNK and up-regulate the expression PPARγ and SOD 1 in HN rats.

Conclusion: Those results demonstrated that bajijiasu could alleviate the pathological changes and physiological and biochemical symptoms of HN rat models by regulating the expression of TGFβ1, PPARγ, JNK, p-JNK, NOX4 and SOD1 but could not lower the blood pressure of HN rats. Those pieces of evidence may provide a new therapeutic method for HN treatment.

Background: An imbalance in the levels of arachidonic acid (ARA) metabolites in cardiovascular disorders and drug-induced cardiotoxicity have been previously described.

Aims: This study aimed to investigate the influence of cyclooxygenase-2 (COX-2) selective inhibitors on the gene expression of ARA-metabolizing genes and beta1 gene in the hearts and kidneys of experimental mice.

Methods: Thirty-five balb/c mice were divided into five groups with seven mice per group. The groups were then given two distinct types of COX-2 selective inhibitors, rofecoxib and celecoxib, in two different doses equivalent to those used in human treatment for 30 days. The mRNA expression of beta1, ace2, and ARA-metabolizing genes, coxs, lipoxygenases (aloxs), and cytochrome p450 (cyp450s) in mice heart and kidneys were assessed. Genes were analyzed using real-time polymerase chain reaction analysis. In addition, rofecoxib-induced histological alterations were examined.

Results: It was found that only the high dose of rofecoxib (5 mg/kg) caused toxicological alterations, a finding that was indicated by a significant increase (P < 0.05) in the relative weight of the mouse hearts and increase in the ventricle wall thickness as observed through pathohistological examination. This increase was associated with a significant increase in the mRNA expression level of the beta1 receptor in both the heart and kidneys of the mice (53- and 12-fold, respectively). The expression of both cox1 and 2 genes was increased 4-fold in the kidneys. In addition, the expression of the alox12 gene increased significantly (by 67-fold in the heart and by 21-fold in the kidney), while alox15 gene expression was upregulated in the heart by 8-fold and 5-fold in the kidney. The genes responsible for synthesizing 20- Hydroxyeicosatetraenoic acid (cyp4a12 and cyp1a1) were significantly upregulated (P < 0.05) in the hearts of high-dose rofecoxib-treated mice by 7- and 17 -fold, respectively. In addition, the expression of epoxyeicosatrienoic acid-synthesizing genes, cyp2c29 and cyp2j5, was increased significantly (P < 0.05) in the hearts of high-dose rofecoxib-treated mice by 4- and 16-fold, respectively.

Conclusion: Rofecoxib caused upregulation of the mRNA expression of the beta 1 gene in association with increased expression of ARA-metabolizing genes in mouse hearts and kidneys. These findings may help us understand the molecular cardiotoxic mechanism of rofecoxib.

According to the World Health Organization (WHO), epilepsy is the 4th most prevalent neurological disorder after migraine, stroke, and Alzheimer's disease. There are numerous types of epileptic syndrome that are reported in children; one of them is Dravet syndrome. It is a neurological disorder of infants' outset during the first year of life. Dravet syndrome is a genetically determined syndrome and the most studied form of genetic epilepsy. Nearly 70-80% of its cases are due to genetic alterations in the SCN1A gene, and almost 16% of cases are due to variations in the PCDH19 gene. Besides that, mutations in SCN1B, SCN2A, and GABRG2, including some novel genes, STXBP1, HCN1, and CDH2 have been observed in DS patients. It is a drug-resistant epileptic syndrome and its complete removal is still challenging. So, novel therapeutic techniques are being used to treat drug-resistant seizures. Recently, new strategies have been made to improve the neuron-specific targeting of AEDs encapsulated by nanocarriers. The nanocarriers will have a major contribution to nano-neuro medicines such as drug delivery, neuroimaging, neuroprotection, neurosurgery, and neuroregeneration. The nanotechnology-mediated techniques also have a fantastic success rate in gene therapy, as reported in recent years. The anti- epileptic drug delivery with the help of nanoparticles, at the targeted position, makes them applicable for the possible treatment of drug-resistant seizures and gives new hope to patients affected with it.

Osteoporosis is becoming more prevalent in the ageing society, however, its treatment is still a problem for both society and individuals. Traditional Chinese Medicine (TCM) has a long history in treating osteoporosis and is receiving increasing attention. Multiple formulas of TCM showed satisfactory effects in treating osteoporosis in both animal models and clinical patients. However, because TCM usually consists of multiple plant and/or animal products, it is difficult to clarify the mechanism of TCM according to the requirements of Western medicine regarding purity, efficacy, dosage, and safety. With increasing researchers have started to investigate the TCM using modern scientific tools such as bioinformatics and network pharmaceutics in osteoporosis and the addition of TCM in the latest version of International Statistical Classification of Diseases and Related Health Problems (ICD-11 version, 2019) by WHO, TCM is showing large potential in treating osteoporosis although there is still a long way. The review aimed to summarize recent advancements of TCM treating osteoporosis.

Objectives: The scientific research community devotes stupendous efforts to control the arguable counterbalance between the undesirable effects of hormone replacement therapy (HRT) and post-menopausal syndrome. The recent emergence of 3rd generation selective estrogen receptor modulators and phytoestrogens has provided a promising alternative to HRT. Hence, we assessed the potential effects of combined Bazedoxifene and Genistein on hippocampal neuro-alterations induced by experimental ovariectomy.

Methods: For this purpose, we utilized forty-eight healthy sexually mature female Wistar rats assorted to control, ovariectomy (OVX), Genistein-treated ovariectomized (OVX+GEN) and Bazedoxifene and Genistein-treated ovariectomized (OVX+BZA+GEN) groups. Hippocampi samples from various groups were examined by H&E, silver stains and immunohistochemical examination for calbindin-D28k, GFAP, and BAX proteins. We also assessed hippocampal mRNA expression of ERK, CREB, BDNF and TrkB.

Results: Our histopathological results confirmed that combined BZA+GEN induced restoration of hippocampal neuronal architecture, significant reduction of GFAP and BAX mean area % and significant upregulation of calbindin-D28k immunoexpression. Furthermore, we observed significant upregulation of ERK, CREB, BDNF and TrkB mRNA expression in the BZA+GEN group compared to the OVX group.

Conclusion: Taken together, our findings have provided a comprehensive assessment of histological, immunohistochemical and cyto-molecular basis of combined Genistein and Bazedoxifene ameliorative impacts on hippocampal neuro-alterations of OVX rats via upregulation of Calbindin, CERB, BDNF, Trk-B and ERK neuronal expression.

Objective: Diabetic nephropathy is an unavoidable complication of chronic uncontrolled diabetes mellitus. The pathogenesis of diabetic nephropathy is multifactorial, and the development of an effective therapy remains to be elucidated. The aim of the present study was to assess the role of NOX2 and Nrf2 in the protective mechanism of thymoquinone (THQ) against streptozotocin (STZ)-induced diabetic nephropathy.

Methods: Rats were injected with STZ (55 mg/kg) to induce diabetes. The diabetic rats were orally treated with THQ (10 mg/kg/day) for eight weeks.

Results: STZ-treated rats exhibit an elevation of serum creatinine, serum urea, and creatinine clearance. The renal abnormalities were associated with increased NADPH oxidase isoform, NOX2 protein expression, and activity, along with elevated malondialdehyde (MDA). In addition, the tumor necrotic factor-alpha (TNF-α) level and nitric oxide (NO) bioavailability, as well as the transforming growth factor-beta (TGF)-β, were markedly increased. On the other hand, the nuclear factor-E2-related factor (Nrf2) protein expression was significantly reduced in diabetic rats compared to the control. However, treatment with THQ significantly reversed these alterations with subsequent ameliorating renal dysfunction and pathological abnormalities.

Conclusion: The present study demonstrates that THQ could protect against STZ-induced diabetic nephropathy by modulating the Nrf2/NOX2 signaling pathway.

Cancers with a high capability for angiogenesis are frequently regarded as being difficult to treat. Anti-angiogenesis drugs are considered the primary therapy for these types of cancers. Due to intrinsic or acquired anti-angiogenesis resistance, therapies result in moderate clinical consequences, despite some hopeful findings. The importance of non-coding RNAs (ncRNAs) such as microRNAs (miRNAs), long non-coding (lncRNAs), and circular RNAs (circRNAs) in drug resistance mechanisms in cancer treatment has been discovered in the previous decade. Anti-angiogenic drug resistance can be influenced by ncRNA dysregulation. Hence, ncRNAs are potential drug resistance targets for new anti-angiogenic drugs in the inhibition of angiogenesis in tumors. Furthermore, some ncRNAs can be employed as biomarkers for anti-angiogenic drug responses and can be used to monitor cancer non-invasively. Combination treatment approaches, combined with routine anti-angiogenesis and some drugs that target the ncRNAs causing resistance, can be potential ways to overcome anti-angiogenesis resistance. For the first time, we explain the mechanisms of anti-angiogenic drug resistance and the related miRNAs and lncRNAs and their signaling pathways in commonly used antiangiogenic drugs implicated in this review article. These ncRNAs could be suggestions for targeting and reducing anti-angiogenic drugs in the future.

Aims and objective: This study aimed to unveil the specific function of lncRNA BBOX1 antisense RNA 1 (BBOX1-AS1) in ESCC cells and the underlying regulatory mechanism.

Background: Esophageal squamous cell carcinoma (ESCC) is a deadly disease. Molecular mechanisms essential to ESCC development and progression require in-depth investigation. Long noncoding RNAs (lncRNAs) have been suggested as crucial effectors in modulating tumor growth.

Methods: RT-qPCR and western blot examined the expression of genes and proteins of concern, respectively. Colony formation and EdU assays assessed the changes in cell proliferation. Sphere formation assay also detected the stemness of ESCC cells. Bioinformatics prediction, along with mechanistic assays (FISH, Subcellular fractionation, RNA pull-down, RIP, and luciferase reporter), was conducted to explore the gene interactions and regulatory relationship.

Results: BBOX1-AS1 was observed to be aberrantly up-regulated in ESCC tissues and cell lines. BBOX1-AS1 depletion exerted suppressive impacts on ESCC cell proliferation and stemness, while BBOX1-AS1 overexpression led to the opposite consequences. Moreover, BBOX1-AS1 was verified to activate Hedgehog signaling pathway via up-regulating PTCH1, and BBOX1-AS1 could sponge miR-506-5p to up-regulate EIF5A, thus stabilizing PTCH1 mRNA. Rescue experiments indicated that BBOX1-AS1 could affect ESCC cell proliferation and stemness via modulation on PTCH1.

Conclusion: To conclude, BBOX1-AS1 activates Hedgehog signaling pathway to facilitate the proliferation and stemness of ESCC cells via miR-506-5p/EIF5A/PTCH1 axis.