查看更多>>摘要：Cardiovascular disease (CVD) is one of the leading causes of death and disability, and has always been a hotspot in clinical and scientific research. The illness brings a heavy economic burden and causes psychological pressure on society and families. The pathogenesis of CVD is complex and has not yet been fully elucidated. Mitochondria provide energy for cardiovascular function. cAMP signaling is closely related to the mechanism of action of mitochondria. Epac, an important effector of cAMP, is involved in a variety of physiopathological mechanisms of CVD. Epac acts on a variety of pathways, including ion level regulation, cardiac hypertrophy, cardiac fibrosis, cardiomyocyte apoptosis, and angiogenesis. In this article, we systematically discuss the mechanism of action of Epac in CVDs to provide (i) ideas for the treatment of CVDs such as arrhythmia and heart failure and (ii) a basis for studying biological pathways and carrying out targeted drug research. Although some of the studied mechanisms are inconsistent, they also illustrate the complexity and importance of the effects of Epac.
查看更多>>摘要：Autophagy is an essential catabolic process in mammalian cells to maintain cellular integrity and viability by degrading the old and damaged cell organelles and other contents with the help of lysosomes. Deregulation in autophagy can be one of the major contributors leading to the continuous cell proliferation and development of tumors. Tetrandrine, a bisbenzylisoquinoline alkaloid known to have potent bioactivities such as anticancer, antimicrobial, anti-inflammatory, antidiabetic, antioxidant, immunosuppressive, cardiovascular, and calcium channel blocking effects. The present review evaluated the effectiveness of tetrandrine in targeting key proteins in the autophagy pathway to induce anticancer effect based on the available literature. An attempt is also made to understand the influence of tetrandrine in regulating autophagy by mTOR dependant and mTOR-independent pathways. In addition, the review also highlights the limitations involved and future perspectives in developing tetrandrine as a chemotherapeutic drug to treat cancer.
查看更多>>摘要：Teriparatide is a commonly used drug indicated for the treatment of osteoporosis in postmenopausal women. Teriparatide can also upregulate Ang-1 expression through the AC/PKA signaling pathway to promote angiogenesis. At present, promoting angiogenesis is a promising but unrealized strategy for the treatment of ischemic cerebral infarction. However, there are few studies on the application of teriparatide in the treatment of cerebral infarction. We used teriparatide to treat ischemic cerebral infarction in rats and obtained three major findings. First, teriparatide can promote angiogenesis, reduce cerebral infarct size, and increase cerebral perfusion by upregulating Ang-1 expression. Second, teriparatide can promote the expression of HO1, SOD2 and inhibit the production of pro-inflammatory cytokines IL-1β, IL-6 by upregulating Nrf2 expression. Third, we further found that teriparatide can mitigate blood-brain barrier disruption and brain edema by downregulating the expressions of MMP9, Ang-2 and AQP4. Our results indicate that teriparatide is neuroprotective through multiple mechanisms of action that include promoting angiogenesis, inhibiting oxidative stress and neuro inflammation, protecting blood-brain barrier, and reducing brain edema.
查看更多>>摘要：The increasing global burden of diabetes mellitus has called for the search for a therapeutic alternative that offers better activities and safety than conventional chemotherapy. Herein, we evaluated the neuroprotective and antioxidant properties of different fractions (ethyl acetate, N-butanol and residual aqueous) of Clompanus pubescens leaves in streptozotocin (STZ)-induced diabetic rats. Our results revealed a significant elevation in the levels of blood glucose, pro-inflammatory cytokines, lipid peroxidation, neuronal activities of acetylcholines-terase, butyrylcholinesterase, nitric oxide, epinephrine, norepinephrine, and Na+/K+-ATPase in diabetic non treated rats. In addition, decreased levels of enzymatic and non-enzymatic antioxidants were observed. Treatment with different fractions of C. pubescens leaves resulted in significant reversal of the biochemical alteration and improved the neurocognitive deficit in STZ induced diabetic rats. However, the ethyl-acetate fraction demonstrated higher activities than the other fractions and was characterized for its phytoconstituents, revealing the presence of Gallic acid (713.00 ppm), catechin (0.91 ppm), ferulic acid (0.98 ppm), rutin (59.82 ppm), quercetin (3.22 ppm) and kaempferol (4.07 ppm). Our molecular docking analysis revealed that these compounds exhibited different binding affinities and potentials for targeting BChE/AChE/ IL-1β/Na+ -K+ -ATPase. However, only Kampferol and ferulic exhibited good drug-like, ADMET, and permeability properties suitable for use as a neuronal drug target agent. Hence, the ethyl-acetate fraction of C. pubescens leaves could be considered as a source of promising bioactive metabolite for the treatment and management of cognitive impairments related to type II diabetes mellitus.
查看更多>>摘要：Pulmonary fibrosis (PF) is a chronic progressive disease that portends a very poor prognosis. It has been suggested that STAT3 is a potential target in PF. This study highlights the importance of cubosomes as a drug delivery system in enhancing the bioavailability of nifuroxazide (NXZD), a poorly soluble STAT3 inhibitor. NXZD-loaded cubosomes (NXZD-LC) were in vitro and in vivo evaluated. In vitro, cubosomes presented a poly-angular nanosized particles with a mean size and zeta potential of 223.73 ± 4.73 nm and - 20.93 ± 2.38 mV, respectively. The entrapment efficiency of nifuroxazide was 90.56 ± 4.25%. The in vivo pharmacokinetic study and the lung tissue accumulation of NXZD were performed by liquid chromatography-tandem mass spectrometry after oral administration to rats. The nanoparticles exhibited a two-fold increase and 1.33 times of bioavailability and lung tissue concentration of NXZD compared to NXZD dispersion, respectively. In view of this, NXZD-LC effectively attenuated PF by targeting STAT3 and NF-κB signals. As a result, NXZD-LC showed a potential anti-inflammatory effect as revealed by the significant decrease in MCP-1, ICAM-1, IL-6, and TNF-α and suppressed fibrogenic mediators as indicated by the significant reduction in TGF-β, TIMP-1, and PDGF-BB in lung tissues. Besides, NXZD-LC improved antioxidant defense mechanisms and decreased LDH and BALF total protein. These effects contributed to decreased collagen deposition. To conclude, cubosomes represent an advantageous pharmaceutical delivery system for enhancing pulmonary delivery of poorly soluble drugs. Additionally, repurposing NXZD as an antifibrotic agent is a promising challenge and new therapeutic approach for unmet therapeutic needs.
查看更多>>摘要：Colistin is a last-resort polypeptide antibiotic widely used to treat against multidrug-resistant Gram-negative bacterial infections. However, this treatment is associated with nephrotoxicity. The aim of this study was to examine the potential protective effect of panduratin A, a bioactive compound of Boesenbergia rotunda, on colistin-induced nephrotoxicity in both in vivo and in vitro models. Intraperitoneal injection of 15 mg/kg colistin for 7 days markedly promoted renal tubular degeneration, increased blood urea nitrogen (BUN) levels, and upregulated the expression of renal injury biomarker and apoptosis proteins. In addition, treatment with colistin increased oxidative stress and apoptosis in mice kidney tissues. Interestingly, these defects were attenuated when co-administered of colistin with panduratin A (2.5 or 25 mg/kg). The underlying mechanisms of panduratin A attenuating colistin toxicity was investigated in human renal proximal tubular cells (RPTEC/TERT1). The mechanisms by which colistin-triggered cytotoxicity was determined by analysis of cell death, reactive oxygen species (ROS) levels, mitochondria function as well as the expression of proteins related to apoptosis pathway. Colistin treatment (200 μg/ml) significantly increased cell apoptosis, elevated ROS production, reduced mitochondrial membrane potential, and decreased anti-apoptotic protein (Bcl-2) expression. These effects were notably suppressed by co-treatment with panduratin A (5 μM). Collectively, panduratin A exerts as a novel nephroprotective agent to protect against colistin-induced renal injury by attenuating mitochondrial damage and renal cell apoptosis.
Luise A. RoserPelin ErkocRebecca IngelfingerMarina Henke...
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查看更多>>摘要：Lichen extracts containing, among other compounds, depsides such as evernic acid, atranorin, and lecanoric acid possess anti-proliferative effects. We aimed to identify lichen metabolites that are responsible for the observed anti-proliferative effects. We performed cytotoxicity, cell colony, cell cycle and apoptosis assays in various cell lines or primary immune cells. We analyzed several cell cycle proteins and apoptosis-related proteins to gain insights into the underlying mechanism. All depsides reduced the viability of the tested cell lines (HCT-116, HEK293T, HeLa, NIH3T3, RAW246.7) in a cell line-dependent manner with lecanoric acid being the most effective. Atranorin did not influence the cell cycle or colony formation in HCT-116 cells, but induced apoptosis in HCT-116 cells. Evernic acid showed no anti-proliferative effects. Lecanoric acid inhibited cell colony formation already at 0.03 μg/ml in HCT-116 cells and induced a G2 cell cycle block in several cell lines. Moreover, lecanoric acid arrested the cell cycle, presumably in the M phase, since expression of cyclin B1 and phosphor-ylated histone H3 was upregulated, whereas the inactive cyclin-dependent kinase 1 (CDK1) was reduced in HCT-116 cells. Most importantly, cell death induced by lecanoric acid was more prominent in cancer cells than in primary human immune and endothelial cells. In conclusion, lecanoric acid seems to mediate its anti-proliferative effects via arrest of cells in the M phase. Our data suggest lecanoric acid may be a potential new candidate for anti-cancer therapy, because it has anti-proliferative effects on cancer cell lines, and does not affect primary immune cells.
查看更多>>摘要：Autophagy is conserved cellular machinery that degrades un-usable proteins and cellular components and has a crucial role in the pathogenesis and drug resistance of various diseases such as lung cancer (LC). Multiple types of endogenous molecules (i.e. miRNAs) have been found to regulate multiple biological processes, such as autophagy. Dysfunction of these molecules is associated with the onset and progression of a variety of human malignancies. Several studies had shown that some miRNAs could mediate autophagy activity in LC cells, which would affect drug resistance as a major problem in LC therapy. Therefore, identifying the underlying molecular targets of miRNAs and their function in autophagy pathways could develop new treatment interventions for LC patients. In this review, we will summarize the interplay between miRNAs, autophagy, and drug resistance of LC patients, as well as the genes and molecular pathways that are involved.
查看更多>>摘要：It has been established that genetic factors partially contribute to type-2 diabetes and vascular disease development. This study determined the effect of kolaviron on the expression profile of genes associated with the insulin signaling pathway and involved in regulating glucose and lipid metabolism, oxidative stress, inflammation, vascular functions, pro-survival and the apoptosis pathway in the heart of type-2 diabetic rats. After induction and confirmation of type-2 diabetes seven days after, the rats were treated with kolaviron for twenty-eight days before being euthanized. Organs were harvested and stored at - 80 °C in a biofreezer. Total RNA was extracted from the ventricle, reverse transcribed to cDNA followed by a real-time quantitative polymerase chain reaction (RT-qPCR) analysis of the expression of mTOR-1, P70S60K, PKC-α, NF-kB, SOD-2, NRF-2, eNOS, AKT-1, ACE, p38 MAPK and the reference gene (GAPDH), after which they were normalized/standardized. The results show an increase in the relative mRNA expression of mTOR/P70S60K/PKCα /P38MAPK/NF-KB/ACE and a decrease in the relative mRNA expression of NRF2/SOD/AKT/eNOS in the heart of the diabetic rats. Nevertheless, kolaviron modulated the expression profile of these genes, which suggest a therapeutic effect and target for vascular dysfunction and complications in type-2 diabetes through the activation of the NRF-2/AKT-1/eNOS signaling pathway and suppression of the NF-kB/PKC signaling pathway.
查看更多>>摘要：We have previously developed several kinds of rapamycin-encapsulated nanoparticles to achieve sustained release of rapamycin to treat hemangioma. However, lack of intrinsic targeting and easy clearance by the immune system are major hurdles that artificial fabricated nanoparticles must overcome. We constructed rapamycin-encapsulated macrophage-derived exosomes mimic nanoparticles-in-microspheres (RNM), to achieve the goal of continuous targeted therapy of hemangiomas. The rapamycin-encapsulated exosome mimic nanoparticles (RN) were firstly prepared by the extrusion-based method from the U937 cells (the human macrophage cell line). After then, RN was encapsulated with PLGA (poly(lactic-co-glycolic acid)) microspheres to obtain RNM. The release profile, targeting activity, and biological activity of RN and RNM were investigated on hemangioma stem cells (HemSCs). RN has a size of 100 nm in diameter, with a rapamycin encapsulation efficacy (EE) of 83%. The prepared microspheres RNM have a particle size of ~30 μm), and the drug EE of RNM is 34%. The sustained release of RNM can remarkably be achieved for 40 days. As expected, RN and RNM showed effective inhibition of cellular proliferation, significant cellular apoptosis, and remarkable repressed expression of angiogenesis factors in HemSCs. Our results showed that RNM is an effective approach for prolonged and effective delivery of rapamycin to hemangiomas.
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