查看更多>>摘要：Neoechinulins are fungal and plant-derived chemicals extracted from Microsporum sp., Eurotium rubrum, Asper-gillus sp., etc. Two analogues of neoechinulin, i.e., A and B, exerted extensive pharmacological properties described in this review. Neoechinulin is an indole alkaloid and has a double bond between C8/C9, which tends to contribute to its cytoprotective nature. Neoechinulin A exhibits protection to PC1 2 cells against nitrosative stress via increasing NAD(P)H reserve capacity and decreasing cellular GSH levels. It also confers protection via rescuing PC1 2 cells from rotenone-induced stress by lowering LDH leakage. This compound has great positive potential against neurodegenerative diseases by inhibiting SIN-1 induced cell death in neuronal cells. Together with these, neoechinulin A tends to inhibit Aβ42-induced microglial activation and confers protection against neuroinflammation. Alongside, it also inhibits cervical cancer cells by caspase-dependent apoptosis and via upregulation of apoptosis inducing genes like Bax, it suppresses LPS-induced inflammation in RAW264.7 mac-rophages and acts as an antidepressant. Whereas, another analogue, Neoechinulin B tends to interfere with the cellular mechanism thereby, inhibiting the entry of influenza A virus and it targets Liver X receptor (LXR) and decreases the infection rate of Hepatitis C. The present review describes the pharmaceutical properties of neoechinulins with notes on their molecular, cellular, and functional basis and their therapeutic properties.
Mark D. KajiJennifer D. NoonanTimothy G. GearyRobin N. Beech...
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查看更多>>摘要：Background and purpose: Nematode glutamate-gated chloride channels (GluCls) are targets of ivermectin (IVM) and moxidectin (MOX), structurally dissimilar macrocyclic lactone (ML) anthelmintics. IVM and MOX possess different pharmacokinetics and efficacy profiles but are thought to have the same binding site, through which they allosterically activate GluCls, apart from the GLC-2 receptor, which is antagonized by IVM. Our goal was to determine GLC-2 sensitivity to MOX, investigate residues involved in antagonism of GLC-2, and to identify differences in receptor-level pharmacology between IVM and MOX. Experimental approach: Two-electrode voltage clamp electrophysiology was used to study the pharmacology of Caenorhabditis elegans GLC-2 receptors heterologously expressed in Xenopus laevis oocytes. In silico homology modeling identified Cel-GLC-2 residues Met291 and Gln292 at the IVM binding site that differ from other GluCls; we mutated these residues to those found in ML-sensitive GluCls, and those of filarial nematode GLC-2. Key results: We discovered that MOX inhibits wild-type C. elegans GLC-2 receptors roughly 10-fold more potently than IVM, and with greater maximal inhibition of glutamate activation (MOX = 86.9 ± 2.5%; IVM = 57.8 ± 5.9%). IVM was converted into an agonist in the Met291Gln mutant, but MOX remained an antagonist. Glutamate responses were abrogated in a Met291Leu Gln292Thr double mutant (mimicking filarial nematode GLC-2), but MOX and IVM were converted into positive allosteric modulators of glutamate at this construct. Conclusions and implications: Our data provides new insights into differences in receptor-level pharmacology between IVM and MOX and identify residues responsible for ML antagonism of GLC-2.
查看更多>>摘要：The oxidative status of twenty-three β-thalassemia/hemoglobin E patients was evaluated after administration of 75 mg/kg deferiprone (GPO-L-ONE?) divided into 3 doses daily for 12 months. Serum ferritin was significantly decreased; the median value at the initial and final assessments was 2842 and 1719 ng/mL, respectively. Progressive improvement with significant changes in antioxidant enzyme activity, including plasma paraoxonase (PON) and platelet-activating factor acetylhydrolase (PAF-AH), and in antioxidant enzymes in red blood cells (glutathione peroxidase (GPx), catalase and superoxide dismutase (SOD)) were observed at 3-6 months of treatment. The levels of total GSH in red blood cells were significantly increased at the end of the study. Improved red blood cell membrane integrity was also demonstrated using the EPR spin labeling technique. Membrane fluidity at the surface and hydrophobic regions of the red blood cell membrane was significantly changed after 12 months of treatment. In addition, a significant increase in hemoglobin content was observed (6.6 ± 0.7 and 7.5 ± 1.3 g/dL at the initial assessment and at 6 months, respectively). Correlations were observed between hemoglobin content, membrane fluidity and antioxidant enzymes in red blood cells. The antioxidant activity of deferiprone may partly be explained by progressive reduction of redox active iron that catalyzes free radical reactions, as demonstrated by the EPR spin trapping technique. In conclusion, iron chelation therapy with deferiprone notably improved the oxidative status in thalassemia, consequently reducing the risk of oxidative-related complications. Furthermore, the improvement in red blood cell quality may improve the anemia situation in patients.
Paulina PietrasAnais AulasMarta M. FayMarta Lesniczak-Staszak...
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查看更多>>摘要：Platinum-based antineoplastic drugs, such as cisplatin, are commonly used to induce tumor cell death. Cisplatin is believed to induce apoptosis as a result of cisplatin-DNA adducts that inhibit DNA and RNA synthesis. Although idea that DNA damage underlines anti-proliferative effects of cisplatin is dominant in cancer research, there is a poor correlation between the degree of the cell sensitivity to cisplatin and the extent of DNA platination. Here, we examined possible effects of cisplatin on post-transcriptional gene regulation that may contribute to cisplatin-mediated cytotoxicity. We show that cisplatin suppresses formation of stress granules (SGs), pro-survival RNA granules with multiple roles in cellular metabolism. Mechanistically, cisplatin inhibits cellular translation to promote disassembly of polysomes and aggregation of ribosomal subunits. As SGs are in equilibrium with polysomes, cisplatin-induced shift towards ribosomal aggregation suppresses SG formation. Our data uncover previously unknown effects of cisplatin on RNA metabolism.
查看更多>>摘要：Hypertension is one of the important causes of cardiovascular diseases, and the imbalance of vascular homeo-stasis caused by oxidative stress and endothelial inflammation occurs throughout hypertension pathogenesis. Therefore, inhibiting oxidative stress and endothelial inflammation is important for treating hypertension. Tianma Gouteng Decoction (TGD) is a Chinese herbal medicine that is commonly used to treat hypertension in China, and demonstrates clinically effective antihypertensive effects. However, its blood pressure reduction mechanism remains unclear. In this study, we further determined the antihypertensive effects of TGD and revealed its underlying mechanism. We established an AngII-induced hypertension mice model, which was treated with TGD for six weeks. We monitored blood pressure, heart rate, and body weight every week. After six weeks, we detected changes in the structure and function of the heart, the structure of blood vessels, and vasomotor factors. We also detected the expression of oxidative stress and inflammation-related genes. We found that TGD can significantly reduce blood pressure, improve cardiac structure and function, and reverse vascular remodeling, which could be due to the inhibition of oxidative stress and inflammation. We also found that the effect of inhibiting oxidative stress and inflammation could be related to the up-regulation of transcription factor EB (TFEB) expression by TGD. Therefore, we used AAV9 to knock down TFEB and observe the role of TFEB in TGD's antihypertensive and cardiovascular protection properties. We found that after TFEB knockdown, the protective effect of TGD on blood pressure and cardiovascular remodeling in AngII-induced hypertensive mice was inhibited, and that it was unable to inhibit oxidative stress and inflammation. Therefore, our study demonstrated for the first time that TGD could exert anti-oxidative stress and anti-inflammatory effects through TFEB and reverse the cardiovascular remodeling caused by hypertension.
查看更多>>摘要：Aquaporin-4 (AQP-4) is an aquaporin composed of six helical transmembrane domains and two highly conserved ASN-pro-ALA (NPA) motifs. It is strongly expressed in rodent and human spinal cord tissues and plays a key role in the pathological process after SCI. After SCI, edema, glial scarring, and inflammation can accelerate the progression of injury and lead to deterioration of function. Many studies have reported that AQP-4 plays an important role in SCI. In particular, it plays an important role in secondary pathological processes (spinal cord edema, glial scar formation, and inflammatory response) after SCI. Loss of AQP-4 has been associated with reduced spinal edema and improved prognosis after SCI in mice. In addition, downregulation of AQP-4 reduces glial scar formation and the inflammatory response after SCI. There is a consensus from numerous studies that AQP-4 may be a potential target for SCI therapy, which guides the ongoing investigation for molecular therapy of SCI. Here, we review the structure of AQP-4, its expression in normal and damaged spinal cord, and its role in SCI, as well as discuss the theoretical basis for the treatment of SCI.
Dana ElkhalifaMenatallah RayanAhmed T. NegmeldinAbdelbary Elhissi...
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查看更多>>摘要：Chemically modified mRNA represents a unique, efficient, and straightforward approach to produce a class of bio pharmaceutical agents. It has been already approved as a vaccination-based method for targeting SARS-CoV-2 virus. The COVID-19 pandemic has highlighted the prospect of synthetic modified mRNA to efficiently and safely combat various diseases. Recently, various optimization advances have been adopted to overcome the limitations associated with conventional gene therapeutics leading to wide-ranging applications in different disease conditions. This review sheds light on emerging directions of chemically modified mRNAs to prevent and treat widespread chronic diseases, including metabolic disorders, cancer vaccination and immunotherapy, musculo-skeletal disorders, respiratory conditions, cardiovascular diseases, and liver diseases.
查看更多>>摘要：Parkinson's disease (PD) is a multifactorial neurodegenerative disease with damages to mitochondria and endoplasmic reticulum (ER), followed by neuroinflammation. We previously reported that a triple herbal extract DA-9805 in experimental PD toxin-models had neuroprotective effects by alleviating mitochondrial damage and oxidative stress. In the present study, we investigated whether DA-9805 could suppress ER stress and neuroinflammation in vitro and/or in vivo. Pre-treatment with DA-9805 (1 μg/ml) attenuated upregulation of glucose-regulated protein 78 (GRP78), C/EBP homologous protein (CHOP) and cleaved caspase-3 in SH-SY5Y neuro-blastoma cells treated with thapsigargin (1μg/ml) or tunicamycin (2 μg/ml). In addition, DA-9805 prevented the production of IL-1β, IL-6, TNF-α and nitric oxide through inhibition of NF-κB activation in BV2 microglial cells stimulated with lipopolysaccharides (LPS). Intraperitoneal injection of LPS (10 mg/kg) into mice can induce acute neuroinflammation and dopaminergic neuronal cell death. Oral administration of DA-9805 (10 or 30 mg/ kg/day for 3 days before LPS injection) prevented loss of dopaminergic neurons and activation of microglia and astrocytes in the substantia nigra in LPS-injected mouse models. Taken together, these results indicate that DA-9805 can effectively prevent ER stress and neuroinflammation, suggesting that DA-9805 is a multitargeting and disease-modifying therapeutic candidate for PD.
查看更多>>摘要：Osteoporosis leads to excessive bone resorption which is not accompanied by equal amount of bone formation. PTH (1 -34) forms the mainstay of bone anabolic therapy. Intermittent PTH (iPTH) has the ability to reconstruct skeleton, a property not shared by other anti-resorptives. In initial phases of PTH treatment, bone formation exceeds bone resorption. However, gradually this phase is replaced by increased bone resorption. Thus, a replacement post PTH discontinuation is much needed. Studies with bisphosp ho nates and Denosumab post PTH withdrawal have yielded promising but variable results. Thus, there is scope for trying new combinations. Our previous studies have shown the superior skeletal effects of neutralizing IL17 antibody (NIL17) over anti-RANKL antibody. Thus, here we investigated if sequential treatment of NIL17 after PTH withdrawal (SHIFT) could serve as a promising therapeutic approach for osteoporosis treatment. Our results show that PTH withdrawal (PTH-W) led to mitigation of its anabolic effects as evidenced by reduced BMD, bone trabecular and cortical micro-architectural parameters. In the continuous PTH (PTH-C) and the Shift group, all these parameters were preserved as par with the sham group. Shift therapy also significantly increased PINP levels. Most importantly, serum CTX-I levels and osteoclast numbers, which were elevated in PTH groups were significantly suppressed in NIL17 monotherapy and shift group. Also, expression of FOXO1 and ATF-4, the main regulators of redox balance and function in osteoblasts, were found to be enhanced maximally in the sequential therapy group. Our study thus advocates use of NIL17 as a replacement therapeutic option post PTH discontinuation.
查看更多>>摘要：Lenvatinib, a small molecule tyrosine kinase inhibitor (TKI), exhibits good inhibitory effect in several types of carcinomas. Specifically, it is the most effective TKI used for treatment of thyroid cancer. To extend pharma-cokinetics data on this anticancer agent, we aimed to identify the metabolites of lenvatinib formed during in vitro incubation of lenvatinib with human hepatic microsomes or recombinant cytochromes P450 (CYPs) by using high performance liquid chromatography and mass spectrometry. The role of CYPs in the oxidation of lenvatinib was initially investigated in hepatic microsomes using specific CYP inhibitors. CYP-catalytic activities in each microsomal sample were correlated with the amounts of lenvatinib metabolites formed by these samples. Further, human recombinant CYPs were employed in the metabolic studies. Based on our data, lenvatinib is metabolized to O-desmethyl lenvatinib, N-descyclopropyl lenvatinib and lenvatinib N-oxide. In the presence of cytochrome b5, recombinant CYP3A4 was the most efficient to form these metabolites. In addition, CYP1A1 significantly contributes to the lenvatinib metabolism. It was even more efficient in forming of O-desmethyl lenvatinib than CYP3A4 in the absence of cytochrome b5. The present study indicates that further research focused on drug-drug interactions, in particular on CYP3A4 and CYP1A1 modulators, is needed. This will pave new avenues towards TKIs-mediated personalized therapy.
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