Rehmapicrogenin attenuates lipopolysaccharide-induced podocyte injury and kidney dysfunctions by regulating nuclear factor E2-related factor 2/antioxidant response element signalling.

BACKGROUND: Apoptosis and oxidative stress in kidneys are critical players in acute kidney injury (AKI). Rehmapicrogenin, a monomeric compound extracted from Rehmanniae radix, has been found to possess nitric oxide inhibitory and anti-inflammatory activities. Thus, this study aimed to investigate the roles and mechanisms of rehmapicrogenin in AKI. METHODS: Lipopolysaccharide (LPS) was used to induce AKI-like conditions. Cell survival conditions were detected by cell counting kit-8 assays and flow cytometry. Several renal function markers including blood urea nitrogen, proteinuria, creatinine, and albumin were measured. Apoptosis and reactive oxygen species (ROS) production were examined by TUNEL and dihydroethidium staining, respectively. Haematoxylin-eosin staining and periodic acid-Schiff staining were conducted to assess histopathological changes. Gene expression was evaluated by western blotting, commercially available kits and immunofluorescence staining. RESULTS: For in vitro analysis, rehmapicrogenin inhibited the LPS-induced podocyte apoptosis by activating the Nrf2/ARE pathway. For in vivo analysis, rehmapicrogenin improved renal functions in LPS-induced mice. Additionally, rehmapicrogenin suppressed LPS-induced podocyte apoptosis and oxidative stress in kidney tissues. Mechanistically, rehmapicrogenin activated the Nrf2/ARE pathway in LPS-induced mice. CONCLUSION: Rehmapicrogenin relieves the podocyte injury and renal dysfunctions through activating the Nrf2/ARE pathway to inhibit apoptosis and oxidative stress.

Expression of FSHR in chondrocytes and the effect of FSH on chondrocytes.

OBJECTIVE: Chondrocytes express many kinds of hormone receptors. The function of Follicle stimulating hormone (FSH) in the ovary is mediated by FSH receptor (FSHR). FSH receptor (FSHR) is found in many non-ovarian tissues, however it has been unclear if chondrocytes express FSHR. The purpose of this study is to determine it. METHODS: Mouse primary chondrocytes and human articular cartilage tissues were examined. The expression and sequence of FSHR mRNA by reverse transcription polymerase chain reaction (RT-PCR) and sequenced, respectively, and its protein expression was tested using western blotting and location was observed under immunofluorescence microscopy. Ovarian tissue was as a positive control. After FSH stimulated mouse chondrocytes, intracellular cAMP levels were assessed by ELISA, and gene expression relative to Mouse WNT Signaling Pathway was tested by RT2 Profiler PCR Arrays. RESULTS: FSHR was detected at the transcriptional level and confirmed to have the same sequence as that of ovary-derived mRNA of FSHR. FSHR proteins presented at the same line as the positive proteins of ovary, in mouse chondrocytes and human cartilage tissue, respectively. FSHR proteins were located at the cell membrane. Intracellular cAMP contents were significantly elevated up to 7-fold in mouse chondrocytes by forskolin (100 mM) (P < 0.001); however, different doses of FSH did not change the cAMP contents in mouse primary chondrocytes. RT2 Profiler PCR Arrays demonstrated that FSH could cause changes in gene expression among the 84 preordained genes, such as Fosl1, Rhou, and Dkk1, in mouse chondrocytes relative to the control. CONCLUSION: Mouse chondrocytes and human articular cartilage express functional FSHR. Moreover, FSH can act on chondrocytes and cause genetic changes.

[Functional electrical stimulation based on a working pattern influences function of lower extremity in subjects with early stroke and effects on diffusion tensor imaging: a randomized controlled trial].

OBJECTIVE: To explore the possible mechanisms for improving lower extremity motor function in patients with early stroke through combining magnetic resonance diffusion tensor imaging (DTI) technology and functional electrical stimulation (FES) based on human walking patterns. METHODS: From August 2012 to September 2013, a total of 48 eligible patients were stratified according to age, gender, disease course, Brunnstrom staging and types of stroke. And the Minimize software was used to divided them randomly into four-channel FES group (n = 18), dual-channel FES group (n = 15) and comfort stimulation group (n = 15). For all three groups, general medication and standard rehabilitation were provided. Based on normal walking pattern design of FES treatment, four-channel FES groups received the stimulations of quadriceps, hamstring, anterior tibialis and medial gastrocnemius. For the dual-channel FES group, the stimulations of tibialis anterior, peroneus longus and peroneus brevis muscles were applied. In comfort electrical stimulation group, the electrode positions were identical to the stimulation group, but there was no current output during stimulation. Before and after 3-week treatment, three groups received weekly rehabilitation evaluations of Fugl-Meyer assessment (FMA), posture assessment of stroke scale (PASS), Brunel balance assessment (BBA), Berg balance scale (BBS) and modified Barthel index (MBI). Before and after treatment, DTI examination was performed for some patients. RESULTS: Among three groups, general patient profiles and pre-treatment evaluations showed no significant difference. For intra-group comparisons versus pre-treatment, at week 1, 2 and 3, the scores of PASS, BBA, BBS, FMA and MBI had statistically significant differences (P < 0.05); At week 3 post-treatment, when four-channel and double-channel FES groups were compared versus pre-treatment, the scores of ipsilateral FA had statistically significant differences (P < 0.05). At week 1 post-treatment, MBI had statistically significant difference among 3 groups (P = 0.037). As compared with placebo, four-channel group had statistically significant difference [(52 ± 12) vs (38 ± 18), P < 0.05]; At week 2 post-treatment, the scores of PASS and MBI were (29 ± 3, 73 ± 13) in four-channel FES group versus (24 ± 8, 60 ± 17) in dual-channel FES group. And the scores of PASS, BBA, BBS, FMA and MBI were (9 ± 3, 8.3 ± 2.4, 37 ± 7, 22 ± 5, 73 ± 13) in four-channel FES group versus (21 ± 7, 6.2 ± 3.1, 24 ± 16, 15 ± 8, 47 ± 20) in comfort electrical stimulation group. When dual-channel FES and comfort stimulation groups were compared, MBI had significant statistical difference [(60 ± 17) vs (47 ± 20), P < 0.05]. At week 3 post-treatment, four-channel and dual-channel FES groups were compared, there was also statistical significance in FMA [(25 ± 5) vs (20 ± 7), P = 0.055]. The scores of PASS, BBS, FMA and MBI were (31 ± 3, 43 ± 8, 25 ± 5, 81 ± 13) in four-channel FES group versus (25 ± 8, 29 ± 17, 17 ± 9, 54 ± 25) in comfort stimulation group respectively. When dual-channel FES and comfort stimulation groups were compared, the scores of MBI were (71 ± 15) and (54 ± 25) respectively. And the difference was statistically significant (P < 0.05). At week 3 post-treatment, the scores of FA significantly increased [four-channel FES group (0.321 ± 0.172) vs comfort stimulation group (0.217 ± 0.135) (P = 0.020)]. When dual-channel FES group (0.333 ± 0.164) and comfort stimulation group (0.217 ± 0.135) (P = 0.049) were compared, the differences were statistically significant. DTI showed that four-channel FES group increased significantly, but contralateral fiber bundle was not obvious. And the improvements of dual-channel FES and comfort stimulation groups were insignificant. CONCLUSION: Compared with traditional dual-channel FES, functional electrical stimulation based on human walking patterns is more efficacious. And it helps to restore brain structure and function and promote motor function recovery in patients with early stroke.

Real-world time-travel experiment shows ecosystem collapse due to anthropogenic climate change.

Predicting climate impacts is challenging and has to date relied on indirect methods, notably modeling. Here we examine coastal ecosystem change during 13 years of unusually rapid, albeit likely temporary, sea-level rise ( > 10 mm yr-1) in the Gulf of Mexico. Such rates, which may become a persistent feature in the future due to anthropogenic climate change, drove rising water levels of similar magnitude in Louisiana's coastal wetlands. Measurements of surface-elevation change at 253 monitoring sites show that 87% of these sites are unable to keep up with rising water levels. We find no evidence for enhanced wetland elevation gain through ecogeomorphic feedbacks, where more frequent inundation would lead to enhanced biomass accumulation that could counterbalance rising water levels. We attribute this to the exceptionally rapid sea-level rise during this time period. Under the current climate trajectory (SSP2-4.5), drowning of ~75% of Louisiana's coastal wetlands is a plausible outcome by 2070.

Network Pharmacology Approach to Investigate the Mechanism of Danggui-Shaoyao-San against Diabetic Kidney Disease.

Background: Danggui-Shaoyao-San (DSS) is a traditional Chinese medicine formula that has been widely used to treat a variety of disorders, including renal diseases. Despite being well-established in clinical practice, the mechanisms behind the therapeutic effects of DSS on diabetic nephropathy (DN) remain elusive. Methods: To explore the therapeutic mechanism, we explored the action mechanism of DSS on DN using network pharmacology strategies. All ingredients were selected from the relevant databases, and active ingredients were chosen on the basis of their oral bioavailability prediction and drug-likeness evaluation. The putative proteins of DSS were obtained from the Traditional Chinese Medicine Systems Pharmacology (TCMSP) database, whereas the potential genes of DN were obtained from the GeneCards and OMIM databases. Enrichment analysis using gene ontology (GO) and the Kyoto encyclopedia of genes and genomes (KEGG) was performed to discover possible hub targets and gene-related pathways. Afterwards, the underlying molecular mechanisms of DSS against DN were validated experimentally in vivo against db/db mice. Results: We identified 91 phytochemicals using the comprehensive network pharmacology technique, 51 of which were chosen as bioactive components. There were 40 proteins and 20 pathways in the target-pathway network. The experimental validation results demonstrated that DSS may reduce the expression of TNF-α, IL-6, and ICAM-1, as well as extracellular matrix deposition, by blocking the JNK pathway activation, which protects against kidney injury. Conclusion: This study discovered the putative molecular mechanisms of action of DSS against diabetic kidney damage through a network pharmacology approach and experimental validation.

Aspirin inhibits human telomerase activation in unstable carotid plaques.

The activation of telomerase in unstable plaques is an important factor in atherosclerosis, and may be predictive of the risk of cerebrovascular diseases. Human telomerase reverse transcriptase (hTERT) is a subunit of telomerase that is essential for telomerase activation. The aim of the present study was to investigate whether aspirin inhibits the activation of telomerase and hTERT in unstable carotid plaques. Polymorphonuclear neutrophils (PMNs) derived from carotid plaques were isolated from the washing medium of angioplasty balloons, while circulating PMNs, isolated from arterial blood, served as the controls. A polymerase chain reaction-based telomeric repeat amplification protocol (TRAP) enzyme-linked immunosorbent assay (ELISA) was used to measure the telomerase activity in the cells following treatment with aspirin. The mRNA and protein expression of hTERT were detected by a reverse transcription-polymerase chain reaction (RT-PCR) and western blot analysis, respectively. The results revealed that the atherosclerotic plaques were positive for telomerase activity, and that aspirin inhibited the telomerase activity of the PMNs derived from the plaques. In addition, aspirin was demonstrated to inhibit the mRNA and protein expression of hTERT through the suppression of hTERT transcriptional activity; however, it had no inhibitory effect on the telomerase activity of the circulating PMNs. Thus, the activation of telomerase in resident PMNs is critical in the instability of carotid plaques. The upregulation of telomerase and hTERT during the progression of atherosclerosis may indicate a role for telomerase in the vascular remodeling that occurs during atherogenesis. Aspirin was demonstrated to inhibit the activation of telomerase via an hTERT-dependent manner in the PMN cells of unstable carotid plaques, and thus hTERT may be considered as a target in the treatment of cerebrovascular diseases.