In the present study, we investigated the effects of type 2 diabetes-induced hyperglycemia on the integrity of the blood–brain barrier and tight junction markers in the rat hippocampus. ...Forty-week-old diabetic (Zucker diabetic fatty, ZDF) rats and littermate control (Zucker lean control, ZLC) rats were used in this study. We evaluated the integrity of the blood–brain barrier by measuring sodium fluorescein extravasation and blood vessel ultrastructure. In addition, tight junction markers, such as zona occludens-1, occludin and claudin-5, were quantified by western blot analysis. ZDF rats showed significantly increased sodium fluorescein leakage in the hippocampus. Tight junction markers, such as occludin and claudin-5, were significantly decreased in the hippocampi of ZDF rats compared to those of ZLC rats. In addition, ZDF rats showed ultrastructural changes with phagocytic findings in the blood vessels. These results suggest that chronic untreated diabetes impairs the permeability of the hippocampal blood–brain barrier by down-regulating occludin and claudin-5, indicating that chronic untreated diabetes may cause hippocampus-dependent dysfunction.
Despite the growing interest in adipose tissue as a therapeutic target of metabolic diseases, the identity of adipocyte precursor cells (preadipocytes) and the formation of adipose tissue during ...embryonic development are still poorly understood. Here, we clarified the identity and dynamic processes of preadipocytes in mouse white adipose tissue during embryogenesis through direct examination, lineage tracing and culture systems. Surprisingly, we found that lipid-lacking but perilipin(+) or adiponectin(+) proliferating preadipocytes started to emerge at embryonic day 16.5, and these cells underwent active proliferation until birth. Moreover, these preadipocytes resided as clusters and were distributed along growing adipose vasculatures. Importantly, the embryonic preadipocytes exhibited considerable coexpression of stem cell markers, such as CD24, CD29 and PDGFRα, and a small portion of preadipocytes were derived from PDGFRβ(+) mural cells, in contrast to the adult preadipocytes present in the stromal vascular fraction. Further analyses with in vitro and ex vivo culture systems revealed a stepwise but dynamic regulation of preadipocyte formation and differentiation during prenatal adipogenesis. To conclude, we unraveled the identity and characteristics of embryonic preadipocytes, which are crucial for the formation and expansion of adipose tissue during embryogenesis.
RING finger protein 43 (RNF43) encodes the transmembrane E3 ubiquitin ligase, which targets the Wnt receptor Frizzled (FZD). RNF43 mutations have been discovered in various human cancers including ...colon, pancreatic, stomach, ovarian, and liver cancers. Functional studies on RNF43 missense mutations have shown that they negatively regulate Wnt signaling; however, there are few functional studies on RNF43 frameshift mutations. In this study, we showed that R117fs and P441fs mutants enhanced Wnt/β-catenin signaling, whereas Q409fs and G659fs mutants retained the ability to suppress Wnt/β-catenin signaling. Specifically, R117fs was unable to ubiquitinate FZD5 due to lack of the RING domain, although it was able to interact with FZD5. Immunofluorescence showed that R117fs failed to internalize FZD5 expressed on the cell surface. We also showed that LGK974, a potent Wnt inhibitor, decreased the Wnt/β-catenin activity by R117fs and P441fs mutations. Together, these results demonstrate that RNF43 frameshift mutations retain normal functionality; thus, targeted anti-cancer therapy can be developed according to the mutation type of RNF43.
Non-small-cell lung cancer (NSCLC) is the most common lung cancer subtype and accounts for more than 80% of all lung cancer cases. Epidermal growth factor receptor (EGFR) phosphorylation by binding ...growth factors such as EGF activates downstream prooncogenic signaling pathways including KRAS-ERK, JAK-STAT, and PI3K-AKT. These pathways promote the tumor progression of NSCLC by inducing uncontrolled cell cycle, proliferation, migration, and programmed death-ligand 1 (PD-L1) expression. New cytotoxic drugs have facilitated considerable progress in NSCLC treatment, but side effects are still a significant cause of mortality. Gallic acid (3,4,5-trihydroxybenzoic acid; GA) is a phenolic natural compound, isolated from plant derivatives, that has been reported to show anticancer effects. We demonstrated the tumor-suppressive effect of GA, which induced the decrease of PD-L1 expression through binding to EGFR in NSCLC. This binding inhibited the phosphorylation of EGFR, subsequently inducing the inhibition of PI3K and AKT phosphorylation, which triggered the activation of p53. The p53-dependent upregulation of miR-34a induced PD-L1 downregulation. Further, we revealed the combination effect of GA and anti-PD-1 monoclonal antibody in an NSCLC-cell and peripheral blood mononuclear-cell coculture system. We propose a novel therapeutic application of GA for immunotherapy and chemotherapy in NSCLC.
Pakistan has a high burden of newborn mortality, which would be significantly preventable through appropriate routine immunization. The purpose of this study was to measure the basic timely childhood ...immunization coverage and to identify determinants of factors influencing childhood immunization coverage in Sindh, Pakistan.
Data from Maternal and Child Health Program Indicator Survey 2013-2014 which was conducted in Sindh province of Pakistan was used. Outcome measure was full coverage of the basic immunization schedule from child's vaccination card. The association of receiving basic immunization with demographic factors, socioeconomic status, mother and child health information sources, and perinatal care factors were tested by binary logistic regression.
Among 2,253 children, 1,156 (51.3%) received age-based full basic immunization. The basic immunization rates were 69.1% for under five weeks old, 38.3% for six to nine weeks, 18.8% for 10-13 weeks, 44.0% for 14 weeks-eight months, 60.4% for nine to 11 months, and 59.1% for over one year. Child's age, number of living children, parents' education level, wealth, the source of mother and child health information, number of antenatal care, and assistance during delivery were associated with completing basic immunization.
The overall full basic immunization coverage in Pakistan was still low. Policy makers should identify children at risk of low immunization coverage and obstacles of receiving antenatal care, implement educational interventions targeting on less educated parents, and conduct mass immunization campaigns for timely and complete immunization.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract Background The International Diabetes Federation consensus recently proposed a new definition for the diagnosis of metabolic syndrome, incorporating ethnically specific waist circumference ...(WC) cutoff points. Objective We investigated the ethnically appropriate WC cutoff values for central obesity in Korean adults to predict increased risk of elevated triacylglycerol, reduced HDL cholesterol, elevated blood pressure, elevated fasting plasma glucose, or two or more of these factors. Design We used data from 6561 adults, aged 20–80 years, who participated in the Korean Health and Nutritional Examination Survey of 1998, a cross-sectional health survey of a nationally representative sample of Koreans. Results Based on the receiver operating characteristic curve analysis, the WC value for predicting metabolic risk factors in Koreans was about 85 cm for men and 80 cm for women. The odds ratio for the risk of two or more metabolic risk factors increased abruptly in men with WC ≥ 90 cm and women with WC ≥ 85 cm. The 80th percentile for WC in the Korean population was 90 cm for men and 86.5 cm for women. Thus, the appropriate WC cutoff point for central obesity in Koreans was determined to be 90 cm for men and 85 cm for women. Conclusions Based on our criteria, the prevalence of central obesity was 19.8% in Korean men and 24.5% in Korean women. These findings suggest the applicability of ethnically specific cutoff points for WC in assessing central obesity.
Monitoring the Earth's radiation belt by Low‐Earth‐Orbit (LEO) satellites has a long history and complemented observations near the high‐altitude equatorial plane. However, most of the previous LEO ...missions suffered from limitations in energy resolution, energy range, L‐shell coverage, or the mission lifetime, which leave room for further improvement in this topic. For <80 keV electrons, the slot‐region outer edge at LEO moves inward with increasing geomagnetic activity, which agrees with previous Van Allen Probes reports. The behavior is more conspicuous for lower‐energy electrons. Latitudinal profiles of outer‐belt electron flux are smoother equatorward of the geosynchronous footprint latitudes (|MLAT| ∼ 66°) than poleward. The NextSat‐1 electron flux is positively correlated to geosynchronous observations, with the coefficient generally higher for higher electron energies. Also, both the geosynchronous and NextSat‐1 data exhibit similar spectral indices close to −3 in the log‐log space. All these results complement and expand previous knowledge on energetic electrons. The main findings are discussed in the context of existing literature.
Plain Language Summary
The Earth's radiation belt consists of energetic particles which can potentially harm space assets and astronauts. Radiation belt science has a long history since the first discovery in the 1950s, and many of the unanswered questions were solved during the Van Allen Probes (VAP) era between 2012 and 2019. However, after the decommissioning of VAP, only a few spacecraft are continuously monitoring the radiation belt. In this study, we introduce the energetic electron data produced by a Korean Low‐Earth‐Orbit satellite, NextSat‐1. Since 2019, the satellite measures electron flux in the energy range between ∼30 keV and ∼2 MeV, at an altitude of 575 km and a local time of 22:30. We compare the data to geosynchronous GOES‐17 observations and find a good correlation between their daily variations (correlation coefficients > 0.6) and reasonable agreement in their power spectral index ranges (between −3.0 and −3.5). NextSat‐1 expands existing knowledge obtained from Medium‐Earth‐Orbit data, such as the inner edge of the outer radiation belt changing with geomagnetic activity and energy. We discuss those findings in the context of previous studies.
Key Points
Energetic electron flux measured by Next‐Generation Small Satellite‐1 (NextSat‐1) exhibits a positive correlation to Geostationary Operational Environmental Satellite 17 observations, with the regression slope of 1 ∼ 2.5
The power spectral indices estimated from NextSat‐1 electron data conform to those of geosynchronous observations and with previous studies
Even for the electrons near the loss cone edge, the slot‐region outer edge moves inward with increasing geomagnetic activity
Heat shock protein 70 (HSP70) is an ATP-dependent molecular chaperone, and it has been shown that its levels increase after exposure to various types of stress, including ischemia. In the present ...study, we investigated the effects of HSP70 against H2O2-induced neuronal stress in NSC34 cells and against spinal cord ischemia in rabbits. Tat-HSP70 proteins facilitated the intracellular delivery of HSP70 into the NSC34 cells and enabled them to cross the blood-brain barrier in the rabbit spinal cord. Tat-HSP70 was effectively transduced into NSC34 cells in a concentration- and time-dependent manner, while control-HSP70 protein could not be delivered intracellularly at any concentration or time after treatment. Treatment with Tat-HSP70 reduced the generation of reactive oxygen species and cell death induced by H2O2, while the control-HSP70 did not show any significant effect on the NSC34 cells exposed to H2O2. In rabbit spinal cord, the administration of Tat-HSP70 showed significant amelioration of neurological defects and neuronal death in the ventral horn of spinal cord. In addition, Tat-HSP70 treatment significantly reduced lipid peroxidation and increased Cu, Zn-superoxide dismutase activities in the spinal cord, but glutathione peroxidase and Mn-superoxide dismutase activities remained unchanged. These results suggest that Tat-HSP70, not control-HSP70, decreases cell damage by reducing oxidative stress in NSC34 cells and rabbit spinal cord, and it can be employed for the reduction of neuronal damage caused after spinal cord ischemia.
•Tat-HSP70 enables to efficiently transduce into the NSC34 cells.•Tat-HSP70 reduces the H2O2-induced neuronal death and oxidative damage in the NSC34 cells.•Tat-HSP70 protects motor neurons from spinal cord ischemia by reducing the lipid peroxidation.
Renal cell carcinoma (RCC), the predominant form of kidney cancer, is characterized by high resistance to radiation and chemotherapy. This study shows that expression of protein cross‐linking enzyme ...transglutaminase 2 (TGase 2) is markedly increased in 7 renal cell carcinoma (RCC) cell lines in comparison to HEK293 and other cancer cell lines, such as NCI 60. However, the key role of TGase 2 in RCC was not clear. The down‐regulation of TGase 2 was found to stabilize p53 expression, thereby inducing a 3‐ to 10‐fold increase in apoptosis for 786‐O, A498, CAKI‐1, and ACHN cell lines by DAPI staining. MEF cells from TGase 2–/– mice showed stabilized p53 under apoptotic stress to compare to MEFs from wild‐type mice. TGase 2 directly cross links the DNA binding domain of p53, leading to p53 depletion via autophagy in RCC. TGase 2 and p53 expression showed an inverse relationship in RCC cells. This finding implies that induced expression of TGase 2 promotes tumor cell survival through p53 depletion in RCC.—Ku, B.M., Kim, D.‐S., Kim, K.‐H., Yoo, B.C., Kim, S.‐H., Gong, Y.‐D., Kim, S.‐Y., Transglutaminase 2 inhibition found to induce p53 mediated apoptosis in renal cell carcinoma. FASEB J. 27, 3487–3495 (2013). www.fasebj.org
BACKGROUND AND PURPOSE—Based on its mechanism, the use of balloon guide catheters (BGCs) may be beneficial during endovascular treatment, regardless of the type of mechanical recanalization modality ...used—stent retriever thrombectomy or thrombaspiration. We evaluated whether the use of BGCs can be beneficial regardless of the first-line mechanical endovascular modality used.
METHODS—We retrospectively reviewed consecutive acute stroke patients who underwent stent retriever thrombectomy or thrombaspiration from the prospectively maintained registries of 17 stroke centers nationwide. Patients were assigned to the BGC or non-BGC group based on the use of BGCs during procedures. Endovascular and clinical outcomes were compared between the BGC and non-BGC groups. To adjust the influence of the type of first-line endovascular modality on successful recanalization and favorable outcome, multivariable analyses were also performed.
RESULTS—This study included a total of 955 patients. Stent retriever thrombectomy was used as the first-line modality in 526 patients (55.1%) and thrombaspiration in 429 (44.9%). BGC was used in 516 patients (54.0%; 61.2% of stent retriever thrombectomy patients; 45.2% of thrombaspiration patients). The successful recanalization rate was significantly higher in the BGC group compared with the non-BGC group (86.8% versus 74.7%, respectively; P<0.001). Furthermore, the first-pass recanalization rate was more frequent (37.0% versus 14.1%; P<0.001), and the number of device passes was fewer in the BGC group (2.5±1.9 versus 3.3±2.1; P<0.001). The procedural time was also shorter in the BGC group (54.3±27.4 versus 67.6±38.2; P<0.001). The use of BGC was an independent factor for successful recanalization (odds ratio, 2.18; 95% CI, 1.54–3.10; P<0.001) irrespective of the type of first-line endovascular modality used. The use of BGC was also an independent factor for a favorable outcome (odds ratio, 1.40; 95% CI, 1.02–1.92; P=0.038) irrespective of the type of first-line endovascular modality used.
CONCLUSIONS—Regardless of the first-line mechanical endovascular modality used, the use of BGC in endovascular treatment was beneficial in terms of both recanalization success and functional outcome.
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