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Hyperglycemia was reported to cause bone marrow hematopoietic niche dysfunction, and high glucose (HG) in the cultured medium induces MSC senescence. The underlying mechanism is unclear. Here, we investigated the role of HG-induced autophagy in bone-marrow-derived mesenchymal stem cell (BMSC) senescence. HG (25 mM) increased expression of Beclin-1, Atg 5, 7 and 12, generation of LC3-II and autophagosome formation which was correlated with development of cell senescence. Pretreatment of HG-MSC with 3-methyladenine (3-MA) prevented senescence but increased apoptosis. N-acetylcysteine (NAC) was effective in abrogating HG-induced autophagy accompanied by prevention of senescence. Diphenyleneiodonium (DPI), an inhibitor of NADPH oxidase, blocked autophagy and senescence in a manner comparable to NAC. 3-MA, NAC and DPI inhibited HG-induced interleukin-6 production in BMSCs. These results suggest that hyperglycemia induces MSC senescence and local inflammation via a novel oxidant-mediated autophagy which contributes to bone marrow niche dysfunction and hematopoietic impairment.

We used gastric cancer cell line AGS and clinical samples to investigate the roles of mitochondrial DNA (mtDNA) alterations and mitochondrial respiratory dysfunction in gastric adenocarcinoma (GAC). A total of 131 clinical samples, including 17 normal gastric mucosa (N-GM) from overweight patients who had received sleeve gastrectomy and 57 paired non-cancerous gastric mucosae (NC-GM) and GAC from GAC patients who had undergone partial/subtotal/total gastrectomy, were recruited to examine the copy number and D310 sequences of mtDNA. The gastric cancer cell line AGS was used with knockdown (KD) mitochondrial transcription factor A (TFAM) to achieve mitochondrial dysfunction through a decrease of mtDNA copy number. Parental (PT), null-target (NT), and TFAM-KD-(A/B/C) represented the parental, control, and TFAM knocked-down AGS cells, respectively. These cells were used to compare the parameters reflecting mitochondrial biogenesis, glycolysis, and cell migration activity. The median mtDNA copy numbers of 17 N-GM, 57 NC-GM, and 57 GAC were 0.058, 0.055, and 0.045, respectively. The trend of decrease was significant (p = 0.030). In addition, GAC had a lower mean mtDNA copy number of 0.055 as compared with the paired NC-GM of 0.078 (p < 0.001). The mean mtDNA copy number ratio (mtDNA copy number of GAC/mtDNA copy number of paired NC-GM) was 0.891. A total of 35 (61.4%) GAC samples had an mtDNA copy number ratio ≤0.804 (p = 0.017) and 27 (47.4%) harbored a D310 mutation (p = 0.047), and these patients had shorter survival time and poorer prognosis. After effective knockdown of TFAM, TFAM-KD-B/C cells expressed higher levels of hexokinase II (HK-II) and v-akt murine thymoma viral oncogene homolog 1 gene (AKT)-encoded AKT, but lower levels of phosphorylated pyruvate dehydrogenase (p-PDH) than did the NT/PT AGS cells. Except for a higher level of p-PDH, the expression levels of these proteins remained unchanged in TFAM-KD-A, which had a mild knockdown of TFAM. Compared to those of NT, TFAM-KD-C had not only a lower mtDNA copy number (p = 0.050), but also lower oxygen consumption rates (OCR), including basal respiration (OCRBR), ATP-coupled respiration (OCRATP), reserve capacity (OCRRC), and proton leak (OCRPL)(all with p = 0.050). In contrast, TFAM-KD-C expressed a higher extracellular acidification rate (ECAR)/OCRBR ratio (p = 0.050) and a faster wound healing migration at 6, 12, and 18 h, respectively (all with p = 0.050). Beyond a threshold, the decrease in mtDNA copy number, the mtDNA D310 mutation, and mitochondrial dysfunction were involved in the carcinogenesis and progression of GACs. Activation of PDH might be considered as compensation for the mitochondrial dysfunction in response to glucose metabolic reprogramming or to adjust mitochondrial plasticity in GAC.

5-methoxytryptophan (5-MTP) is a newly discovered tryptophan metabolite which controls stress-induced inflammatory signals. To determine whether 5-MTP protects against stress-induced mesenchymal stem cell (MSC) senescence, we incubated bone marrow-derived MSC (BM-MSC) in high-glucose medium or regular medium for 2 weeks followed by addiction of 5-MTP (10 μM) or vehicle for 48 h. 5-MTP reduced p16 and p21 expression, senescence-associated β-Gal (SA-β-Gal) and IL-6 secretion and increased BrdU incorporation. 5-MTP exerted a similar effect on BM-MSC senescence induced by a sublethal concentration of H 2 O 2 . 5-MTP enhanced FoxO3a expression and increased superoxide dismutase and catalase activities in HG BM-MSCs. Silencing of FoxO3a with siRNA abrogated 5-MTP-mediated reduction of SA-β-Gal and IL-6 secretion but not p21 or p16. Since mechanistic target of rapamycin (mTOR) is involved in cellular senescence, we determined whether 5-MTP influences mTOR expression. Our data reveal that mTOR protein level was depressed in HG-MSC which was rescued by 5-MTP. Rapamycin abrogated 5-MTP-mediated suppression of p16, p21, SA-β-Gal and IL-6 and rise of BrdU incorporation. Our findings suggest that 5-MTP protects MSCs against stress-induced senescence via FoxO3a and mTOR upregulation and has potential to improve cell expansion for cell therapy.

Cyclooxygenase-2(COX-2) overexpression promotes inflammation and tumorigenesis. COX-2 expression in response to diverse stimuli is tightly controlled to avoid persistent overexpression. 5-methoxyindole metabolites of L-tryptophan represent a new class of compounds that control COX-2 expression at the transcriptional level. Two of the metabolites, the newly discovered 5-methoxytryptophan (5-MTP, also known as cytoguardin) and N-acetyl 5-methoxytryptamine (melatonin) are the focus of this review. 5-MTP is produced by mesenchymal cells such as fibroblasts via 5-hydroxytryptophan (5-HTP). It inhibits COX-2 transcriptional activation induced by diverse proinflammatory and mitogenic factors. Cancer cells are deficient in cytoguardin production which contributes to COX-2 overexpression. Fibroblast-generated 5-MTP is capable of restoring the control of COX-2 overexpression in cancer cells. 5-MTP blocks cancer cell migration and invasion in vitro and inhibits tumor growth and cancer metastasis in a xenograft model. Melatonin possesses similar COX-2 suppressing and anti-cancer properties albeit at supra-pharmacological concentrations. By contrast, 5-hydroxyindole metabolites of L-tryptophan such as 5-hydroxytryptamine (serotonin), 5-hydroxytryptophol and other serotonin catabolites do not control COX-2 expression. 5-hydroxytryptophan inhibits COX-2 expression through conversion to 5-MTP. The physiological relevance of 5-MTP as an endogenous regulator of inflammation and cancer metastasis remains to be investigated. On the other hand, 5-methoxyindole metabolites of tryptophan are valuable lead compounds for development of new anti-inflammatory drugs and cancer chemoprevention.

Numerous inflammatory cytokines control the pathogenesis of periodontitis, an infectious bacterial disease, via interacting with immune and tissue cells. Antrodia cinnamomea is the origin of the triterpenoid Antcin K, renowned for its immunomodulatory and anti-inflammatory properties. However, the therapeutic performances of Antcin K on periodontitis remain unclear. Lipopolysaccharide (LPS) is the primary virulence factor of Porphyromonas gingivalis , a common periodontal pathogen, which augments the synthesis of proinflammatory cytokines for instance IL-1β, IL-6, IL-8, and IL-17A in primary human gingival fibroblasts (HGFs). Interestingly, treatment of HGFs with Antcin K inhibited LPS-induced proinflammatory cytokines production. RNA sequencing analysis indicated that the PI3K-Akt pathway is potentially linked in Antcin K’s anti-inflammatory function. We revealed that the PI3K, Akt, and NF-κB pathways mediate Antcin K’s suppression of proinflammatory cytokines production. Specifically, our in vivo study demonstrated that Antcin K blocks pathogenesis of periodontal disease in a ligature-mediated periodontitis model. Therefore, we suggest that Antcin K may be a potential therapeutic candidate for controlling periodontal disease.

We review three distance measurement techniques beyond the local universe: (1) gravitational lens time delays, (2) baryon acoustic oscillation (BAO), and (3) HI intensity mapping. We describe the principles and theory behind each method, the ingredients needed for measuring such distances, the current observational results, and future prospects. Time-delays from strongly lensed quasars currently provide constraints on H 0 with < 4 % uncertainty, and with 1 % within reach from ongoing surveys and efforts. Recent exciting discoveries of strongly lensed supernovae hold great promise for time-delay cosmography. BAO features have been detected in redshift surveys up to z ≲ 0.8 with galaxies and z ∼ 2 with Ly- α forest, providing precise distance measurements and H 0 with < 2 % uncertainty in flat Λ CDM. Future BAO surveys will probe the distance scale with percent-level precision. HI intensity mapping has great potential to map BAO distances at z ∼ 0.8 and beyond with precisions of a few percent. The next years ahead will be exciting as various cosmological probes reach 1 % uncertainty in determining H 0 , to assess the current tension in H 0 measurements that could indicate new physics.

Fast radio burst FRB 110523, discovered in archival data, reveals Faraday rotation and scattering that suggests dense magnetized plasma near the source; this means that to infer the source of the burst, models should involve young stellar populations such as magnetars. A fast radio burster characterized An analysis of magnetization and scintillation data from the fast radio burst FRB 110523, discovered in archival data, provides clues about the environment of the burst — and its distance from us. Fast radio bursts are relatively newly discovered phenomena that have yet to be explained. They emit non-repeating, broadband, millisecond flashes and appear to originate from distant parts of the Universe and from objects only hundreds of kilometres in size or less. The new data from FRB 110523 reveal Faraday rotation and scattering that suggest dense magnetized plasma near the source, favouring models involving young stellar populations such as magnetars. Fast radio bursts are bright, unresolved, non-repeating, broadband, millisecond flashes, found primarily at high Galactic latitudes, with dispersion measures much larger than expected for a Galactic source 1 , 2 , 3 , 4 , 5 , 6 , 7 . The inferred all-sky burst rate 8 is comparable to the core-collapse supernova rate 9 out to redshift 0.5. If the observed dispersion measures are assumed to be dominated by the intergalactic medium, the sources are at cosmological distances with redshifts of 0.2 to 1 (refs 10 and 11 ). These parameters are consistent with a wide range of source models 12 , 13 , 14 , 15 , 16 , 17 . One fast burst 6 revealed circular polarization of the radio emission, but no linear polarization was detected, and hence no Faraday rotation measure could be determined. Here we report the examination of archival data revealing Faraday rotation in the fast radio burst FRB 110523. Its radio flux and dispersion measure are consistent with values from previously reported bursts and, accounting for a Galactic contribution to the dispersion and using a model of intergalactic electron density 10 , we place the source at a maximum redshift of 0.5. The burst has a much higher rotation measure than expected for this line of sight through the Milky Way and the intergalactic medium, indicating magnetization in the vicinity of the source itself or within a host galaxy. The pulse was scattered by two distinct plasma screens during propagation, which requires either a dense nebula associated with the source or a location within the central region of its host galaxy. The detection in this instance of magnetization and scattering that are both local to the source favours models involving young stellar populations such as magnetars over models involving the mergers of older neutron stars, which are more likely to be located in low-density regions of the host galaxy.

Chronic kidney disease (CKD) is a commonly occurring complex renal syndrome that causes overall mortality in many diseases. The clinical manifestations of CKD include renal tubulointerstitial fibrosis and loss of renal function. Metallothionein-I/II (MT-I/II) is potentially expressed in the liver and kidney, and possesses antioxidant and metal detoxification properties. However, whether MT-I/II expression is associated with the prognosis of nephropathy remains unknown. In this study, we investigated the MT-I/II level in human CKD, using immunohistochemistry. MT-I/II is located on the proximal tubules and is notably reduced in patients with CKD. MT-I/II expression was significantly correlated with the functional and histological grades of CKD. In an aristolochic acid (AAI)-induced nephropathy mouse model, MT-I/II was abundantly increased after AAI injection for 7 days, but decreased subsequently compared to that induced in the acute phase when injected with AAI for 28 days. Furthermore, we found that ammonium pyrrolidinedithiocarbamate (PDTC) restored AAI-induced MT-I/II reduction in HK2 cells. The injection of PDTC ameliorated AAI-induced renal tubulointerstitial fibrosis and reduced the concentrations of blood urea nitrogen and creatinine in mouse sera. Taken together, our results indicate that MT-I/II reduction is associated with advanced CKD, and the retention of renal MT-I/II is a potential therapeutic strategy for CKD.

COVID-19, which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), first broke out at the end of 2019. Despite rapidly spreading around the world during the first half of 2020, it remained well controlled in Taiwan without the implementation of a nationwide lockdown. This study aimed to evaluate the PM 2.5 concentrations in this country during the 2020 COVID-19 pandemic and compare them with those during the corresponding period from 2019. We obtained measurements (taken every minute or every 3 minutes) from approximately 1,500 PM 2.5 sensors deployed in industrial areas of northern and southern Taiwan for the first quarters (January–March) of both years. Our big data analysis revealed that the median hourly PM 2.5 levels decreased by 3.70% (from 16.3 to 15.7 µg m −3 ) and 10.6% (from 32.4 to 29.3 µg m −3 ) in the north and south, respectively, between these periods owing to lower domestic emissions of PM 2.5 precursors (viz., nitrogen dioxide and sulfur dioxide) and, to a lesser degree, smaller transported emissions of PM 2.5 , e.g., from China. Additionally, the spatial patterns of the PM 2.5 in both northern and southern Taiwan during 2020 resembled those from the previous year. Finally, controlling local PM 2.5 emission sources critically contributes to reducing the number of COVID-19 cases.

Non-thermal plasma (NTP) has been widely applied in the food and agricultural industries. It is still unknown whether natural bioactive compounds in seeds are affected by NTP treatment. Our goal was to examine whether the bioactive compounds in djulis (Chenopodium formosanum Koidz.) seed are changed after NTP treatment. The betacyanin, anthocyanin, total phenolic content (TPCs), total flavonoids (TFs), 2,2-diphenyl-1-picrylhydrazyl radical scavenging effects (DPPH), gallic acid, and rutin were compared in NTP-treated seed and an untreated control. Levels of betacyanin, anthocyanin, and TPCs in the seed were found to be significantly increased after the nitrogen (N2)-NTP treatment compared with the control (p < 0.001). Inversely, the air-NTP treatment significantly weakened the performance of these bioactive compounds in the seed as compared to the control. Levels of TFs in both the air- and N2-NTP treated seed were significantly lower than those in the control (p < 0.001). After the NTP treatment, DPPH was still at high levels, similar to those in the control. The djulis seed extract had antioxidant and anti-inflammatory effects on THP-1 (human-monocyte-cell line) cells. N2-NTP generated nitrogen reactive species that activated the bioactive compounds in the seed. In contrast, air-NTP produced oxygen and nitrogen reactive species inhibited the expression of these bioactive compounds.