In the present study, acute onset of severe lupus nephritis was successfully treated in mice using a new, benzamide‐linked, small molecule that targets immune modulation and the NLRP3 inflammasome. ...Specifically, 6‐(2,4‐difluorophenyl)‐3‐(3‐(trifluoromethyl)phenyl)‐2H‐benzoe1,3oxazine‐2,4(3H)‐dione (Cf‐02) (a) reduced serum levels of IgG anti‐dsDNA, IL‐1β, IL‐6, and TNF‐α, (b) inhibited activation of dendritic cells and differentially regulated T cell functions, and (c) suppressed the NF‐κB/NLRP3 inflammasome axis, targeting priming and activating signals of the inflammasome. Moreover, treatment with Cf‐02 significantly inhibited secretion of IL‐1β in lipopolysaccharide‐stimulated macrophages, but this effect was abolished by autophagy induction. These results recommend Cf‐02 as a promising drug candidate for the serious renal conditions associated with systemic lupus erythematosus. Future investigations should examine whether Cf‐02 may also be therapeutic in other types of chronic kidney disease involving NLRP3 inflammasome‐driven signaling.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Abstract
In the past decade, single-cell technologies have revealed the heterogeneity of the tumor-immune microenvironment at the genomic, transcriptomic, and proteomic levels and have furthered our ...understanding of the mechanisms of tumor development. Single-cell technologies have also been used to identify potential biomarkers. However, spatial information about the tumor-immune microenvironment such as cell locations and cell–cell interactomes is lost in these approaches. Recently, spatial multi-omics technologies have been used to study transcriptomes, proteomes, and metabolomes of tumor-immune microenvironments in several types of cancer, and the data obtained from these methods has been combined with immunohistochemistry and multiparameter analysis to yield markers of cancer progression. Here, we review numerous cutting-edge spatial ‘omics techniques, their application to study of the tumor-immune microenvironment, and remaining technical challenges.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Hyperthermia (HT) has shown feasibility and potency as an anticancer therapy. Administration of HT in the chemotherapy has previously enhanced the cytotoxicity of drugs against pancreatic cancer. ...However, the drugs used when conducting these studies are substantially conventional chemotherapeutic agents that may cause unwanted side effects. Additionally, the thermal dosage in the treatment of cancer cells could also probably harm the healthy cells. The purpose of this work was to investigate the potential of the two natural polyphenolic compounds, epigallocatechin gallate (EGCG) and chlorogenic acid (CGA), as heat synergizers in the thermal treatment of the PANC-1 cells. Furthermore, we have introduced a unique strategy entitled the thermal cycling-hyperthermia (TC-HT) that is capable of providing a maximum synergy and minimal side effect with the anticancer compounds. Our results demonstrate that the combination of the TC-HT and the CGA or EGCG markedly exerts the anticancer effect against the PANC-1 cells, while none of the single treatment induced such changes. The synergistic activity was attributed to the cell cycle arrest at the G2/M phase and the induction of the ROS-dependent mitochondria-mediated apoptosis. These findings not only represent the first in vitro thermal synergistic study of natural compounds in the treatment of pancreatic cancer, but also highlight the potential of the TC-HT as an alternative strategy in thermal treatment.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Summary
A major challenge of modern agricultural biotechnology is the optimization of plant architecture for enhanced productivity, stress tolerance and water use efficiency (WUE). To optimize plant ...height and tillering that directly link to grain yield in cereals and are known to be tightly regulated by gibberellins (GAs), we attenuated the endogenous levels of GAs in rice via its degradation. GA 2‐oxidase (GA2ox) is a key enzyme that inactivates endogenous GAs and their precursors. We identified three conserved domains in a unique class of C20 GA2ox, GA2ox6, which is known to regulate the architecture and function of rice plants. We mutated nine specific amino acids in these conserved domains and observed a gradient of effects on plant height. Ectopic expression of some of these GA2ox6 mutants moderately lowered GA levels and reprogrammed transcriptional networks, leading to reduced plant height, more productive tillers, expanded root system, higher WUE and photosynthesis rate, and elevated abiotic and biotic stress tolerance in transgenic rice. Combinations of these beneficial traits conferred not only drought and disease tolerance but also increased grain yield by 10–30% in field trials. Our studies hold the promise of manipulating GA levels to substantially improve plant architecture, stress tolerance and grain yield in rice and possibly in other major crops.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
IL-36 cytokines are proinflammatory and have an important role in innate and adaptive immunity, but the role of IL-36 signaling in renal tubulointerstitial lesions (TILs), a major prognostic feature ...of renal inflammation and fibrosis, remains undetermined. In this study, increased IL-36
expression detected in renal biopsy specimens and urine samples from patients with renal TILs correlated with renal function impairment. We confirmed the increased expression of IL-36
in the renal tubular epithelial cells of a mouse model of unilateral ureteral obstruction (UUO) and related cell models using mechanically induced pressure, oxidative stress, or high mobility group box 1. In contrast, the kidneys of IL-36 receptor (IL-36R) knockout mice exhibit attenuated TILs after UUO. Compared with UUO-treated wild-type mice, UUO-treated IL-36 knockout mice exhibited markedly reduced NLRP3 inflammasome activation and macrophage/T cell infiltration in the kidney and T cell activation in the renal draining lymph nodes.
, recombinant IL-36
facilitated NLRP3 inflammasome activation in renal tubular epithelial cells, macrophages, and dendritic cells and enhanced dendritic cell-induced T cell proliferation and Th17 differentiation. Furthermore, deficiency of IL-23, which was diminished in IL-36R knockout UUO mice, also reduced renal TIL formation in UUO mice. In wild-type mice, administration of an IL-36R antagonist after UUO reproduced the results obtained in UUO-treated IL-36R knockout mice. We propose that IL-36 signaling contributes to the pathogenesis of renal TILs through the activation of the NLRP3 inflammasome and IL-23/IL-17 axis.
Dysregulation of NACHT, LRR, and PYD domains‐containing protein 3 (NLRP3) inflammasome is involved in many chronic inflammatory diseases, including gouty arthritis. Activation of the NLRP3 ...inflammasome requires priming and activation signals: the priming signal controls the expression of NLRP3 and interleukin (IL)‐1β precursor (proIL‐1β), while the activation signal leads to the assembly of the NLRP3 inflammasome and to caspase‐1 activation. Here, we reported the effects of the alcoholic extract of Taiwanese green propolis (TGP) on the NLRP3 inflammasome in vitro and in vivo. TGP inhibited proIL‐1β expression by reducing nuclear factor kappa B activation and reactive oxygen species (ROS) production in lipopolysaccharide‐activated macrophages. Additionally, TGP also suppressed the activation signal by reducing mitochondrial damage, ROS production, lysosomal rupture, c‐Jun N‐terminal kinases 1/2 phosphorylation and apoptosis‐associated speck‐like protein oligomerization. Furthermore, we found that TGP inhibited the NLRP3 inflammasome partially via autophagy induction. In the in vivo mouse model of uric acid crystal‐induced peritonitis, TGP attenuated the peritoneal recruitment of neutrophils, and the levels of IL‐1β, active caspase‐1, IL‐6 and monocyte chemoattractant protein‐1 in lavage fluids. As a proof of principle, in this study, we purified a known compound, propolin G, from TGP and identified this compound as a potential inhibitor of the NLRP3 inflammasome. Our results indicated that TGP might be useful for ameliorating gouty inflammation via inhibition of the NLRP3 inflammasome.
Taiwanese green propolis inhibited NLRP3 inflammasome through (1) reducing LPS‐mediated NLRP3 and proIL‐1β expression by NF‐κB downregulation; (2) reducing MSU‐mediated caspase‐1 activation by preserving mitochondrial integrity and inhibiting lysomal rupture; (3) augmenting autophagy.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Background
The let‐7 family of microRNAs has been considered as tumor suppressors in various cancers; however, the role of let‐7c in oral squamous cell carcinoma has not been determined yet.
Methods
...In this study, phenotypical behaviors and the radio/chemoresistance were examined subsequent to overexpression of let‐7c. In addition, the expression of let‐7c in cancer stem cells (CSCs) was evaluated and the effect of let‐7c on stemness characteristics was assessed. Also, luciferase activity assays were performed to test whether interleukin (IL)‐8 was a putative target of let‐7c.
Results
Our results confirmed that the expression of let‐7c in CSCs was reduced, while overexpression of let‐7c attenuated the oncogenicity. Moreover, ectopic expression of let‐7c in CSCs downregulated the stemness hallmarks and the radio/chemoresistance. Expression and secretion of IL‐8 in oral CSCs were both reduced following overexpression of let‐7c. Besides, the inhibitory effect of let‐7c on various stemness phenotypes was reverted by IL‐8, indicating that lower expression of let‐7c may confer higher cancer stemness through a failure to downregulate IL‐8.
Conclusion
These findings revealed the significance of let‐7c in the contribution of oral cancer stemness and radio/chemoresistance. Targeting let‐7c and its downstream IL‐8 may be beneficial to prevent cancer recurrence and metastasis of oral squamous cell carcinoma.
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CMK, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Epithelial–mesenchymal transition (EMT) has been implicated in fibrogenesis and carcinogenesis; however, the exact role of EMT‐inducer Slug in the progression of precancerous oral submucous fibrosis ...(OSF) has not been investigated. In the current study, we showed that the expression of Slug was upregulated in OSF tissues and associated with various myofibroblast markers. After silence of Slug in fibrotic buccal mucosal fibroblasts (fBMFs), the elevated myofibroblast activities and fibrosis markers were all downregulated. Our data revealed that arecoline, an areca nut alkaloid, increased the expression of Slug in normal BMFs, and inhibition of Slug successfully prevented the arecoline‐induced myofibroblast activation. Additionally, overexpression of Slug in BMFs stimulated the activities of myofibroblasts, indicating that upregulation of Slug by arecoline contributes to the myofibroblast transdifferentiation. Most importantly, Slug was able to bind to the E‐box of type I collagen, leading to increased expression of type I collagen. Altogether, this study demonstrated the abnormal elevation of Slug in OSF and its significance in arecoline‐induced fibrogenesis. Moreover, downregulation of Slug could be a potential target for OSF remedy via suppression of myofibroblast activities and type I collagen.
In normal BMFs, arecoline stimulation will elevate the expression of Slug, which directly binds to the promotor of type I collagen, leading to increased collagen deposition and myofibroblasts transdifferentiation. In fibrotic BMFs, inhibition of Slug will reduce the expression of the myofibroblast marker, α‐SMA, and the myofibroblast activities as well as downregulate the ECM accumulation, which may relieve the fibrotic condition.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
This study aimed to report the long-term survival of fixed-bearing medial unicompartmental knee arthroplasty (UKA) with a mean of 14-year follow-up, and to determine possible risk factors of failure.
...We retrospectively evaluated 337 fixed-bearing medial UKAs implanted between 2003 and 2014. Demographic and radiographic parameters were measured, including pre-operative and post-operative anatomical femorotibial angle (aFTA), posterior tibial slope (PTS), and anatomical medial proximal tibial angle (aMPTA). Multivariate logistic regression analysis was applied to figure out risk factors.
The mean follow-up time was 14.0 years. There were 32 failures categorized into implant loosening (n = 11), osteoarthritis progression (n = 7), insert wear (n = 7), infection (n = 4), and periprosthetic fracture (n = 3). Cumulative survival was 91.6% at 10 years and 90.0% at 15 years. No statistically significant parameters were found between the overall survival and failure groups. Age and hypertension were significant factors of implant loosening with odds ratio (OR) 0.909 (p = 0.02) and 0.179 (p = 0.04) respectively. In the insert wear group, post-operative aFTA and correction of PTS showed significance with OR 0.363 (p = 0.02) and 0.415 (p = 0.03) respectively. Post-operative aMPTA was a significant factor of periprosthetic fracture with OR 0.680 (p < 0.05).
The fixed-bearing medial UKA provides successful long-term survivorship. Tibial component loosening is the major cause of failure. Older age and hypertension were factors with decreased risk of implant loosening.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Ohwia caudata (Thunb.) H. Ohashi (Leguminosae) also called as "Evergreen shrub" and Artemisia argyi H.Lév. and Vaniot (Compositae) also named as "Chinese mugwort" those two-leaf extracts frequently ...used as herbal medicine, especially in south east Asia and eastern Asia. Anthracyclines such as doxorubicin (DOX) are commonly used as effective chemotherapeutic drugs in anticancer therapy around the world. However, chemotherapy-induced cardiotoxicity, dilated cardiomyopathy, and congestive heart failure are seen in patients who receive DOX therapy, with the mechanisms underlying DOX-induced cardiac toxicity remaining unclear. Mitochondrial dysfunction, oxidative stress, inflammatory response, and cardiomyocytes have been shown to play crucial roles in DOX-induced cardiotoxicity. Isoliquiritigenin (ISL, 10 mg/kg) is a bioactive flavonoid compound with protective effects against inflammation, neurodegeneration, cancer, and diabetes. Here, in this study, our aim is to find out the Artemisia argyi (AA) and Ohwia caudata (OC) leaf extract combination with Isoliquiritigenin in potentiating and complementing effect against chemo drug side effect to ameliorate cardiac damage and improve the cardiac function. In this study, we showed that a combination of low (AA 300 mg/kg; OC 100 mg/kg) and high-dose(AA 600 mg/kg; OC 300 mg/kg) AA and OC water extract with ISL activated the cell survival-related AKT/PI3K signaling pathway in DOX-treated cardiac tissue leading to the upregulation of the antioxidant markers SOD, HO-1, and Keap-1 and regulated mitochondrial dysfunction through the Nrf2 signaling pathway. Moreover, the water extract of AA and OC with ISL inhibited the inflammatory response genes IL-6 and IL-1β, possibly through the NFκB/AKT/PI3K/p38α/NRLP3 signaling pathways. The water extract of AA and OC with ISL could be a potential herbal drug treatment for cardiac hypertrophy, inflammatory disease, and apoptosis, which can lead to sudden heart failure.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
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