Over the past few years, the rapid development of tactile sensing technology has contributed significantly to the realization of intuitional touch control and intelligent human-machine interaction. ...Apart from physical touch or pressure sensing, proximity sensing as a complementary function can extend the detection mode of common single functional tactile sensors. In this work, we present a transparent, matrix-structure dual functional capacitive sensor which integrates the capability of proximity and pressure sensing in one device, and the excellent spatial resolution offered by the isolated response of capacitive pixels enables us to realize precise location identification of approaching objects and loaded pressure with fast response, high stability and high reversibility.
The tumor necrosis factor alpha (TNF-α)–TNF-α receptor (TNFR) interaction plays a central role in the pathogenesis of various autoimmune diseases, particularly rheumatoid arthritis, and is therefore ...considered a key target for drug discovery. However, natural compounds that can specifically block the TNF-α–TNFR interaction are rarely reported. (-)-Epigallocatechin-3-gallate (EGCG) is the most active, abundant, and thoroughly investigated polyphenolic compound in green tea. However, the molecular mechanism by which EGCG ameliorates autoimmune arthritis remains to be elucidated. In the present study, we found that EGCG can directly bind to TNF-α, TNFR1, and TNFR2 with similar μM affinity and disrupt the interactions between TNF-α and TNFR1 and TNFR2, which inhibits TNF-α-induced L929 cell death, blocks TNF-α-induced NF-κB activation in 293-TNF-α response cell line, and eventually leads to inhibition of TNF-α-induced NF-κB signaling pathway in HFLS and MH7A cells. Thus, regular consumption of EGCG in green tea may represent a potential therapeutic agent for the treatment of TNF-α-associated diseases.
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•EGCG directly binds to TNF-α, TNFR1, and TNFR2 with similar μM affinity.•EGCG disrupts the interactions between TNF-α and TNFR1 and TNFR2.•EGCG inhibits TNF-α-induced L929 cell death and blocks TNF-α-induced NF-κB activation in 293-TNF-α response cell line.•EGCG inhibits TNF-α-induced NF-κB signaling pathway in HFLS and MH7A cells.•EGCG can’t inhibit LPS-induced NF-κB activation in HFLS and MH7A cells.
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•Caffeine ameliorates the lipid profiles of ovariectomized (OVX) rats.•Caffeine improves bone metabolism-related blood indicators in OVX rats.•Caffeine did not affect organ weights ...and coefficients or bone quality in OVX rats.•Caffeine did not exert a damaging effect on the skeletal system of OVX rats.
Caffeine (1,3,7-trimethylxanthine) is a naturally occurring plant xanthine alkaloid present in many commonly consumed beverages worldwide, including tea, coffee, and cocoa. Although moderate caffeine intake is generally considered to exert positive effects on human health, its effect on bone metabolism remains controversial. The aim of this study was to systematically evaluate the pharmacological effect of long-term administration of caffeine on ovariectomy-induced postmenopausal osteoporosis in female rats. A sham operation or ovariectomy was performed to establish the ovariectomy rat model. The ovariectomized (OVX) rats were divided into five subgroups: OVX with vehicle (model), OVX with raloxifene hydrochloride (RLX, positive control; 4 mg/kg body weight/day), and OVX with low-, medium-, and high-dose caffeine (9.6, 19.2, and 38.4 mg/kg of body weight/day, respectively). Their corresponding treatments were administered intragastrically for 13 weeks. In-vivo studies showed that treatment with caffeine effectively improved the lipid profiles and increased the concentration of calcium in the serum of OVX rats. Medium- or high-dose treatment with caffeine significantly decreased the activities of alkaline and acid phosphatases in OVX rats. In addition, treatment with caffeine (at any dose) did not adversely affect organ weights, organ coefficients, femoral length, bone mineral density, biomechanical properties, or bone microarchitecture in OVX rats. Collectively, our study demonstrated that caffeine did not exert a damaging effect on the skeletal system of OVX rats.
Excessive osteoclast differentiation and activation are closely associated with the development and progression of osteoporosis. Natural plant-derived compounds that can inhibit osteoclastogenesis ...are an efficient strategy for the prevention and treatment of osteoporosis. Tereticornate A (TA) is a natural terpene ester compound extracted from the leaves and branches of Eucalyptus gracilis, with antiviral, antibacterial, and anti-inflammatory activities. However, the effect of TA on osteoclastogenesis and the underlying molecular mechanism remain unclear. Based on the key role of the NF-κB pathway in the regulation of osteoclastogenesis and the observation that TA exhibits an anti-inflammatory effect by inhibiting NF-κB activity, we speculated that TA could exert anti-osteoclastogenesis activity. Herein, TA could inhibit the RANKL-induced osteoclast differentiation and formation of F-actin rings in RAW 264.7 cells. Mechanistically, TA downregulated the expression of c-Src and TRAF6, and also suppressed the RANKL-stimulated canonical RANK signaling pathways, including AKT, MAPK (p38, JNK, and ERK), and NF-κB; ultimately, downregulating the expression of NFATc1 and c-Fos, the key transcriptional factors required for the expression of genes (e.g., TRAP, cathepsin K, β-Integrin, MMP-9, ATP6V0D2, and DC-STAMP) that govern osteoclastogenesis. Our findings demonstrated that TA could effectively inhibit RANKL-induced osteoclastogenesis via the downregulation of c-Src and TRAF6 and the inhibition of RANK signaling pathways. Thus, TA could serve as a novel osteoclastogenesis inhibitor and might have beneficial effects on bone health.
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•Tereticornate A (TA) inhibits RANKL-induced osteoclastogenesis and formation of F-actin rings in RAW 264.7 cells.•TA inhibits osteoclast-specific protein and gene expression during osteoclastogenesis.•TA inhibits the AKT, MAPK, and NF-κB pathways in RANKL-stimulated RAW 264.7 cells.•TA inhibits RANKL-induced expression of NFATc1 and c-Fos in RAW 264.7 cells.
Dysregulation of osteoclasts or excessive osteoclastogenesis significantly –contributes to the occurrence and development of osteolytic diseases, including osteoporosis, inflammatory bone erosion, ...and tumor-induced osteolysis. The protein-protein interaction between the receptor activator of nuclear factor (NF)-κB (RANK) and its ligand (RANKL) mediates the differentiation and activation of osteoclasts, making it a key therapeutic target for osteoclastogenesis inhibition. However, very few natural compounds exerting anti-osteoclastogenesis activity by inhibiting the RANKL-RANK interaction have been found. Niloticin is a natural tetracyclic triterpenoid compound with anti-viral, antioxidative, and mosquitocidal activities. However, its role in osteoclastogenesis remains unknown. The present study found that niloticin directly binds to RANK with an equilibrium dissociation constant of 5.8 μM, blocking RANKL-RANK interaction, thereby inhibiting RANKL-induced AKT, MAPK (p38, JNK, and ERK1/2), and NF-κB (IKKα/β, IκBα, and p65) pathways activation, and reducing the expression of key osteoclast differentiation-related regulatory factors (NFATc1, c-Fos, TRAP, c-Src, β3-Integrin, and cathepsin K) in osteoclast precursors, ultimately negatively regulating osteoclastogenesis. These findings suggest that niloticin could serve as a novel osteoclastogenesis inhibitor and might have beneficial effects on bone health.
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•Niloticin inhibits RANKL-induced osteoclastogenesis in RAW 264.7 cells.•Niloticin directly binds to RANK with high affinity and blocks RANKL-RANK interaction.•Niloticin inhibits the AKT, MAPK, and NF-κB pathways in RANKL-stimulated RAW 264.7 cells.•Niloticin suppresses RANKL-induced expression of osteoclast-specific proteins and genes during osteoclastogenesis.
Tumor necrosis factor (TNF)-stimulated nuclear factor-kappa B (NF-κB) signaling plays very crucial roles in cancer development and progression, and represents a potential target for drug discovery. ...Roburic acid is a newly discovered tetracyclic triterpene acid isolated from oak galls and exhibits anti-inflammatory activity. However, whether roburic acid exerts antitumor effects through inhibition of TNF-induced NF-κB signaling remains unknown. Here, we demonstrated that roburic acid bound directly to TNF with high affinity (
= 7.066 μM), blocked the interaction between TNF and its receptor (TNF-R1), and significantly inhibited TNF-induced NF-κB activation. Roburic acid exhibited antitumor activity in numerous cancer cells and could effectively induce G0/G1 cell cycle arrest and apoptosis in colorectal cancer cells. Importantly, roburic acid inhibited the TNF-induced phosphorylation of IKKα/β, IκBα, and p65, degradation of IκBα, nuclear translocation of p65, and NF-κB-target gene expression, including that of XIAP, Mcl-1, and Survivin, in colorectal cancer cells. Moreover, roburic acid suppressed tumor growth by blocking NF-κB signaling in a xenograft nude mouse model of colorectal cancer. Taken together, our findings showed that roburic acid directly binds to TNF with high affinity, thereby disrupting its interaction with TNF-R1 and leading to the inhibition of the NF-κB signaling pathway, both
and
. The results indicated that roburic acid is a novel TNF-targeting therapeutics agent in colorectal cancer as well as other cancer types.
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•Caffeine promoted growth and migration of paclitaxel-treated cancer cells.•Caffeine inhibited apoptosis in paclitaxel-treated cancer cells.•Caffeine down-regulated paclitaxel-induced ...α-tubulin acetylation in vitro and in vivo.•Caffeine decreased paclitaxel-induced inhibition of tumor growth.
Caffeine (1,3,7-trimethylxanthine) is a xanthine alkaloid found in a number of dietary products consumed worldwide, such as coffee, tea, and soft beverages, and is known to act as a modifying agent for cytotoxic chemotherapeutic drugs. Studies have shown that caffeine reduces the cytotoxic effects of paclitaxel and inhibits paclitaxel-induced apoptosis; however, the underlying mechanism remains unclear. Here, we investigated whether caffeine inhibits the antitumor activity of paclitaxel via down-regulation of α-tubulin acetylation. In vitro studies, involving MTT assay, wound-healing assay, cell apoptosis assay, and western blotting analysis of A549 and HeLa cells, were performed. A549 and HeLa cell-based xenografts were established, and western blotting and immunohistochemical staining were performed for in vivo studies. The results showed that caffeine promoted the growth of cancer cells treated with paclitaxel. Additionally, caffeine enhanced migration ability, inhibited apoptosis, and decreased the acetylation of α-tubulin in paclitaxel-treated cancer cells. Furthermore, caffeine decreased the inhibitory effect of paclitaxel on tumor growth through down-regulation of α-tubulin acetylation in vivo. Taken together, these findings demonstrate that caffeine inhibits the anticancer activity of paclitaxel via down-regulation of α-tubulin acetylation, suggesting that patients receiving treatment with taxanes, such as paclitaxel, should avoid consuming caffeinated beverages or foods.
Inflammation plays important roles at different stages of diabetes mellitus, tumorigenesis, and cardiovascular diseases. (-)-Epigallocatechin gallate (EGCG) can attenuate inflammatory responses ...effectively. However, the immediate early mechanism of EGCG in inflammation remains unclear. Here, we showed that EGCG attenuated the inflammatory response in the immediate early stage of EGCG treatment by shutting off Notch signaling and that the effect did not involve the 67-kDa laminin receptor, the common receptor for EGCG. EGCG eliminated mature Notch from the cell membrane and the nuclear Notch intercellular domain, the active form of Notch, within 2 min by rapid degradation
the proteasome pathway. Transcription of the Notch target gene was downregulated simultaneously. Knockdown of Notch 1/2 expression by RNA interference impaired the downregulation of the inflammatory response elicited by EGCG. Further study showed that EGCG inhibited lipopolysaccharide-induced inflammation and turned off Notch signaling in human primary macrophages. Taken together, our results show that EGCG targets Notch to regulate the inflammatory response in the immediate early stage.
Glucose-6-phosphate dehydrogenase (G6PDH) is the rate-limiting enzyme in the pentose phosphate pathway (PPP) and plays a crucial role in the maintenance of redox homeostasis by producing nicotinamide ...adenine dinucleotide phosphate (NADPH), the major intracellular reductant. G6PDH has been shown to be a biomarker and potential therapeutic target for renal cell carcinoma (RCC). Here, we report a previously unknown biochemical mechanism through which caffeine, a well-known natural small molecule, regulates G6PDH activity to disrupt cellular redox homeostasis and suppress RCC development and progression. We found that caffeine can inhibit G6PDH enzymatic activity. Mechanistically, caffeine directly binds to G6PDH with high affinity (
K
D
= 0.1923 μM) and competes with the coenzyme NADP
+
for G6PDH binding, as demonstrated by the decreased binding affinities of G6PDH for its coenzyme and substrate. Molecular docking studies revealed that caffeine binds to G6PDH at the structural NADP
+
binding site, and chemical cross-linking analysis demonstrated that caffeine inhibits the formation of dimeric G6PDH. G6PDH inhibition abrogated the inhibitory effects of caffeine on RCC cell growth. Moreover, inhibition of G6PDH activity by caffeine led to a reduction in the intracellular levels of NADPH and reactive oxygen species (ROS), and altered the expression of redox-related proteins in RCC cells. Accordingly, caffeine could inhibit tumor growth through inhibition of G6PDH activity
in vivo
. Taken together, these results demonstrated that caffeine can target G6PDH to disrupt redox homeostasis and inhibit RCC tumor growth, and has potential as a therapeutic agent for the treatment of RCC.
Objective The aim of this study was to evaluate the dynamic changes of serum neopterin and its significance as biomarker in differentiation of MODS from sepsis. Methods Fifty eight critical illness ...patients and 21 healthy controls were included in the study. Of the included 58 critical illness patients, 37 cases were diagnosed of sepsis (sepsis group) and other 21 were non-sepsis subjects (non-sepsis group). Of the 37 sepsis patients, 17 were diagnosed of multiple organ dysfunction syndrome (MODS group). The serum level of neopterin of the above subjects were examined by enzyme linked immunosorbent assay and compared between groups. Results The serum level of neopterin were 0.885±0.34(ng/mL), 3.77±2.08(ng/mL), 14.80±6.78(ng/mL) and 23.90±11.26(ng/mL) for healthy control, non-sepsis, non-MODS and MODS groups respectively with significant statistical difference (F=52.71, p<0.001). Serum neopterin level of non-sepsis, non-MODS and MODS groups were statistical different in the time points of 0, 24h, 48h, 72h, and 96h (p<0.05). The serum neopterin level was significant higher in MODS group compared to nonsepsis and non-MODS groups (p<0.05). Using the serum neopterin as biomarker in differentiation of MODS from sepsis, the diagnostic sensitivity, specificity and AUC were 70.59% (95%CI:44.04-89.69) %, 80.00% (95%CI:56.34- 94.27)% and 0.74(95%CI:0.57-0.91)% respectively. Conclusion Serum neopterin levels in patients with sepsis were elevated and can be used as a promising biomarker in differentiation of MODS from sepsis.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
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