Transient simulation of the electrical hysteresis in a metal/polymer/metal nanostructure.

The time-dependent quantum transportation through a metal/polymer/metal system is theoretically investigated on the basis of a Su-Schrieffer-Heeger model combined with the hierarchical equations of motion formalism. Using a non-adiabatic dynamical method, the evolution of the electron subspace and lattice atoms with time can be obtained. It is found that the calculated transient currents vary with time and reach stable values after a response time under the bias voltages. However, the stable current as the system reaches its dynamical steady state exhibits a discrepancy between two sweep directions of the bias voltage, which results in pronounced electrical hysteresis loops in the current-voltage curve. By analyzing the evolution of instantaneous energy eigenstates, the occupation number of the instantaneous eigenstates, and the lattice of the polymer, we show that the formation of excitons and the delay of their annihilation are responsible for the hysteretic current-voltage characteristics, where electron-phonon interactions play the key factor. Furthermore, the hysteresis width and amplitude can also be modulated by the strength of the electron-phonon coupling, level-width broadening function, and temperature. We hope these results about past condition-dependent switching performance at a sweep voltage can provide further insight into some of the basic issues of interest in hysteresis processes in conducting polymers.

The effect of the intramolecular disorder on hot exciton dynamics in polymer solar cells.

In polymer solar cells (PSCs), the contribution of hot excitons to charge generation is strongly limited by their relatively low yield and ultrafast internal conversion (IC) process. In recent years, different strategies have been proposed to modulate the hot exciton dynamics, but a direct correlation between the microscopic properties of the polymer and hot exciton dynamics is still not completely clear. Here, we theoretically investigate the effect of intramolecular disorder, including the diagonal disorder (DD) and off-diagonal disorder (ODD), on the hot exciton dynamics based on the tight-binding model calculations. We find that the effect of ODD on the hot exciton yield is more significant than that of DD. In addition, we find that the IC relaxation time of hot excitons depends nonmonotonically on the intensity of DD and ODD, indicating that the intramolecular disorder can modulate the competitive relationship between the spontaneous dissociation of hot excitons and the IC process. This work provides a guide for promoting charge generation in PSCs dominated by hot exciton dissociation.

Integrative analysis of the steroidal alkaloids distribution and biosynthesis of bulbs Fritillariae Cirrhosae through metabolome and transcriptome analyses.

BACKGROUND: Bulbus Fritillariae Cirrhosae (BFC) is an endangered high-altitude medicine and food homology plant with anti-tumor, anti-asthmatic, and antitussive activities as it contains a variety of active ingredients, especially steroidal alkaloids. Bulbus Fritillariae Thunbergia (BFT) is another species of Fritillaria that grows at lower altitude areas. Production of plant-derived active ingredients through a synthetic biology strategy is one of the current hot topics in biological research, which requires a complete understanding of the related molecular pathways. Our knowledge of the steroidal alkaloid biosynthesis in Fritillaria species is still very limited. RESULTS: To promote our understanding of these pathways, we performed non-target metabolomics and transcriptome analysis of BFC and BFT. Metabolomics analysis identified 1288 metabolites in BFC and BFT in total. Steroidal alkaloids, including the proposed active ingredients of Fritillaria species peimine, peimisine, peiminine, etc., were the most abundant alkaloids detected. Our metabolomics data also showed that the contents of the majority of the steroidal alkaloids in BFC were higher than in BFT. Further, our comparative transcriptome analyses between BFC and BFT identified differentially expressed gene sets among these species, which are potentially involved in the alkaloids biosynthesis of BFC. CONCLUSION: These findings promote our understanding of the mechanism of steroidal alkaloids biosynthesis in Fritillaria species.

A phase II open label, single arm study of hypofractionated stereotactic radiotherapy with chemoradiotherapy using intensity-modulated radiotherapy for newly diagnosed glioblastoma after surgery: the HSCK-010 trial protocol.

BACKGROUND: The most frequently diagnosed primary brain tumor is glioblastoma (GBM). Nearly all patients experience tumor recurrence and up to 90% of which is local recurrence. Thus, increasing the therapeutic ratio of radiotherapy using hypofractionated stereotactic radiotherapy (HSRT) can reduce treatment time and may increase tumor control and improve survival. To evaluate the efficacy and toxicity of the combination of HSRT and intensity-modulated radiotherapy (IMRT) with temozolomide after surgery in GBM patients and provide evidence for further randomized controlled trials. METHODS/DESIGN: HSCK-010 is an open-label, single-arm phase II trial (NCT04547621) which includes newly diagnosed GBM patients who underwent gross total resection. Patients will receive the combination of 30 Gy/5fx HSRT, and 20 Gy/10fx IMRT adjuvant therapy with concurrent temozolomide and adjuvant chemotherapy. The primary endpoint is overall survival (OS). Secondary outcomes include progression-free survival (PFS) rate, objective-response rate (ORR), quality of life (Qol) before and after the treatment, cognitive function before and after the treatment, and rate of treatment-related adverse events (AE). The combination of HSRT and IMRT with temozolomide can benefit the patients after surgery with good survival, acceptable toxicity, and reduced treatment time. TRIAL REGISTRATION: NCT04547621 . Registered on 14 September 2020.

Sub-bandgap photoexcited dynamics at an organic donor/acceptor photovoltaic interface.

Although sub-bandgap light absorption signals in organic donor/acceptor (D/A) photovoltaic systems have been studied extensively, the underlying origins, as well as the impacting factors, are still elusive. By theoretically constructing an organic D/A interface under a femtosecond electric pulse pumping, we obtain an insightful understanding of this issue. First, a careful comparison between the absorption spectra of the D/A interface and the individual donor (acceptor) demonstrates the existence of two weak absorption signals below the donor (acceptor) optical gap. Furthermore, we clarify that the lower-energy signal originates from "cold" charge transfer (CT) absorption, while the higher-energy signal is from "hot" CT absorption. Finally, effects of several key factors, such as the interface structure and the photoexciting condition, on CT absorptions are discussed. These findings should be of vital importance both to understand the sub-bandgap excited states and to recognize their roles in organic photovoltaic devices.

Strongly enhanced luminous efficiency of organic light emitting diodes in molecular heterojunctions.

We report a comprehensive theory based on the extended Su-Schrieffer-Heeger (SSH) model to study the interconversion from the dark triplet exciton state to a bright singlet one in molecular heterojunctions, containing both intrachain and interchain excitons. By studying the spin mixing and the projection of excitons onto the pure singlet and triplet excitons, unlike usual methods, we found that the internal electroluminescent quantum efficiency, which is largely determined by the singlet fraction, can be widely tuned by the spin-orbit coupling strength, the intensity of hyperfine interaction, electron-phonon coupling and the site energy offset of the two chains constituting the molecular heterojunctions. In addition, the interchain excitons possess a higher fraction of singlet states in comparison with the intrachain excitons. Remarkably, it can reach up to 52% by proper choice of the above-mentioned physical parameters. Our results outline a novel approach to further improve the luminous efficiency of organic light emitting diodes.

Functional Teas from the Stems of Penthorum chinense Pursh.: Phenolic Constituents, Antioxidant and Hepatoprotective Activity.

Penthorum chinense Pursh (PCP), a medicinal and edible plant, is traditionally used for liver protection and treatment of liver diseases. In this study, we compared the differences of composition and activity of flowers, stems and leaves of PCP to select a bioactive part. The stems of PCP with stronger antioxidant activity (6.25-100 µg/mL) and lower cytotoxicity (25-200 µg/mL) than the flowers and leaves were a better bioactive part. Then the chemical composition and hepatoprotective effects of an aqueous extract and an 70% ethanolic extract made with stems of PCP were investigated. We found that the 70% ethanolic extract enriched more polyphenols and flavonoids and possessed significantly stronger hepatoprotective activity than the aqueous extract in the dose range of 25-200 µg/mL, which indicated that 70% ethanol is the better solvent of PCP in extraction technology. Moreover, ethyl acetate extract of stems of PCP (PSE) was used to evaluate the hepatoprotective ability of PCP against oxidative damage using an in vitro model of a normal rat's liver cell (BRL-3A). Besides, 12 phenolic compounds were identified from PSE by ultra-performance liquid chromatography followed by electrospray ionization mass spectrometry (UPLC-ESI-MS). Obtained results strongly support the traditional use of PCP and prove stems of PCP to be an important source of bioactive compounds associated with hepatoprotective activity.

Neutrophil-to-Lymphocyte Ratio and 30-Day Mortality in Patients with Acute Intracerebral Hemorrhage.

BACKGROUND: Although a highly significant association has been described between neutrophil-to-lymphocyte ratio (NLR) and mortality in patients with various types of stroke, the association between NLR and mortality in intracerebral hemorrhage (ICH) patients remains unclear. METHODS: In this observational study, we enrolled 224 ICH patients. They were divided into 2 groups based on their 30-day outcomes. Multivariate logistic regression was performed to identify independent risk factors of 30-day mortality. An optimal cutoff value for the continuous NLR was calculated by applying a receiver operating curve analysis to discriminate between the survival and death groups. RESULTS: Among 224 patients, 26 died. No significant difference in NLR at admission was observed between the 2 groups (surviving: 2.39 ± 1.75 versus nonsurviving: 3.09 ± 2.16, P= .065), whereas NLR on the next morning following admission was significantly higher in the patients who died (12.53 ± 9.33) than in those who survived (5.53 ± 4.68) (P <.001). On multivariate logistic analysis, Glasgow Coma Scale score (odds ratio [OR] .805, 95% confidence interval [CI] .661-.979, P = .030), age (≥80 years; OR .203, CI .055-.750, P = .017), ICH volume (≥30 cm(3); OR .112, CI .108-.699, P = .019), and NLR on the next morning (OR 1.091, CI 1.002-1.188, P = .044) were independent risk factors of 30-day mortality. An NLR of 7.35 was identified as the optimal cutoff value. The area under the curve of NLR for 30-day mortality was .762 (P < .001). The mortality was significantly higher in patients with an NLR of 7.35 or higher than in those with an NLR less than 7.35 (31.6% versus 4.8%, P <.001). CONCLUSIONS: Higher NLR exhibited an increased mortality in ICH patients. NLR could be used to predict 30-day outcome in ICH patients.

HSCCC Separation of the Two Iridoid Glycosides and Three Phenolic Compounds from Veronica ciliata and Their in Vitro Antioxidant and Anti-Hepatocarcinoma Activities.

Five main compounds, including two iridoid glycosides (catalposide, verproside) and three phenolic compounds (luteolin, 4-hydroxy benzoic acid, 3,4-dihydroxy benzoic acid), were separated and prepared from the crude extract of Veronica ciliata by high-speed countercurrent chromatography. n-Hexane/n-butanol/water (1.5:5:5, v/v/v) was used for the separation of catalposide and verproside. n-Hexane/n-butanol/water (3:2:5, v/v/v) was used for the separation of luteolin, 4-hydroxy benzoic acid and 3,4-dihydroxy benzoic acid. The head-to-tail elution mode was used with a flow rate of 5.0 mL/min and a rotary speed of 800 rpm. Finally, a total of 1.28 mg luteolin, 6 mg 4-hydroxy benzoic acid, 2 mg 3,4-dihydroxy benzoic acid, 2 mg verproside and 10 mg catalposide with purities of 98%, 99.1%, 99.5%, 99.8% and 99%, respectively, were obtained from 200 mg of crude extract. In addition, their structure was identified using MS, ¹H-NMR and (13)C-NMR. To the best of our knowledge, this is the first report of the separation and purification of iridoid glycosides and phenolic compounds from V. ciliata by high-speed countercurrent chromatography (HSCCC). Among these compounds, luteolin, 4-hydroxy benzoic acid and 3,4-dihydroxy benzoic acid were separated from V. ciliata Fisch. for the first time. The results of the antioxidant activity show that protocatechuic acid and luteolin have strong antioxidant activity compared to 2,6-di-tert-butyl-4-methylphenol (BHT) and vitamin C (Vc). Five compounds also exhibited strong anti-hepatocarcinoma activities.

Revealing the Role of Dynamic and Static Disorder on Charge-Transfer-State Absorption in Polymer Solar Cells.

In polymer solar cells (PSCs), charge-transfer (CT) state absorption plays an important role in evaluating the CT-state energy and energy loss. However, due to the disordered nature of polymers, a comprehensive understanding of CT absorption properties remains elusive. Especially, the dominant role of dynamic and static disorder in determining CT absorption is frequently debated. Herein, we theoretically constructed an organic donor-acceptor model to investigate the impact of these two types of disorders on CT absorption properties. It is demonstrated that the CT absorption properties depend significantly on the type of disorder. Specifically, it is found that dynamic disorder has a more significant impact on the peak and position of CT absorption as well as the broadening properties, compared to static disorder. The study indicates that minimizing dynamic disorder can lead to a reduction in overall disorder, which is beneficial for improving the performance of PSCs.

Prevotella histicola ameliorates DSS-induced colitis by inhibiting IRE1α-JNK pathway of ER stress and NF-κB signaling.

Inflammatory bowel disease (IBD) is a chronic and recurrent gastrointestinal inflammation regulated by intricate mechanisms. Recently, prebiotics is considered as promising nutritional strategy for the prevention and treatment of IBD. Prevotella histicola (P. histicola), an emerging probiotic, possesses apparently anti-inflammatory bioactivity. However, the role and underlying mechanism of P. histicola on IBD remain unclear. Hence, we probe into the effect of P. histicola on dextran sulfate sodium (DSS)-induced colitis and clarified the potential mechanism. Our results revealed that DSS-induced colonic inflammatory response and damaged epithelial barrier in mice were attenuated by oral administration of P. histicola. Moreover, supplementary P. histicola significantly enriched short-chain fatty acid (SCFA)-producing bacteria (Lactobacillus, and Bacillus) and reduced pathogenic bacteria (Erysipelotrichaceae, Clostridium, Bacteroides) in DSS-induced colitis. Notably, In DSS-treated mice, endoplasmic reticulum stress (ERS) was persistently activated in colonic tissue. Conversely, P. histicola gavage suppressed expansion of endoplasmic reticulum, downregulated PERK-ATF4-CHOP and IRE1α-JNK pathway. In vitro, the P. histicola supernatant eliminated LPS-induced higher production of pro-inflammatory cytokines regulated by NF-κB and impairment of epithelial barrier by inhibiting IRE1α-JNK signaling in Caco-2 cell. In summary, our study indicated that P. histicola mitigated DSS-induced chronic colitis via inhibiting IRE1α-JNK pathway and NF-κB signaling. These findings provide the new insights into the promotion of gut homeostasis and the application potential of P. histicola as a prebiotic for IBD in the future.

The role of SUMO specific peptidase 3 in secondary inflammation of ischemic stroke in mice.

Ischemic stroke is the main cause of death and disability, and microglia play a crucial role in the pathophysiology of hypoxic ischemic brain injury. We found that SENP3 is highly expressed in the early stages of ischemic stroke in both in vivo and in vitro mouse models, and may be related to the deSUMOylation of the key kinase MKK7 in the TLR4/p-JNK signaling pathway. Knocking down SENP3 can inhibit the deSUMOylation of MKK7, thereby inhibiting the activation of the TLR4/p-JNK signaling pathway in an in vitro stroke model. Proteomic analysis showed that SENP3 undergoes phosphorylation at the T429 site after ischemic stroke. Computer simulation predictions show a significant enhancement of the interaction between pT429-SENP3 and MKK7, which has been confirmed through experiments on the interaction of biological macromolecules (SPR). The mitochondrial metabolic abnormalities caused by energy abnormalities in the early stages of stroke provide a good explanation for the phosphorylation of SENP3. Therefore, we used the mitochondrial complex inhibitor TTFA to reverse demonstrate that the phosphorylation of SENP3 comes from the large amount of adenosine triphosphate produced by mitochondrial abnormal metabolism caused by early oxygen glucose deficiency. Finally, proteomic analysis indicates that a significant amount of oxidative phosphorylation does occur in the early stages of stroke. In summary, targeted regulation of SENP3 phosphorylation to affect the deSUMOylation of MKK7 may inhibit secondary inflammation in ischemic stroke.

Stereotactic central/core ablative radiation therapy: results of a phase I study of a novel strategy to treat bulky tumor.

Purpose: Bulky tumor remains as a challenge to surgery, chemotherapy and conventional radiation therapy. Hence, in efforts to overcome this challenge, we designed a novel therapeutic paradigm via strategy of Stereotactic Central/Core Ablative Radiation Therapy (SCART).), which is based on the principles of SBRT (stereotactic body radiation therapy and spatially fractionated radiation therapy (SFRT). We intend to safely deliver an ablative dose to the core of the tumor and with a low dose at tumor edge. The purpose of the phase 1 study was to determine dose-limiting toxicities (DLT)s and the Maximum Tolerated Dose (MTD) of SCART. Methods and materials: We defined a SCART-plan volume inside the tumor, which is proportional to the dimension of tumor. VMAT/Cyberknife technique was adopted. In the current clinical trial; Patients with biopsy proven recurrent or metastatic bulky cancers were enrolled. The five dose levels were 15 Gy X1, 15Gy X3, 18GyX3, 21GyX3 and 24GyX3, while keeping the whole tumor GTV's border dose at 5Gy each fraction. There was no restriction on concurrent systemic chemotherapy agents. Results: 21 patients were enrolled and underwent SCART. All 21 patients have eligible data for study follow-up. Radiotherapy was well tolerated with all treatment completed as scheduled. The dose was escalated for two patients to 24GyX3. No grade 3 or higher toxicity was observed in any of the enrolled patients. The average age of patients was 66 years (range: 14-85) and 13 (62%) patients were male. The median SCART dose was 18Gy (range: 15 - 24). Six out of the 18 patients with data for overall survival (OS) died, and the median time to death was 16.3 months (range: 1 - 25.6). The mean percent change for tumor shrinkage between first visit volumes and post-SCART volumes was 49.5% (SD: 40.89, p-value:0.009). Conclusion: SCART was safely escalated to 24 GyX 3 fractions, which is the maximum Tolerated Dose (MTD) for SCART. This regimen will be used in future phase II trials.

Acetaminophen-induced liver injury: Molecular mechanism and treatments from natural products.

Acetaminophen (APAP) is a widely used analgesic and antipyretic over-the-counter medicine worldwide. Hepatotoxicity caused by APAP overdose is one of the leading causes of acute liver failure (ALF) in the US and in some parts of Europe, limiting its clinical application. Excessive APAP metabolism depletes glutathione and increases N-acetyl-p-benzoquinoneimide (NAPQI) levels, leading to oxidative stress, DNA damage, and cell necrosis in the liver, which in turn leads to liver damage. Studies have shown that natural products such as polyphenols, terpenes, anthraquinones, and sulforaphane can activate the hepatocyte antioxidant defense system with Nrf2 as the core player, reduce oxidative stress damage, and protect the liver. As the key enzyme metabolizing APAP into NAPQI, cytochrome P450 enzymes are also considered to be intriguing target for the treatment of APAP-induced liver injury. Here, we systematically review the hepatoprotective activity and molecular mechanisms of the natural products that are found to counteract the hepatotoxicity caused by APAP, providing reference information for future preclinical and clinical trials of such natural products.

Water extract from Herpetospermum pedunculosum attenuates oxidative stress and ferroptosis induced by acetaminophen via regulating Nrf2 and NF-κB pathways.

ETHNOPHARMACOLOGICAL RELEVANCE: The seeds of Herpetospermum pedunculosum seeds is a traditional Tibetan medicine possessing hepatoprotective effect, but their protective effect on APAP-induced liver injury has not yet been explored. AIM OF THE STUDY: This study aimed at exploring the protective effect and mechanism of the water extract from the seeds of Herpetospermum pedunculosum (HPWE) on APAP-induced liver injury in vitro and in vivo. MATERIALS AND METHODS: In vitro and in vivo models of liver injury were established by APAP treatment of BRL-3A cells or mice. The effect and mechanism of action of HPWE were explored by using cell viability assay, ELISA, immunofluorescence assay, RT-qPCR, histological observation and immunohistochemistry staining, western blotting and high-content imaging system. RESULTS: In vitro experiments showed that HPWE treatment significantly promoted the cell viability, decreased ALT/AST level, and inhibited the ROS accumulation induced by APAP. Furthermore, HPWE and Fer-1 alleviated erastin-induced cell ferroptosis, upregulated GPX4 and SLC7A11 expression, and reduced lipid peroxides production. Further study showed that APAP could also downregulate the expression of GPX4 and SLC7A11, causing cell ferroptosis, and HPWE and Fer-1 counteracted this process. Our in vivo experiments showed that pretreatment with HPWE in APAP-treated mice significantly alleviated the serum ALT/AST level, decreased necrotic cells and inflammatory cell infiltration, upregulated the expression of GPX4 and SLC7A11. Further, it was demonstrated that HPWE treatment downregulated Nrf2 and its downstream target genes, i.e. HO-1 and NQO1 expression at the mRNA and protein levels. HPWE treatment also inhibited the activation of NF-κB p65 and downregulated its target genes, i.e. TNF-α and IL-1ß, expression. CONCLUSION: The present study showed that HPWE could relieve oxidative stress and ferroptosis via activating Nrf2 signaling pathway and inhibiting NF-κB mediated pathway.

Protocatechuic aldehyde acts synergistically with dacarbazine to augment DNA double-strand breaks and promote apoptosis in cutaneous melanoma cells.

BACKGROUND: Despite rapid developments in immunotherapy and targeted therapy, dacarbazine (DTIC)-based chemotherapy still has been placed at the first-line for advanced melanoma patients who are after failure of immunotherapy or targeted therapy. However, the limited response rate and survival benefit challenge the DTIC-based chemotherapy for advanced melanoma patients. METHODS: Two melanoma cell lines, A375 and SK-MEL-28 were cultured with PA and DTIC over a range of concentrations for 72 h and the cell viabilities were detected by CCK8 assay. The Bliss model and ZIP model were used for calculating the synergistic effect of PA and DTIC. DNA double-strand breaks in the two cell lines were examined by the Comet assay, and cell apoptosis was analyzed by flow cytometry. The short hairpin RNA (shRNA)-mediated knockdown, Real-time polymerase chain reaction (RT-PCR) and Western blot were performed for molecular analysis. RESULTS: In the present study, we report that Protocatechuic aldehyde (PA) synergistically enhances the cytotoxicity of DTIC to two melanoma cell lines, A375 and SK-MEL-28. The combination of PA and DTIC augments DNA double-strand breaks and increases cell apoptosis. Further mechanism study reveals that PA destabilizes MGMT protein (O-6-Methylguanine-DNA Methyltransferase) through the ubiquitin-proteasome process and directly repairs DTIC-induced genetic lesions. Knockdown of MGMT compromises the synergistic effect between PA and DTIC. CONCLUSION: Our study demonstrates that the bioactive compound, Protocatechuic aldehyde, synergistically promotes the cytotoxicity of DTIC to melanoma cells through destabilization of MGMT protein. It could be a potential candidate for melanoma chemotherapy.

Total alkaloids of Fritillaria unibracteata var. wabuensis bulbus ameliorate chronic asthma via the TRPV1/Ca2+/NFAT pathway.

BACKGROUND: Asthma is a chronic inflammatory disease that is challenging to treat. Fritillaria unibracteata var. wabuensis (FUW) is the plant origin for the famous Chinese antitussive medicine Fritillaria Cirrhosae Bulbus. The total alkaloids of Fritillaria unibracteata var. wabuensis bulbus (TAs-FUW) have anti-inflammatory properties and may be used to treat asthma. PURPOSE: To explore whether TAs-FUW have bioactivity against airway inflammation and a therapeutic effect on chronic asthma. METHODS: The alkaloids were extracted via ultrasonication in a cryogenic chloroform-methanol solution after ammonium-hydroxide percolation of the bulbus. UPLC-Q-TOF/MS was used to characterize the composition of TAs-FUW. An ovalbumin (OVA)-induced asthmatic mouse model was established. We used whole-body plethysmography, ELISA, western blotting, RT-qPCR, and histological analyses to assess the pulmonary pathological changes in these mice after TAs-FUW treatment. Additionally, TNF-α/IL-4-induced inflammation in BEAS-2B cells was used as an in vitro model, whereby the effects of various doses of TAs-FUW on the TRPV1/Ca2+-dependent NFAT-induced expression of TSLP were assessed. Stimulation and inhibition of TRPV1 receptors by capsaicin (CAP) and capsazepine (CPZ), respectively, were used to validate the effect of TAs-FUW. RESULTS: The UPLC-Q-TOF/MS analysis revealed that TAs-FUW mainly contain six compounds (peiminine, peimine, edpetiline, khasianine, peimisine, and sipeimine). TAs-FUW improved airway inflammation and obstruction, mucus secretion, collagen deposition, and leukocyte and macrophage infiltration, and downregulated TSLP by inhibiting the TRPV1/NFAT pathway in asthmatic mice. In vitro, the application of CPZ demonstrated that the TRPV1 channel is involved in TNF-α/IL-4-mediated regulation of TSLP. TAs-FUW suppressed TNF-α/IL-4-induced TSLP generation expression by regulating the TRPV1/Ca2+/NFAT pathway. Furthermore, TAs-FUW reduced CAP-induced TSLP release by inhibiting TRPV1 activation. Notably, sipeimine and edpetiline each were sufficient to block the TRPV1-mediated Ca2+ influx. CONCLUSION: Our study is the first to demonstrate that TNF-α/IL-4 can activate the TRPV1 channel. TAs-FUW can alleviate asthmatic inflammation by suppressing the TRPV1 pathway and thereby preventing the increase in cellular Ca2+ influx and the subsequent NFAT activation. The alkaloids in FUW may be used for complementary or alternative therapies in asthma.

Cytoplasmic Endonuclease G promotes nonalcoholic fatty liver disease via mTORC2-AKT-ACLY and endoplasmic reticulum stress.

Endonuclease G (ENDOG), a nuclear-encoded mitochondrial intermembrane space protein, is well known to be translocated into the nucleus during apoptosis. Recent studies have shown that ENDOG might enter the mitochondrial matrix to regulate mitochondrial genome cleavage and replication. However, little is known about the role of ENDOG in the cytosol. Our previous work showed that cytoplasmic ENDOG competitively binds with 14-3-3γ, which released TSC2 to repress mTORC1 signaling and induce autophagy. Here, we demonstrate that cytoplasmic ENDOG could also release Rictor from 14-3-3γ to activate the mTORC2-AKT-ACLY axis, resulting in acetyl-CoA production. Importantly, we observe that ENDOG could translocate to the ER, bind with Bip, and release IRE1a/PERK to activate the endoplasmic reticulum stress response, promoting lipid synthesis. Taken together, we demonstrate that loss of ENDOG suppresses acetyl-CoA production and lipid synthesis, along with reducing endoplasmic reticulum stress, which eventually alleviates high-fat diet-induced nonalcoholic fatty liver disease in female mice.

Ingredients with anti-inflammatory effect from medicine food homology plants.

Inflammation occurs when the immune system responses to external harmful stimuli and infection. Chronic inflammation induces various diseases. A variety of foods are prescribed in the traditional medicines of many countries all over the world, which gave birth to the concept of medicine food homology. Over the past few decades, a number of secondary metabolites from medicine food homology plants have been demonstrated to have anti-inflammatory effects. In the present review, the effects and mechanisms of the medicine food homology plants-derived active components on relieving inflammation and inflammation-mediated diseases were summarized and discussed. The information provided in this review is valuable to future studies on anti-inflammatory ingredients derived from medicine food homology plants as drugs or food supplements.

GSK3ß mediates the spatiotemporal dynamics of NLRP3 inflammasome activation.

Subcellular machinery of NLRP3 is essential for inflammasome assembly and activation. However, the stepwise process and mechanistic basis of NLRP3 engagement with organelles remain unclear. Herein, we demonstrated glycogen synthase kinase 3ß (GSK3ß) as a molecular determinant for the spatiotemporal dynamics of NLRP3 inflammasome activation. Using live cell multispectral time-lapse tracking acquisition, we observed that upon stimuli NLRP3 was transiently associated with mitochondria and subsequently recruited to the Golgi network (TGN) where it was retained for inflammasome assembly. This occurred in relation to the temporal contact of mitochondria to Golgi apparatus. NLRP3 stimuli initiate GSK3ß activation with subsequent binding to NLRP3, facilitating NLRP3 recruitment to mitochondria and transition to TGN. GSK3ß activation also phosphorylates phosphatidylinositol 4-kinase 2 Α (PI4k2A) in TGN to promote sustained NLRP3 oligomerization. Our study has identified the interplay between GSK3ß signaling and the organelles dynamics of NLRP3 required for inflammasome activation and opens new avenues for therapeutic intervention.