CMAUP database update 2024: extended functional and association information of useful plants for biomedical research.

Knowledge of the collective activities of individual plants together with the derived clinical effects and targeted disease associations is useful for plant-based biomedical research. To provide the information in complement to the established databases, we introduced a major update of CMAUP database, previously featured in NAR. This update includes (i) human transcriptomic changes overlapping with 1152 targets of 5765 individual plants, covering 74 diseases from 20 027 patient samples; (ii) clinical information for 185 individual plants in 691 clinical trials; (iii) drug development information for 4694 drug-producing plants with metabolites developed into approved or clinical trial drugs; (iv) plant and human disease associations (428 737 associations by target, 220 935 reversion of transcriptomic changes, 764 and 154121 associations by clinical trials of individual plants and plant ingredients); (v) the location of individual plants in the phylogenetic tree for navigating taxonomic neighbors, (vi) DNA barcodes of 3949 plants, (vii) predicted human oral bioavailability of plant ingredients by the established SwissADME and HobPre algorithm, (viii) 21-107% increase of CMAUP data over the previous version to cover 60 222 chemical ingredients, 7865 plants, 758 targets, 1399 diseases, 238 KEGG human pathways, 3013 gene ontologies and 1203 disease ontologies. CMAUP update version is freely accessible at https://bidd.group/CMAUP/index.html.

NPASS database update 2023: quantitative natural product activity and species source database for biomedical research.

Quantitative activity and species source data of natural products (NPs) are important for drug discovery, medicinal plant research, and microbial investigations. Activity values of NPs against specific targets are useful for discovering targeted therapeutic agents and investigating the mechanism of medicinal plants. Composition/concentration values of NPs in individual species facilitate the assessments and investigations of the therapeutic quality of herbs and phenotypes of microbes. Here, we describe an update of the NPASS natural product activity and species source database previously featured in NAR. This update includes: (i) new data of ∼95 000 records of the composition/concentration values of ∼1 490 NPs/NP clusters in ∼390 species, (ii) extended data of activity values of ∼43 200 NPs against ∼7 700 targets (∼40% and ∼32% increase, respectively), (iii) extended data of ∼31 600 species sources of ∼94 400 NPs (∼26% and ∼32% increase, respectively), (iv) new species types of ∼440 co-cultured microbes and ∼420 engineered microbes, (v) new data of ∼66 600 NPs without experimental activity values but with estimated activity profiles from the established chemical similarity tool Chemical Checker, (vi) new data of the computed drug-likeness properties and the absorption, distribution, metabolism, excretion and toxicity (ADMET) properties for all NPs. NPASS update version is freely accessible at http://bidd.group/NPASS.

Simultaneously blocking ANGPTL3 and CD47 prevents the progression of atherosclerosis through regulating lipid metabolism, macrophagic efferocytosis and lipid peroxidation.

Atherosclerosis (AS) ultimately cause major adverse cardiovascular events (MACEs). While traditional strategies by lipid-reducing have reduced MACEs, many patients continue to face significant risks. It might attribute to the upregulation of CD47 expression in AS lesions, that mediated anti-efferocytosis of macrophages. Therefore, we propose simultaneously blocking ANGPTL3, a vital regulator of lipid metabolism, and CD47 might be a potential approach for AS therapy. Firstly, we investigate the role of a novel anti-ANGPTL3 nanobody-Fc (FD03) in AS. We found that FD03 treatment significantly decreased circulating lipids, plaque size, and lipid deposition in apoE-/- mice compared to control Ab, but there was a twofold increase in plaque formation in comparison to baseline. However, immunofluorescence indicated the upregulation of CD47 expression in the plaques even after FD03 treatment compared to normal vascular tissue. Next, a bifunctional protein containing signal regulatory protein alpha (SIRPα) and FD03 (SIRPαD1-FD03) was constructed to block CD47 and ANGPTL3 concurrently, which had high purity, robust stability, and high affinity to CD47 and ANGPTL3 with biological activity in vitro. Furthermore, SIRPαD1-FD03 fusion protein exhibited the enhanced therapeutic effect on AS compared with SIRPαD1-Fc or FD03, regressing plaque contents and the necrotic core equal to baseline. Mechanistically, SIRPαD1-FD03 reduced serum lipids, augmented the efferocytosis rate and macrophage M2 polarization, and decreased the reactive oxygen species (ROS) and lipid peroxidation level in atherosclerotic plaques. Collectively, our project suggests an effective approach for AS by simultaneously blocking ANGPTL3 and CD47 to regulate lipid metabolism, macrophage activity and lipid peroxidation.

Simultaneously blocking ANGPTL3 and IL-1ß for the treatment of atherosclerosis through lipid-lowering and anti-inflammation.

OBJECTIVE: Blood lipid levels play a critical role in the progression of atherosclerosis. However, even with adequate lipid reduction, significant residual cardiovascular risk remains. Therefore, it is necessary to seek novel therapeutic strategies for atherosclerosis that can not only lower lipid levels but also inhibit inflammation simultaneously. METHODS: The fusion protein FD03-IL-1Ra was designed by linking the Angiopoietin-like 3 (ANGPTL3) nanobody and human interleukin-1 receptor antagonist (IL-1Ra) sequences to a mutated human immunoglobulin gamma 1 (IgG1) Fc. This construct was transfected into HEK293 cells for expression. The purity and thermal stability of the fusion protein were assessed using SDS-PAGE, SEC-HPLC, and differential scanning calorimetry. Binding affinities of the fusion protein to ANGPTL3 and IL-1 receptor were measured using Biacore T200. The biological activity of the fusion protein was validated through in vitro experiments. The therapeutic efficacy of the fusion protein was evaluated in an ApoE-/- mouse model of atherosclerosis, including serum lipid level determination, histological analysis of aorta and aortic sinus sections, and detection of inflammatory and oxidative stress markers. ImageJ software was utilized for quantitative image analysis. Statistical analysis was performed using one-way ANOVA followed by Bonferroni post hoc test. RESULTS: The FD03-IL-1Ra fusion protein was successfully expressed, with no polymer formation detected, and it demonstrated good thermal and conformational stability. High affinity for both murine and human ANGPTL3 was exhibited by FD03-IL-1Ra, and it was able to antagonize hANGPTL3's inhibition of LPL activity. FD03-IL-1Ra also showed high affinity for both murine and human IL-1R, inhibiting IL-6 expression in A549 cells induced by IL-1ß stimulation, as well as suppressing IL-1ß-induced activity inhibition in A375.S2 cells. Our study revealed that the fusion protein effectively lowered serum lipid levels and alleviated inflammatory responses in mice. Furthermore, the fusion protein enhanced plaque stability by increasing collagen content within atherosclerotic plaques. CONCLUSIONS: These findings highlighted the potential of bifunctional interleukin-1 receptor antagonist and ANGPTL3 antibody fusion proteins for ameliorating the progression of atherosclerosis, presenting a promising novel therapeutic approach targeting both inflammation and lipid levels.

Oxidative Catalytic Depolymerization of Lignin into Value-Added Monophenols by Carbon Nanotube-Supported Cu-Based Catalysts.

Lignin valorisation into chemicals and fuels is of great importance in addressing energy challenges and advancing biorefining in a sustainable manner. In this study, on the basis of the high microwave absorption performance of carbon nanotubes (CNTs), a series of copper-oxide-loaded CNT catalysts (CuO/CNT) were developed to facilitate the oxidative depolymerization of lignin under microwave heating. This catalyst can promote the activation of hydrogen peroxide and air, effectively generating a range of reactive oxygen species (ROS). Through the application of electron paramagnetic resonance techniques, these ROS generated under different oxidation conditions were detected to elucidate the oxidation mechanism. The results demonstrate that the •OH and O2•- play a crucial role in the formation of aldehyde and ketone products through the cleavage of lignin Cß-O and Cα-Cß bonds. We further evaluated the catalytic performance of the CuO/CNT catalysts with three typical lignin feedstocks to determine their applicability for lignin biorefinery. The bio-enzymatic lignin produced a 13.9% monophenol yield at 200 °C for 20 min under microwave heating, which was higher than the 7% yield via hydrothermal heating conversion. The selectivity of G-/H-/S-type products was slightly affected, while lignin substrate had a noticeable effect on the selective production. Overall, this study explored the structural characteristics of CuO/CNT catalysts and their implications for lignin conversion and offered an efficient oxidation approach that holds promise for sustainable biorefining practices.

A bifunctional fusion protein protected against diabetic nephropathy by suppressing NLRP3 activation.

Diabetic nephropathy (DN), the principal pathogeny of end-stage renal disease (ESRD), is related to metabolic disorders, chronic inflammation, and oxidative stress. It was reported that high expression of interleukin-17A (IL-17A) was intimately related to the progression of DN, and targeting IL-17A exhibited regulating effects on inflammation and autoimmunity but had only limited impact on the oxidative stress damage in DN. Recent studies showed that interleukin-22 (IL-22) could inhibit mitochondrial damage and inflammatory response. Thus, the cytokine IL-22 was first fused to anti-IL-17A antibody for endowing the antibody with the anti-hyperglycemia and anti-inflammation activity. Our study demonstrated that the fusion molecule, anti-IL17A/IL22 fusion protein, could not only lead to the increase of M1 macrophages and the decrease of M2 macrophages, further improving the immune microenvironment, but also prevent the loss of mitochondrial membrane potential by reducing the production of ROS in murine DN model. In addition, the fusion protein could block TRAF6/NF-κB and AKT/ROS/TXNIP signaling pathways, further synergistically restraining the production of NLRP3, thus suppressing the inflammatory response and playing beneficial effect on slowing down the progression of DN. In conclusion, our findings demonstrated that the bifunctional IL-17A antibody and IL-22 fusion protein were of great benefit to DN, which highlighted a potential therapeutic strategy. KEY POINTS: • Anti-IL17A/IL22 fusion protein could improve the immune microenvironment and reduce the production of ROS. • Anti-IL17A/IL22 fusion protein could block TRAF6/NF-κB and AKT/ROS/TXNIP signaling pathways and then restrain the activation of NLRP3.

MASI: microbiota-active substance interactions database.

Xenobiotic and host active substances interact with gut microbiota to influence human health and therapeutics. Dietary, pharmaceutical, herbal and environmental substances are modified by microbiota with altered bioavailabilities, bioactivities and toxic effects. Xenobiotics also affect microbiota with health implications. Knowledge of these microbiota and active substance interactions is important for understanding microbiota-regulated functions and therapeutics. Established microbiota databases provide useful information about the microbiota-disease associations, diet and drug interventions, and microbiota modulation of drugs. However, there is insufficient information on the active substances modified by microbiota and the abundance of gut bacteria in humans. Only ∼7% drugs are covered by the established databases. To complement these databases, we developed MASI, Microbiota-Active Substance Interactions database, for providing the information about the microbiota alteration of various substances, substance alteration of microbiota, and the abundance of gut bacteria in humans. These include 1,051 pharmaceutical, 103 dietary, 119 herbal, 46 probiotic, 142 environmental substances interacting with 806 microbiota species linked to 56 diseases and 784 microbiota-disease associations. MASI covers 11 215 bacteria-pharmaceutical, 914 bacteria-herbal, 309 bacteria-dietary, 753 bacteria-environmental substance interactions and the abundance profiles of 259 bacteria species in 3465 patients and 5334 healthy individuals. MASI is freely accessible at http://www.aiddlab.com/MASI.

A novel nanobody-heavy chain antibody against Angiopoietin-like protein 3 reduces plasma lipids and relieves nonalcoholic fatty liver disease.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is a metabolic disease mainly on account of hypercholesterolemia and may progress to cirrhosis and hepatocellular carcinoma. The discovery of effective therapy for NAFLD is an essential unmet need. Angiopoietin-like protein 3 (ANGPTL3), a critical lipid metabolism regulator, resulted in increased blood lipids and was elevated in NAFLD. Here, we developed a nanobody-heavy chain antibody (VHH-Fc) to inhibit ANGPTL3 for NAFLD treatment. RESULTS: In this study, we retrieved an anti-ANGPTL3 VHH and Fc fusion protein, C44-Fc, which exhibited high affinities to ANGPTL3 proteins and rescued ANGPLT3-mediated inhibition of lipoprotein lipase (LPL) activity. The C44-Fc bound a distinctive epitope within ANGPTL3 when compared with the approved evinacumab, and showed higher expression yield. Meanwhile, C44-Fc had significant reduction of the triglyceride (~ 44.2%), total cholesterol (~ 36.6%) and LDL-cholesterol (~ 54.4%) in hypercholesterolemic mice and ameliorated hepatic lipid accumulation and liver injury in NAFLD mice model. CONCLUSIONS: We discovered a VHH-Fc fusion protein with high affinity to ANGPTL3, strong stability and also alleviated the progression of NAFLD, which might offer a promising therapy for NAFLD.

Low-Complexity Hyperbolic Embedding Schemes for Temporal Complex Networks.

Hyperbolic embedding can effectively preserve the property of complex networks. Though some state-of-the-art hyperbolic node embedding approaches are proposed, most of them are still not well suited for the dynamic evolution process of temporal complex networks. The complexities of the adaptability and embedding update to the scale of complex networks with moderate variation are still challenging problems. To tackle the challenges, we propose hyperbolic embedding schemes for the temporal complex network within two dynamic evolution processes. First, we propose a low-complexity hyperbolic embedding scheme by using matrix perturbation, which is well-suitable for medium-scale complex networks with evolving temporal characteristics. Next, we construct the geometric initialization by merging nodes within the hyperbolic circular domain. To realize fast initialization for a large-scale network, an R tree is used to search the nodes to narrow down the search range. Our evaluations are implemented for both synthetic networks and realistic networks within different downstream applications. The results show that our hyperbolic embedding schemes have low complexity and are adaptable to networks with different scales for different downstream tasks.

Urgently reveal longly hidden toxicant in a familiar fabrication process of biomass-derived environment carbon material.

Biomass-derived N-doped carbon (BNC) is an important environmental material and widely used in the fields of water purification and soil remediation. However, the toxicant in the commonly used synthesis process of BNC materials have been largely ignored. Herein, we firstly report the presence of a highly toxic by-product (KCN) in the activation process of BNC materials consequential of the carbothermal reduction reaction. Because this carbothermal reduction reaction also regulates the N-doping and pore development of BNC materials, the KCN content directly relates with the properties of BNC material properties. Accordingly, a high KCN content (∽ 611 mg) can occur in the production process of per g BNC material with high specific surface area (∽ 3600 m2/g). Because the application performance of BNC material is determined by the surface area and available N doping, therefore, production of a BNC material with high performance entails high risk. Undoubtedly, this study proves a completely new risk recognition on a familiar synthesis process of biomass-based material. And, strict protective device should be taken in fabrication process of biomass-derived carbon material.

Targeting PARP and autophagy evoked synergistic lethality in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC), one of the most lethal malignancies worldwide, has limited efficient therapeutic options. Here, we first demonstrated that simultaneously targeting poly (ADP-ribose) polymerase (PARP) and autophagy could evoke striking synergistic lethality in HCC cells. Specifically, we found that the PARP inhibitor Niraparib induced cytotoxicity accompanied by significant autophagy formation and autophagic flux in HCC cells. Further experiments showed that Niraparib induced suppression of the Akt/mTOR pathway and activation of the Erk1/2 cascade, two typical signaling pathways related to autophagy. In addition, the accumulation of reactive oxygen species was triggered, which was involved in Niraparib-induced autophagy. Blocking autophagy by chloroquine (CQ) in combination with Niraparib further enhanced cytotoxicity, induced apoptosis and inhibited colony formation in HCC cells. Synergistic inhibition was also observed in Huh7 xenografts in vivo. Mechanistically, we showed that autophagy inhibition abrogated Niraparib-induced cell-cycle arrest and checkpoint activation. Cotreatment with CQ and Niraparib promoted the formation of γ-H2AX foci while inhibiting the recruitment of the homologous recombination repair protein RAD51 to double-strand break sites. Thus, the present study developed a novel promising strategy for the management of HCC in the clinic and highlighted a potential approach to expand the application of PARP inhibitors.

Interleukin-22 ameliorated acetaminophen-induced kidney injury by inhibiting mitochondrial dysfunction and inflammatory responses.

Acetaminophen (APAP) overdose can lead to acute, severe kidney injury, which has recently attracted considerable attention among researchers and clinicians. Unfortunately, there are no well-established treatments for APAP-induced renal injury, and the molecular mechanism of APAP-induced kidney injury is still unclear. Herein, we explored the protective effects of interleukin (IL)-22 on APAP-induced renal injury and the underlying molecular basis. We found that IL-22 could significantly alleviate the accumulation of reactive oxygen species (ROS) and ameliorate mitochondrial dysfunction, reducing APAP-induced renal tubular epithelial cell (TEC) death in vitro and in vivo. Furthermore, IL-22 could downregulate the APAP-induced NLRP3 inflammasome activation and mature IL-1ß release in kidney injury. Additionally, the APAP-mediated upregulation of the serum levels of IL-18, TNF-α, IL-6, and IL-1ß was obviously decreased, suggesting IL-22 has inhibitory effects on inflammatory responses. Conclusively, our study demonstrated that IL-22 exerted ameliorative effects on APAP-induced kidney injury by alleviating mitochondrial dysfunction and NLRP3 inflammasome activation, suggesting that IL-22 represents a potential therapeutic approach to treat APAP-induced kidney injury. KEY POINTS: • IL-22 could ameliorate APAP that triggered oxidative stress and mitochondrial dysfunction. • IL-22 could reduce APAP that caused inflammatory responses. Graphical abstract.

Comparison of safety between self-expanding metal stents as a bridge to surgery and emergency surgery based on pathology: a meta-analysis.

BACKGROUND: To explore the long-term oncological safety of using self-expanding metal stents (SEMS) as a bridge to surgery for acute obstructive colorectal cancer by comparing the pathological results of emergency surgery (ES) with elective surgery after the placement of SEMS. METHODS: Studies comparing SEMS as a bridge to surgery with emergency surgery for acute obstructive colorectal cancer were retrieved through the databases of Pubmed, Embase, and Cochrane libraries, and a meta-analysis was conducted based on the pathological results of the two treatments. Risk ratios (OR) or mean differences (MD) with 95% confidence intervals (CI) were calculated for the outcomes under random effects model. RESULTS: A total of 27 studies were included, including 3 randomized controlled studies, 2 prospective studies, and 22 retrospective studies, with a total of 3737 patients. The presence of perineural invasion (RR = 0.58, 95% CI 0.48, 0.71, P < 0.00001), lymphovascular invasion (RR = 0.68, 95% CI 0.47, 0.99, P = 0.004) and vascular invasion (RR = 0.66, 95% CI 0.45, 0.99, P = 0.04) in SEMS group were significantly higher than those in ES group, and there was no significant difference in lymphatic invasion (RR = 0.92, 95% CI 0.77, 1.09, P = 0.33). The number of lymph nodes harvested in SEMS group was significantly higher than that in ES group (MD = - 3.18, 95% CI - 4.47, - 1.90, P < 0.00001). While no significant difference was found in the number of positive lymph nodes (MD = - 0.11, 95% CI - 0.63, 0.42, P = 0.69) and N stage [N0 (RR = 1.03, 95% CI 0.92, 1.15, P = 0.60), N1 (RR = 0.99, 95% CI 0.87, 1.14, P = 0.91), N2 (RR = 0.94, 95% CI 0.77, 1.15, P = 0.53)]. CONCLUSIONS: SEMS implantation in patients with acute malignant obstructive colorectal cancer may lead to an increase in adverse tumor pathological characteristics, and these characteristics are mostly related to the poor prognosis of colorectal cancer. Although the adverse effect of SEMS on long-term survival has not been demonstrated, their adverse effects cannot be ignored. The use of SEMS as the preferred treatment for patients with resectable obstructive colorectal cancer remains to be carefully weighed, especially when patients are young or the surgical risk is not very high.

Recombinant human arginase I elicited immunosuppression in activated macrophages through inhibiting autophagy.

Arginase I has been documented to impair T cell function and attenuate cellular immunity, however, there is little evidence to reveal the effect of arginase I on macrophage function. Recently, recombinant human arginase I (rhArg) has been developed for cancer therapy and is in clinical trial for hepatocellular carcinoma, whereas the potential immunosuppression induced by rhArg limited its therapeutic efficacy. To improve the clinical outcome of rhArg, addressing the immune suppression appears to be particularly important. In this study, we found that rhArg attenuated macrophage functions, including inhibiting macrophage cell proliferation, nitric oxide (NO) and reactive oxygen species (ROS) production, cytokine secretion, MHC-II surface expression, and phagocytosis, thereby inducing immunosuppression in lipopolysaccharides (LPS)/interferon-γ (IFN-γ)-activated macrophages. Notably, we observed that rhArg downregulated autophagy in activated macrophages. Moreover, application of trehalose (an autophagy inducer) significantly restored the impaired immune function in activated macrophages, suggesting the essential role of autophagy in rhArg-induced immunosuppression. To further illustrate the effect of autophagy in immunosuppression, we then observed the effect of 3-MA (an autophagy inhibitor) on the immune function of macrophages. As expected, inhibiting autophagy by 3-MA attenuated immune functions in activated macrophages. Collectively, this study elucidated that rhArg induced immunosuppression in activated macrophages via inhibiting autophagy, providing potential strategy to ameliorate the immune suppression which is of great significance to cancer therapy and facilitating the development of rhArg as a potential therapy for malignant carcinomas.

Development of Tactile Imaging for Underwater Structural Damage Detection.

Underwater structural damage inspection has mainly relied on diver-based visual inspection, and emerging technologies include the use of remotely operated vehicles (ROVs) for improved efficiency. With the goal of performing an autonomous and robotic underwater inspection, a novel Tactile Imaging System for Underwater Inspection (TISUE) is designed, prototyped, and tested in this paper. The system has two major components, including the imaging subsystem and the manipulation subsystem. The novelty lies in the imaging subsystem, which consists of an elastomer-enabled contact-based optical sensor with specifically designed artificial lighting. The completed TISUE system, including optical imaging, data storage, display analytics, and a mechanical support subsystem, is further tested in a laboratory experiment. The experiment demonstrates that high-resolution and high-quality images of structural surface damage can be obtained using tactile 'touch-and-sense' imaging, even in a turbid water environment. A deep learning-based damage detection framework is developed and trained. The detection results demonstrate the similar detectability of five damage types in the obtained tactile images to images obtained from regular (land-based) structural inspection.

Adsorption antagonism and synergy of arsenate(V) and cadmium(II) onto Fe-modified rice straw biochars.

Arsenic-containing water poses a serious threat to human health. In this study, two types of Fe-modified rice straw biochars [(Fe-impregnated biochar (FeIm char) and pre-modified rice straw biochar (PMRS char)] were prepared, in which three ratios [1, 5, and 10% (w/w)] of Fe modification were evaluated, resulting in six different Fe-modified biochars. Then, a series of adsorption experiments, using single- and binary-metal solutions of As(V) and Cd(II), were conducted to investigate the performances of modified biochars on metal adsorption compared to pristine rice straw biochar (RS char). Results indicated Fe modification improved the As(V) adsorption capacity of biochar. PMRS char showed higher adsorption of As(V) than FeIm char. At the 5% Fe modification ratio (FMR), the As(V) removal by PMRS char (at 10 g/L dosage) from 100 mg/L As(V) solution was approximately 69.6%, which was higher than 46.1% of FeIm char or 22.6% of RS char. In contrast, the adsorption of Cd(II) was decreased after modified at 5 or 10% FMR. Interestingly, for treating solution containing As(V) and Cd(II) together, the adsorption of As(V) onto FeIm char or PMRS char prepared at 5 or 10% FMR remained higher than that onto RS char, while the simultaneous removal of Cd(II) ion by either modified biochar was kept over 50%. Thus, the finding of this study suggested Fe-modified biochars, especially prepared via the pyrolysis of FeCl3 pre-soaking rice straw, could be a promising adsorbent for the remediation of complex As(V)-containing wastewater.

Correction to: Adsorption antagonism and synergy of arsenate(V) and cadmium(II) onto Fe-modified rice straw biochars.

Unfortunately, in the original publication of the article, Prof. Yong Sik Ok's affiliation was incorrectly published. The author's affiliation is as follows.

Disrupting CD47-SIRPα axis alone or combined with autophagy depletion for the therapy of glioblastoma.

CD47-targeting immune checkpoint inhibitors have been investigated for immunotherapy of several cancers, glioblastoma, one of the most common tumors in brain, was still a challenge for CD47-targeting therapy. Herein, we reported novel strategies for glioblastoma therapy via blocking CD47-signal regulatory protein-α (SIRPα) by SIRPα-Fc alone or in combination with autophagy inhibition. Our results showed that SIRPα-Fc increased macrophages-triggered cytotoxicity and phagocytosis of glioblastoma cells then elicited potent anti-tumor efficacy. During the treatment, SIRPα-Fc induced autophagy and autophagic flux in glioblastoma cells and Akt/mammalian target of rapamycin (mTOR) inactivation was participated in the autophagy activation. Inhibition of autophagy by pharmacological agents or small-interfering RNA increased SIRPα-Fc-triggered macrophage phagocytosis and cytotoxicity. Importantly, when compared with SIRPα-Fc treatment, blocking both CD47/SIRPα and autophagy significantly increased infiltration of macrophages and apoptosis of tumor cells, triggering potentiated anti-glioblastoma effect and extended median survival. Further experiments showed that adaptive immune response, including CD8+ T-cell subsets, was also played a crucial role in SIRPα-Fc-induced glioblastoma rejection. Our results indicated that SIRPα-Fc alone or combined with autophagy inhibitors elicited potent anti-glioblastoma effect, highlighting potential therapeutic strategies of glioblastoma via blocking CD47/SIRPα alone or in combination with autophagy inhibitor.

Dihydroquercetin ameliorated acetaminophen-induced hepatic cytotoxicity via activating JAK2/STAT3 pathway and autophagy.

Acetaminophen (APAP) overdose is currently the leading cause of acute liver disease, but therapeutic treatment strategies are commonly limited. Although dihydroquercetin (DHQ) is an attractive botanical antioxidant, its protective potential for liver disease remains elusive. The present study investigated the protective effects of DHQ against APAP-induced hepatic cytotoxicity. Primary mouse hepatocytes were treated with different concentrations of DHQ followed by APAP administration. Our data showed that DHQ relieved APAP-induced growth inhibition and lactate dehydrogenase (LDH) release in a dose-dependent manner, as well as inhibited APAP-induced necrosis and extracellular signal regulated kinase-c-Jun-N-terminal kinase (ERK-JNK) stress. In addition, reactive oxygen species (ROS) accumulation and mitochondria dysfunction were also reversed by DHQ treatment. Further study revealed that DHQ induced phosphorylation of Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) cascade and thus modulated expression of anti-apoptotic Bcl-2 family proteins. Moreover, DHQ induced autophagy which mediated its protective effects in hepatocytes. The protection was abrogated through pharmacological blockage of autophagy by chloroquine (CQ). These studies demonstrated, for the first time, that DHQ possessed hepatocellular protective effects in the context of APAP-induced cytotoxicity and subsequently revealed that the mechanisms comprised activation of JAK2/STAT3 signaling pathway and autophagy. These altogether highlighted the significant therapeutic potential of this agent during acute liver failure and other types of liver diseases.

Inhibition of autophagy potentiated the anti-tumor effects of VEGF and CD47 bispecific therapy in glioblastoma.

Glioblastoma, characterized by extensive microvascular proliferation and invasive tumor growth, is one of the most common and lethal malignancies in adults. Benefits of the conventional anti-angiogenic therapy were only observed in a subset of patients and limited by diverse relapse mechanism. Fortunately, recent advances in cancer immunotherapy have offered new hope for patients with glioblastoma. Herein, we reported a novel dual-targeting therapy for glioblastoma through simultaneous blockade of VEGF and CD47 signaling. Our results showed that VEGFR1D2-SIRPαD1, a VEGF and CD47 bispecific fusion protein, exerted potent anti-tumor effects via suppressing VEGF-induced angiogenesis and activating macrophage-mediated phagocytosis. Meanwhile, autophagy was activated by VEGFR1D2-SIRPαD1 through inactivating Akt/mTOR and Erk pathways in glioblastoma cells. Importantly, autophagy inhibitor or knockdown of autophagy-related protein 5 potentiated VEGFR1D2-SIRPαD1-induced macrophage phagocytosis and cytotoxicity against glioblastoma cells. Moreover, suppression of autophagy led to increased macrophage infiltration, angiogenesis inhibition, and tumor cell apoptosis triggered by VEGF and CD47 dual-targeting therapy, thus eliciting enhanced anti-tumor effects in glioblastoma. Our data revealed that VEGFR1D2-SIRPαD1 alone or in combination with autophagy inhibitor could effectively elicit potent anti-tumor effects, highlighting potential therapeutic strategies for glioblastoma through disrupting angiogenetic axis and CD47-SIRPα anti-phagocytic axis alone or in combination with autophagy inhibition.