Baicalin attenuates neuronal damage associated with SDH activation and PDK2-PDH axis dysfunction in early reperfusion.

BACKGROUND: Energy deficiency and oxidative stress are interconnected during ischemia/reperfusion (I/R) and serve as potential targets for the treatment of cerebral ischemic stroke. Baicalin is a neuroprotective antioxidant, but the underlying mechanisms are not fully revealed. PURPOSE: This study explored whether and how baicalin rescued neurons against ischemia/reperfusion (I/R) attack by focusing on the regulation of neuronal pyruvate dehydrogenase kinase 2 (PDK2)-pyruvate dehydrogenase (PDH) axis implicated with succinate dehydrogenase (SDH)-mediated oxidative stress. STUDY DESIGN: The effect of the tested drug was explored in vitro and in vivo with the model of oxygen-glucose deprivation/reoxygenation (OGD/R) and middle cerebral artery occlusion/reperfusion (MCAO/R), respectively. METHODS: Neuronal damage was evaluated according to cell viability, infarct area, and Nissl staining. Protein levels were measured by western blotting and immunofluorescence. Gene expression was investigated by RT-qPCR. Mitochondrial status was also estimated by fluorescence probe labeling. RESULTS: SDH activation-induced excessive production of reactive oxygen species (ROS) changed the protein expression of Lon protease 1 (LonP1) and hypoxia-inducible factor-1ɑ (HIF-1ɑ) in the early stage of I/R, leading to an upregulation of PDK2 and a decrease in PDH activity in neurons and cerebral cortices. Treatment with baicalin prevented these alterations and ameliorated neuronal ATP production and survival. CONCLUSION: Baicalin improves the function of the neuronal PDK2-PDH axis via suppression of SDH-mediated oxidative stress, revealing a new signaling pathway as a promising target under I/R conditions and the potential role of baicalin in the treatment of acute ischemic stroke.

Effects of Radix dichroae extract supplementation on growth performance, oocysts output and gut microbiota in growing lambs with coccidiosis.

Coccidiosis is an intestinal protozoan disease of sheep, that causes substantial economic losses in the industry due to its intestinal protozoan origins. Many anti-protozoan drugs including ionophores, triazines, and sulfonamides have been widely used to treat sheep coccidiosis. Still, anticoccidial resistance and drug residues in edible tissues have prompted an urgent search for alternatives. In this study, the anti-coccidial effectiveness of the Radix dichroae extract was compared to that of the conventional anti-coccidial drug diclazuril. Here, eighteen 45-day-old lambs naturally-infected with Eimeria spp. were randomly allocated in three groups: control group, Radix dichroae extract group and diclazuril group. The results showed that the body weight gain (BWG) during the treatment and withdrawal periods was considerably improved in the coccidiosis-infected sheep treated with Radix dichroae extract and diclazuril compared to the control group, respectively. Additionally, the Radix dichroae extract and diclazuril had fewer oocysts per gram (OPG) than the control group, showing similar anti-coccidial effects on days 14, 21, 28, 35 and 78, respectively. Furthermore, Radix dichroae extract and diclazuril treatment altered the structure and composition of gut microbiota, promoting the relative abundance of Actinobacteriota, Firmicutes, Alistipes, and Bifidobacterium, while decreasing the abundance of Bacteroidota, Marinilaceae, Helicobacteraceae, and Prevotella. Moreover, Spearman's correlation analysis further revealed a correlation between the OPG and BWG and gut microorganisms. Collectively, the results indicated that Radix dichroae extract had similar anti-coccidial effects as diclazuril, and could regulate gut microbiota balance in growing lambs.

Andrographolide Attenuates Oxidized LDL-Induced Activation of the NLRP3 Inflammasome in Bone Marrow-Derived Macrophages and Mitigates HFCCD-Induced Atherosclerosis in Mice.

Andrographolide (AND) is a bioactive component of the herb Andrographis paniculata and a well-known anti-inflammatory agent. Atherosclerosis is a chronic inflammatory disease of the vasculature, and oxidized LDL (oxLDL) is thought to contribute heavily to atherosclerosis-associated inflammation. The aim of this study was to investigate whether AND mitigates oxLDL-mediated foam cell formation and diet-induced atherosclerosis (in mice fed a high-fat, high-cholesterol, high-cholic acid [HFCCD] diet) and the underlying mechanisms involved. AND attenuated LPS/oxLDL-mediated foam cell formation, IL-1[Formula: see text] mRNA and protein (p37) expression, NLR family pyrin domain containing 3 (NLRP3) mRNA and protein expression, caspase-1 (p20) protein expression, and IL-1[Formula: see text] release in BMDMs. Treatment with oxLDL significantly induced protein and mRNA expression of CD36, lectin-like oxLDL receptor-1 (LOX-1), and scavenger receptor type A (SR-A), whereas pretreatment with AND significantly inhibited protein and mRNA expression of SR-A only. Treatment with oxLDL significantly induced ROS generation and Dil-oxLDL uptake; however, pretreatment with AND alleviated oxLDL-induced ROS generation and Dil-oxLDL uptake. HFCCD feeding significantly increased aortic lipid accumulation, ICAM-1 expression, and IL-1[Formula: see text] mRNA expression, as well as blood levels of glutamic pyruvic transaminase (GPT), total cholesterol, and LDL-C. AND co-administration mitigated aortic lipid accumulation, the protein expression of ICAM-1, mRNA expression of IL-1[Formula: see text] and ICAM-1, and blood levels of GPT. These results suggest that the working mechanisms by which AND mitigates atherosclerosis involve the inhibition of foam cell formation and NLRP3 inflammasome-dependent vascular inflammation as evidenced by decreased SR-A expression and IL-1[Formula: see text] release, respectively.

Capsaicin improves hypertension and cardiac hypertrophy via SIRT1/NF-κB/MAPKs pathway in the hypothalamic paraventricular nucleus.

BACKGROUND: Hypertension has seriously affected a large part of the adult and elderly population. The complications caused by hypertension are important risk factors for cardiovascular disease accidents. Capsaicin, a pungent component of chili pepper has been revealed to improve hypertension. However, its potential mechanism in improving hypertension remains to be explored. PURPOSE: In the present study, we aimed to investigate whether capsaicin could attenuate the SIRT1/NF-κB/MAPKs pathway in the paraventricular nucleus of hypothalamus (PVN). METHODS: We used spontaneous hypertensive rats (SHRs) as animal model rats. Micro osmotic pump was used to give capsaicin through PVN for 28 days, starting from age12-week-old. RESULTS: The results showed that capsaicin significantly reduced blood pressure from the 16th day of infusion onward. At the end of the experimental period, we measured cardiac hypertrophy index and the heart rate (HR), and the results showed that the cardiac hypertrophy and heart rate of rats was significantly improved upon capsaicin chronic infusion. Norepinephrine (NE) and epinephrine (EPI) in plasma of SHRs treated with capsaicin were also decreased. Additionally, capsaicin increased the protein expression and number of positive cells of SIRT1 and the 67-kDa isoform of glutamate decarboxylase (GAD67), decreased the production of reactive oxygen species (ROS), number of positive cells of NOX2, those of Angiotensin Converting Enzyme (ACE) and p-IKKß, tyrosine hydroxylase (TH), the gene expression levels of NOX4 and pro-inflammatory cytokines. Capsaicin also decreased the relative protein expressions of protein in MAPKs pathway. CONCLUSION: Current data indicated that capsaicin within the PVN improves hypertension and cardiac hypertrophy via SIRT1/NF-κB/MAPKs pathway in the PVN of SHRs, supporting its potential as candidate drug for preventing and improving hypertension.

Andrographolide Inhibits Lipotoxicity-Induced Activation of the NLRP3 Inflammasome in Bone Marrow-Derived Macrophages.

Andrographolide is the major bioactive component of the herb Andrographis paniculata and is a potent anti-inflammatory agent. Obesity leads to an excess of free fatty acids, particularly palmitic acid (PA), in the circulation. Obesity also causes the deposition of ectopic fat in nonadipose tissues, which leads to lipotoxicity, a condition closely associated with inflammation. Here, we investigated whether andrographolide could inhibit PA-induced inflammation by activating autophagy, activating the antioxidant defense system, and blocking the activation of the NLRP3 inflammasome. Bone marrow-derived macrophages (BMDMs) were primed with lipopolysaccharide (LPS) and then activated with PA. LPS/PA treatment increased both the mRNA expression of NLRP3 and IL-1[Formula: see text] and the release of IL-1[Formula: see text] in BMDMs. Andrographolide inhibited the LPS/PA-induced protein expression of caspase-1 and the release of IL-1[Formula: see text]. Furthermore, andrographolide attenuated LPS/PA-induced mtROS generation by first promoting autophagic flux and catalase activity, and ultimately inhibiting activation of the NLRP3 inflammasome. Our results suggest that the mechanisms by which andrographolide downregulates LPS/PA-induced IL-1[Formula: see text] release in BMDMs involve promoting autophagic flux and catalase activity. Andrographolide may thus be a candidate to prevent obesity- and lipotoxicity-driven chronic inflammatory disease.

Immune modulations of the tumor microenvironment in response to phototherapy.

The tumor microenvironment (TME) promotes pro-tumor and anti-inflammatory metabolisms and suppresses the host immune system. It prevents immune cells from fighting against cancer effectively, resulting in limited efficacy of many current cancer treatment modalities. Different therapies aim to overcome the immunosuppressive TME by combining various approaches to synergize their effects for enhanced anti-tumor activity and augmented stimulation of the immune system. Immunotherapy has become a major therapeutic strategy because it unleashes the power of the immune system by activating, enhancing, and directing immune responses to prevent, control, and eliminate cancer. Phototherapy uses light irradiation to induce tumor cell death through photothermal, photochemical, and photo-immunological interactions. Phototherapy induces tumor immunogenic cell death, which is a precursor and enhancer for anti-tumor immunity. However, phototherapy alone has limited effects on long-term and systemic anti-tumor immune responses. Phototherapy can be combined with immunotherapy to improve the tumoricidal effect by killing target tumor cells, enhancing immune cell infiltration in tumors, and rewiring pathways in the TME from anti-inflammatory to pro-inflammatory. Phototherapy-enhanced immunotherapy triggers effective cooperation between innate and adaptive immunities, specifically targeting the tumor cells, whether they are localized or distant. Herein, the successes and limitations of phototherapy combined with other cancer treatment modalities will be discussed. Specifically, we will review the synergistic effects of phototherapy combined with different cancer therapies on tumor elimination and remodeling of the immunosuppressive TME. Overall, phototherapy, in combination with other therapeutic modalities, can establish anti-tumor pro-inflammatory phenotypes in activated tumor-infiltrating T cells and B cells and activate systemic anti-tumor immune responses.

Study on the differences of gut microbiota composition between phlegm-dampness syndrome and qi-yin deficiency syndrome in patients with metabolic syndrome.

Background: Metabolic syndrome (MS) is a group of complex medical conditions that can lead to serious cardiovascular and cerebrovascular diseases. According to the theory of traditional Chinese medicine (TCM), MS can be divided into two main subtypes termed 'phlegm-dampness syndrome' (TSZE) and 'qi-yin deficiency syndrome' (QYLX). At present, the research into intestinal microbiota of different TCM syndromes of MS and its association with clinical manifestation is lacking. Materials and methods: Using 16S rRNA sequencing, we performed a cross-sectional analysis of human gut microbiota between two different TCM syndromes (QYLX and TSZE, n=60) of MS, and their differences with healthy participants (n=30). Results: We found that the QYLX and TSZE groups differ from the healthy control group in the overall gut microbiota composition, and some specific microbial taxa and functional pathways. Moreover, significantly differentially abundant taxa and distinct BMI-correlated taxa were observed between QYLX and TSZE groups, suggesting the potential contribution of gut microbiota to the distinction between the two TCM syndromes. The predicted functional profiles also showed considerable differences, especially pathways related to amino acid metabolism and lipopolysaccharide synthesis. Conclusion: Our study highlights the gut microbiota's contribution to the differentiation between two TCM syndromes of MS and may provide the rationale for adopting different microbiota-directed treatment strategies for different TCM syndromes of MS in the future.

Coenzyme Q10 Supplementation Increases Removal of the ATXN3 Polyglutamine Repeat, Reducing Cerebellar Degeneration and Improving Motor Dysfunction in Murine Spinocerebellar Ataxia Type 3.

Coenzyme Q10 (CoQ10), a well-known antioxidant, has been explored as a treatment in several neurodegenerative diseases, but its utility in spinocerebellar ataxia type 3 (SCA3) has not been explored. Herein, the protective effect of CoQ10 was examined using a transgenic mouse model of SCA3 onset. These results demonstrated that a diet supplemented with CoQ10 significantly improved murine locomotion, revealed by rotarod and open-field tests, compared with untreated controls. Additionally, a histological analysis showed the stratification of cerebellar layers indistinguishable from that of wild-type littermates. The increased survival of Purkinje cells was reflected by the reduced abundance of TUNEL-positive nuclei and apoptosis markers of activated p53, as well as lower levels of cleaved caspase 3 and cleaved poly-ADP-ribose polymerase. CoQ10 effects were related to the facilitation of the autophagy-mediated clearance of mutant ataxin-3 protein, as evidenced by the increased expression of heat shock protein 27 and autophagic markers p62, Beclin-1 and LC3II. The expression of antioxidant enzymes heme oxygenase 1 (HO-1), glutathione peroxidase 1 (GPx1) and superoxide dismutase 1 (SOD1) and 2 (SOD2), but not of glutathione peroxidase 2 (GPx2), were restored in 84Q SCA3 mice treated with CoQ10 to levels even higher than those measured in wild-type control mice. Furthermore, CoQ10 treatment also prevented skeletal muscle weight loss and muscle atrophy in diseased mice, revealed by significantly increased muscle fiber area and upregulated muscle protein synthesis pathways. In summary, our results demonstrated biochemical and pharmacological bases for the possible use of CoQ10 in SCA3 therapy.

Omega-3 Fatty Acids Improve Chronic Kidney Disease-Associated Pruritus and Inflammation.

Background and Objectives: Chronic kidney disease-associated pruritus (CKD-aP) is a common symptom in hemodialysis patients. A frequent and intense itching sensation largely torments patients, impacts quality of life outcomes, and it has an independent association with mortality. The objective of this study is to investigate the effects of oral supplementation with omega-3 polyunsaturated fatty acid (omega-3 PUFA) on circulating interleukin-6 (IL-6), cardiometabolic parameters, skin moisturization, and the consequent symptoms of pruritus in hemodialysis patients. Materials and Methods: Volunteers on maintenance hemodialysis with very severe pruritus symptoms were enrolled in this prospective cohort study. Subjects were instructed to consume 1000 mg fish oil once daily for 3 months. Pruritus scoring, skin moisture, plasma IL-6, and cardiometabolic parameters were measured at baseline, and at the first, second, and third month post-supplementation with fish oil for assessment of the clinical significance. Results: A total of 27 patients who had a mean age of 67.33 ± 11.06 years and 3.98 ± 3.23 years on hemodialysis completed the study. Supplementation with omega-3 PUFA significantly decreased IL-6 levels (p < 0.001), but increased the levels of c-reactive protein (CRP) (p < 0.05). Evaluation of the cardiovascular risk showed significant (all p < 0.001) decreases in the total cholesterol (CHO), low-density lipoprotein (LDL), and triglycerides (TG) levels, and an increase in the high-density lipoprotein (HDL) level. A significant decrease in plasma creatinine (CR) was observed (p < 0.001), but the decrease was limited. Supplementation with omega-3 PUFA significantly improved (all p < 0.001) skin hydration on both the face and arms, as well as disease-related symptoms of pruritus. Conclusion: Omega-3 PUFA supplementation improved inflammation, renal function, cardiovascular parameters, dry skin conditions, and the consequent symptoms of pruritus in hemodialysis patients.

Integrated lipidomics and network pharmacology analysis of the protective effects and mechanism of Yuanzhi San on rats with cognitive impairment.

Cognitive impairment (CI) can seriously affect people's mental and physical health. Yuanzhi San (YZS) is a classic prescription for treating CI, but the mechanisms need further exploration. The aim of this study is to explore the effect of YZS on promoting the learning and memory ability of CI rats induced by d-galactose combined with aluminum chloride. Behavioral experiments had been used to comprehensively evaluate the established CI model. Brain histological morphology and the expressions of calcium ion signaling pathway related factors in serum were used to evaluate the effect of YZS against CI. Lipids in rat serum were analyzed by ultra-performance liquid chromatography-mass spectrometry (UHPLC-MS) and chemical pattern recognition methods. Network pharmacology was used to find potential chemical compounds, targets, and related signaling pathways against CI with treatment of YZS. The integrated lipidomics and network pharmacology analysis were conducted by Cytoscape software. The results showed that YZS could alleviate neurodegenerative impairment. It was verified that model rats had longer latency time, shorter exploration paths, lower new objects recognition indexes, and shorter exercise time and distances compared with the normal rats in behavioral experiments, indicating that the model rats were successfully established. Rats of YZS 6.67 had significant differences in retention time (p < 0.05), number of entrances (p < 0.01), new object recognition indexes (p < 0.05, p < 0.01), exercise time (p < 0.05), and content of Ca [2]+, CAM, APP, CREB (p < 0.01), CAMK2 (p < 0.05). Rats of YZS 6.67 had five cell layers in hippocampus histological morphology. Behavioral experiments results showed that YZS had an active effect on CI rats. From lipidomics analysis, 129 lipids were screened out by conditions of VIP > 1 and p < 0.05, and 17 lipid markers were identified from the databases, which were divided mainly into five types. Pathway analysis indicated that linoleic acid, α-linolenic acid, arachidonic acid, and glycerophospholipid metabolisms were potential target pathways closely involved in the mechanism YZS's effects against CI. Network pharmacology focused on 84 chemical compounds, 130 intersection targets, and 10 hub genes of YZS's effects against CI. Six hub genes and four lipid compounds had intrinsic contact with arachidonic acid metabolism, glycerophospholipid metabolism and linoleate metabolism. The study revealed that YZS could improve animal cognitive behaviors, the expression of factors associated with memory in serum and the histological morphology of hippocampus. Four lipid compounds, three metabolic pathways, and six hub genes of YZS could effectively modulated CI. These results collectively suggest that the main mechanism of YZS in improving CI involves lipid metabolism, which affects biological processes and targets of action in the body.

A Network Pharmacology Study on the Active Components and Targets of the Radix Ginseng and Radix Bupleuri Herb Pair for Treating Nonalcoholic Fatty Liver Disease.

OBJECTIVE: To explore the potential active components and corresponding target herb pairs of Radix Ginseng (Renshen) and Radix Bupleuri (Chaihu) in the treatment of nonalcoholic fatty liver disease (NAFLD) through network pharmacology and in vitro experiments. METHODS: The active components and potential targets of the herb pair of Renshen and Chaihu were screened through a network database system, and Venn analysis was performed with the obtained NAFLD targets. The intersecting targets were analysed for gene ontology (GO) functions and Kyoto Encyclopedia of Genes and Genome (KEGG) pathways, and a protein-protein interaction (PPI) network was generated. Cytoscape software was used to construct active component-target networks of the Renshen and Chaihu herb pair. Free fatty acids were added to the HepG2 cell line to create high-fat models that were treated with different concentrations of stigmasterol. The effect of stigmasterol on the lipid metabolism in HepG2 cells and PPARγ-knockdown cells was determined by oil red O staining, Nile red staining, and TG level. PPARγ and UCP-1 mRNA, and protein expression levels were detected by qRT-PCR and Western blot analyses, respectively. RESULTS: Twenty active components obtained from the Renshen and Chaihu herb pair were identified. The herb pair active component-target network showed that both Renshen and Chaihu contained stigmasterol and kaempferol as active components. The PPI network comprised 63 protein nodes. GO enrichment analysis and KEGG pathway enrichment analysis showed that the targets were mainly involved in lipid metabolism. Eight core targets were identified: AKT1, PPARG, MAPK3, TNF, TP53, SIRT1, STAT3, and PPARA. In vitro experiments demonstrated that stigmasterol reduced lipid accumulation and TG levels in HepG2 cells, and the mechanism may have been related to the activation of the PPARγ-UCP-1 signalling pathway. CONCLUSION: This study preliminarily illustrated the potential components and corresponding core targets of the Renshen and Chaihu herb pair in treating NAFLD. The effect of stigmasterol on the PPARγ-UCP-1 signalling pathway in enhancing lipid metabolism may represent one of the mechanisms of the Renshen and Chaihu herb pair in the treatment of NAFLD. The results provide new evidence and research insights to reveal the roles of Renshen and Chaihu in the management of NAFLD.

Novel Insights into Total Flavonoids of Rhizoma Drynariae against Meat Quality Deterioration Caused by Dietary Aflatoxin B1 Exposure in Chickens.

Aflatoxin B1 (AFB1) is a group of highly toxic mycotoxins that are commonly found in human and animal foods and threaten animal and human food safety. Total flavonoids of Rhizoma Drynaria (TFRD), a traditional Chinese medicinal herb, exert multiple biological activities such as immunomodulatory, anti-inflammatory, and anti-oxidation effects. Here, a total of 160 healthy 21-day-old male broilers were randomly divided into four groups: the CON group, the TFRD group, the AFB1 group, and the AFB1 + TFRD group. The study found that AFB1 exposure altered the breast meat quality-related indicators, including meat sensory and physical indicators. Metabolomics analysis further showed that the change in meat quality was closely associated with significantly differential metabolites of breast muscle. Furthermore, spotlighted amino acid content contributes to changes in the secondary structure of the myofibrillar protein by Raman spectroscopy analysis, which was associated with the oxidative stress and inflammatory response in AFB1-exposed breast meat. Meanwhile, dietary 125 mg/kg TFRD supplementation could effectively restore the changes in breast meat quality. Taken together, these results by multi-technical analysis revealed that AFB1 exposure causes deterioration of chicken meat quality and that TFRD may be a potential herbal extract to antagonize mycotoxicity.

Synergistic interventional photothermal therapy and immunotherapy using an iron oxide nanoplatform for the treatment of pancreatic cancer.

Pancreatic cancer (PC) is the most lethal malignancy due to its high metastatic ability and poor drug permeability. Here, a synergized interventional photothermal-immunotherapy strategy was developed with imaging guidance and temperature monitoring by magnetic resonance imaging (MRI) technique, for the local treatment of metastatic PC. A tumor microenvironment (TME)-responsive nanoplatform was fabricated via coating of DSPE-PEG and indocyanine green (ICG) onto imiquimod (IMQ) loaded amorphous iron oxide nanoparticles (IONs). This unique nanoplatform, IMQ@IONs/ICG, served as a contrast agent for MRI, a drug delivery vehicle for IMQ and ICG, and a catalyst for TME modulation. The biodegradable IMQ@IONs/ICG was also non-toxic, and improved the penetration of the loaded drugs in PC to maximize thermal ablation of the tumor and minimize damage to the surrounding healthy tissue. For the treatment of aggressive, metastatic Panc02-H7 pancreatic tumors in mice, ION-assisted MRI was employed to guide the administration of interventional photothermal therapy (IPTT) and monitor the temperature distribution in target tumor and surrounding tissue during treatment. The local IPTT treatment induced in situ immunogenic cell death (ICD), and, in combination with released IMQ, triggered a strong antitumor immunity, leading to decreased metastases and increased CD8+ in spleen and tumors. With precise local treatment and monitoring, treated primary tumors were completely eradicated, mesentery metastases were dramatically reduced, and the survival time was significantly prolonged, without damage to normal tissue and systemic autoimmunity. Overall, this synergistic strategy represents a promising approach to treat PC with significant potential for clinical applications. STATEMENT OF SIGNIFICANCE: Pancreatic cancer (PC) is one of the most lethal malignancies because it is non-permeable to drugs and highly metastatic. In this study, we designed a tumor microenvironment-responsive amorphous iron oxide nanoplatform (ION) to co-deliver photothermal agent (ICG) and toll-like-receptor-7 agonist (IMQ). This biodegradable nanoplatform IMQ@IONs/ICG improved the penetration of the loaded drugs in pancreatic tumor. With MR imaging guidance and temperature monitoring, the precise interventional photothermal therapy on mouse Panc02-H7 orthotopic tumors releases tumor antigens to initiate tumor-special immune responses, amplified by the released IMQ. Our results demonstrate that IMQ@IONs/ICG overcomes the obstacle of drug delivery to pancreatic tumors, and when combined with photothermal therapy, induces a systemic antitumor immunity to control metastatic tumors.

Tongxinluo Exerts Inhibitory Effects on Pyroptosis and Amyloid-ß Peptide Accumulation after Cerebral Ischemia/Reperfusion in Rats.

Amyloid-ß peptide (Aß) accumulation is a detrimental factor in cerebral ischemia/reperfusion (I/R) injuries accounting for dementia induced by ischemic stroke. In addition to blood brain barrier (BBB), the glymphatic system mediated by aquaporin-4 (AQP-4) on astrocytic endfeet functions as an important pathway for the clearance of Aß in the brain. Cerebral I/R induced astrocytic pyroptosis potentially causes the AQP-4 polarization loss and dysfunctional BBB-glymphatic system exacerbating the accumulation of Aß. Furthermore, Aß toxicity has been identified as a trigger of pyroptosis and BBB damage, suggesting an amplified effect of Aß accumulation after cerebral I/R. Therefore, based on our previous work, this study was designed to explore the intervention effects of Tongxinluo (TXL) on astrocytic pyroptosis and Aß accumulation after cerebral I/R in rats. The results showed that TXL intervention obviously alleviated the degree of pyroptosis by downregulating expression levels of cleaved caspase-11/1, N-terminal gasdermin D, nucleotide-binding oligomerization domain-like receptors pyrin domain containing 3 (NLRP3), interleukin-6 (IL-6), and cleaved IL-1ß and abated astrocytic pyroptosis after cerebral I/R. Moreover, TXL intervention facilitated to restore AQP-4 polarization and accordingly relieve Aß accumulation around astrocytes in ischemic cortex and hippocampus as well as the formation of toxic Aß (Aß 1-42 oligomer). Our study indicated that TXL intervention could exert protective effects on ischemic brain tissues against pyroptotic cell death, inhibit astrocytic pyroptosis, and reduce toxic Aß accumulation around astrocytes in cerebral I/R injuries. Furthermore, our study provides biological evidence for the potential possibility of preventing and treating poststroke dementia with TXL in clinical practice.

Transcriptomic analysis of mechanism of melanoma cell death induced by photothermal therapy.

Melanoma is a malignancy with poor prognosis. Its incidence rate has been on the rise and it poses high health and economic challenges to different populations. Photothermal therapy (PTT) served as an effective local therapy in treating various tumors, particularly cutaneous carcinoma like melanoma. To fully understand the mechanisms of tumor cell death induced by PTT, we investigated gene expression and immune cells compositions of B16-F10 tumors after PTT treatment. A total of 256 differentially expressed genes (DEGs) were identified, with 215 being downregulated and 41 upregulated by PTT. Functional annotation showed that most DEGs involved in immune response and inflammatory response. Immune cells compositions inference revealed changes in many immune cells including regulatory T cells, M2 macrophage and B cells after PTT treatment. Our results help delineate the mechanism of cell death at the transcriptional level triggered by non-invasive PTT treatment of melanoma without exogenous light absorbing agents.

Cancer photo-immunotherapy: from bench to bedside.

Targeted therapy and immunotherapy in combination is considered the ideal strategy for treating metastatic cancer, as it can eliminate the primary tumors and induce host immunity to control distant metastases. Phototherapy, a promising targeted therapy, eradicates primary tumors using an appropriate dosage of focal light irradiation, while initiating antitumor immune responses through induced immunogenic tumor cell death. Recently, phototherapy has been employed to improve the efficacy of immunotherapies such as chimeric antigen receptor T-cell therapy and immune checkpoint inhibitors. Phototherapy and immunoadjuvant therapy have been used in combination clinically, wherein the induced immunogenic cell death and enhanced antigen presentation synergy, inducing a systemic antitumor immune response to control residual tumor cells at the treatment site and distant metastases. This review summarizes studies on photo-immunotherapy, the combination of phototherapy and immunotherapy, especially focusing on the development and progress of this unique combination from a benchtop project to a promising clinical therapy for metastatic cancer.

Bufalin: A Systematic Review of Research Hotspots and Antitumor Mechanisms by Text Mining and Bioinformatics.

Bufalin is an anticancer drug extract from traditional Chinese medicine. Several articles about bufalin have been published. However, the literature on bufalin has not yet been systematically studied. This study aimed to identify the study status and knowledge structures of bufalin and to summarize the antitumor mechanism. Data were retrieved and downloaded from the PubMed database. The softwares of BICOMB, gCLUTO, Ucinet 6.0, and NetDraw2.084 were used to analyze these publications. The bufalin related genes were recognized and tagged by ABNER software. Then these BF-related genes were performed by Gene Ontology (GO) enrichment analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways analysis, and protein-protein interaction (PPI) network analysis. A total of 474 papers met the search criteria from 2000 to 2019. By biclustering clustering analysis, the 50 high-frequency main MeSH terms/subheadings were classified into 5 clusters. The clusters of drug therapy and the mechanism of bufalin were hotspot topics. A total of 50 genes were identified as BF-related genes. PPI network analysis showed that inducing apoptosis was the main effect of bufalin, and apoptosis-related gene Caspase 3 was the most reported by people. Bufalin could inhibit the proliferation, invasion, and metastasis of cancer cells through multiple signaling pathways, such as PI3K/AKT, Hedgehog, MAPK/JNK, Wnt/[Formula: see text]-catenin, TGF-[Formula: see text]/Smad, Integrin signaling pathway, and NF-KB signaling pathway via KEGG analysis. Through the quantitative analysis of bufalin literature, we revealed the research status and hot spots in this field and provided some guidance for further research.

Hispidulin: A promising flavonoid with diverse anti-cancer properties.

In recent years, natural products have increasingly attracted more attention because of their potential anticancer activity and low intrinsic toxicity. Hispidulin is a natural flavonoid with a wide range of biological activities, including anti-inflammatory, antifungal, antiplatelet, anticonvulsant, anti-osteoporotic, and notably anticancer activities. Numerous in vivo and in vitro studies have shown that hispidulin, as a potential anticancer drug, affects cell proliferation, apoptosis, cell cycle, angiogenesis, and metastasis. Moreover, hispidulin exhibits synergistic anti-tumor effects when combined with some common clinical anticancer drugs (e.g., gemcitabine, 5-fluoroucil, sunitinib, temozolomide, and TRAIL). The combination of hispidulin and chemotherapeutic drugs reduces the efflux of chemotherapeutic drugs, enhances the chemosensitivity of cancer cells, and reverses drug resistance. Herein, we outlined the anticancer effects of hispidulin in various cancers and its intracellular molecular targets and related mechanisms of its anticancer activity. Based on the available literature, it can be established that hispidulin has significant potential to become an important complementary medicine for cancer prevention and treatment. However, more in-depth in vitro and in vivo studies should be conducted to support its translation from bench to bedside.

HS-GC-IMS-Based metabonomics study of Baihe Jizihuang Tang in a rat model of chronic unpredictable mild stress.

The aim of this study was to investigate the differences in volatile organic compounds (VOCs) obtained from the feces of a Baihe Jizihuang Tang (BHT)-treated rat depression model. Rats were subjected to chronic unpredictable mild stress (CUMS), and the differences in VOCs were analyzed by headspace-gas chromatography-ion mobility spectrometry (HS-GC-IMS), NIST software, principal component analysis, and orthogonal partial least squares discriminant analysis. Eleven biomarkers were identified on the basis of VOC migration time, and their relative peak intensities were analyzed. A metabonomic model was established using multivariate statistical analysis. The study demonstrated the metabonomics of CUMS rats and the intervention effect of BHT and also highlighted the potential therapeutic effects of the traditional Chinese medicine (TCM) Jingfang for the clinical treatment of complex diseases, which was in line with the holistic and systemic approaches of TCM. This study augments the use of metabonomics based on HS-GC-IMS in research studies. Using this method, there is no need to pre-process samples by extraction or derivatization, and the VOC component of the sample can be detected directly and rapidly. In conclusion, this study establishes a simple, convenient, and fast technique, which can help identify clinical biomarkers for rapid medical diagnosis.