Identification of altered metabolic functional components using metabolomics to analyze the different ages of fruiting bodies of Sanghuangporus vaninii cultivated on cut log substrates.

Sanghuangporus vaninii is a profitable traditional and medicinal edible fungus with uncommon therapeutic properties and medicinal value. The accumulation of active ingredients in this fungus that is used in traditional Chinese medicine is affected by its years of growth, and their pharmacological activities are also affected. However, the effects of age on the medicinal value of fruiting bodies of S. vaninii cultivated on cut log substrate remain unclear. In this study, an untargeted liquid chromatography mass spectrometry (LC-MS)-based metabolomics approach was performed to characterize the profiles of metabolites from 1-, 2- and 3-year-old fruiting bodies of S. vaninii. A total of, 156 differentially accumulated metabolites (DAMs) were screened based on the criterion of a variable importance projection greater than 1.0 and p < 0.01, including 75% up regulated and 25% down regulated. The results of enrichment of metabolic pathways showed that the metabolites involved the biosynthesis of plant secondary metabolites, biosynthesis of amino acids, central carbon metabolism in cancer, steroid hormone biosynthesis, linoleic acid metabolism, prolactin signaling pathway, and arginine biosynthesis, and so on. The biosynthesis of plant secondary metabolites pathway was significantly activated. Five metabolites were significantly elevated within the growth of fruiting bodies, including 15-keto-prostaglandin F2a, (4S, 5R)-4,5,6-trihydroxy-2-iminohexanoate, adenylsuccinic acid, piplartine, and chenodeoxycholic acid. 15-keto-prostaglandin F2a is related to the pathway of arachidonic acid metabolism and was significantly increased up to 1,320- and 535-fold in the 2- and 3-year-old fruiting bodies, respectively, compared with those in the 1-year-old group. The presence of these bioactive natural products in S. vaninii is consistent with the traditional use of Sanghuang, which prompted an exploration of its use as a source of natural prostaglandin in the form of foods and nutraceuticals. These findings may provide insight into the functional components of S. vaninii to develop therapeutic strategies.

Hypothalamic neuroendocrine integration of reproduction and metabolism in mammals.

Reproduction in mammals is an extremely energy-intensive process and is therefore tightly controlled by the body's energy status. Changes in the nutritional status of the body cause fluctuations in the levels of peripheral metabolic hormone signals, such as leptin, insulin, and ghrelin, which provide feedback to the hypothalamus and integrate to coordinate metabolism and fertility. Therefore, to link energy and reproduction, energetic information must be centrally transmitted to gonadotropin-releasing hormone (GnRH) neurons that act as reproductive gating. However, GnRH neurons themselves are rarely directly involved in energy information perception. First, as key factors in the control of GnRH neurons, we describe the direct role of Kisspeptin and Arg-Phe amide-related peptide-3 (RFRP-3) neurons in mediating metabolic signaling. Second, we focused on summarizing the roles of metabolic hormone-sensitive neurons in mediating peripheral energy hormone signaling. Some of these hormone-sensitive neurons can directly transmit energy information to GnRH neurons, such as Orexin neurons, while others act indirectly through other neurons such as Kisspeptin, RFRP-3 neuron, and (pituitary adenylate cyclase-activating polypeptide) PACAP neurons. In addition, as another important aspect of the integration of metabolism and reproduction, the impact of reproductive signaling itself on metabolic function was also considered, as exemplified by our examination of the role of Kisspeptin and RFRP-3 in feeding control. This review summarizes the latest research progress in related fields, in order to more fully understand the central neuropeptide network that integrates energy metabolism and reproduction.

Plum-blossom needle tapping enhances the efficacy of ALA photodynamic therapy for facial actinic keratosis in Chinese population: a randomized, multicenter, prospective, and observer-blind study.

BACKGROUND: Photodynamic therapy (PDT) with 5-aminolevulinic acid (ALA) is a reliable treatment for actinic keratosis (AK), but its effect needs to be enhanced in thick lesions. Plum-blossom needle is a traditional Chinese cost-effective instrument for enhancing the transdermal delivery of ALA. However, whether it could improve the efficacy of AK treatment has not yet been investigated. OBJECTIVE: To compare the efficacy and safety of plum-blossom needle-assisted PDT in facial AK in the Chinese population. METHODS: In this multicenter, prospective study, a total of 142 patients with AKs (grades I-III) were randomized into the plum-blossom needle-assisted PDT group (P-PDT) and control PDT group (C-PDT). In the P-PDT group, each AK lesion was tapped vertically by a plum-blossom needle before the application of 10% ALA cream. In the C-PDT group, each lesion was only wiped with regular saline before ALA cream incubation. Then, 3 hours later, all the lesions were irradiated with light-emitting diode (LED) at a wavelength of 630 nm. PDT was performed once every 2 weeks until all lesion patients achieved complete remission or completed six sessions. The efficacy (lesion response) and safety (pain scale and adverse events) in both groups were evaluated before each treatment and at every follow-up visit at 3-month intervals until 12 months. RESULTS: In the P-PDT and C-PDT groups, the clearance rates for all AK lesions after the first treatment were 57.9% and 48.0%, respectively (P < 0.05). For grade I AK lesions, the clearance rates were 56.5% and 50.4%, respectively (P = 0.34). For grade II AK lesions, the clearance rates were 58.0% and 48.9%, respectively (P = 0.1). For grade III AK lesions, the clearance rates were 59.0% and 44.2%, respectively (P < 0.05). Moreover, grade III AK lesions in the P-PDT group required fewer treatment sessions (P < 0.05). There was no significant difference in the pain score between the two groups (P = 0.752). CONCLUSION: Plum-blossom needle tapping may enhance the efficacy of ALA-PDT by facilitating ALA delivery in the treatment of AK.

Xanthohumol inhibits non-small cell lung cancer via directly targeting T-lymphokine-activated killer cell-originated protein kinase.

Xanthohumol is a principal prenylated chalcone isolated from hops. Previous studies have shown that xanthohumol was effective against various types of cancer, but the mechanisms, especially the direct targets for xanthohumol to exert an anticancer effect, remain elusive. Overexpression of T-lymphokine-activated killer cell-originated protein kinase (TOPK) promotes tumorigenesis, invasion and metastasis, implying the likely potential for targeting TOPK in cancer prevention and treatment. In the present study, we found that xanthohumol significantly inhibited the cell proliferation, migration and invasion of non-small cell lung cancer (NSCLC) in vitro and suppressed tumor growth in vivo, which is well correlated with inactivating TOPK, evidenced by reduced phosphorylation of TOPK and its downstream signaling histone H3 and Akt, and decreased its kinase activity. Moreover, molecular docking and biomolecular interaction analysis showed that xanthohumol was able to directly bind to the TOPK protein, suggesting that TOPK inactivation by xanthohumol is attributed to its ability to directly interact with TOPK. The findings of the present study identified TOPK as a direct target for xanthohumol to exert its anticancer activity, revealing novel insight into the mechanisms underlying the anticancer activity of xanthohumol.

New insights on low-temperature storage regulating garlic greening and the accumulation of pigment precursors via glutathione metabolism and energy cycles.

To explore regulation mechanism of temperature on garlic greening and pigment precursors' accumulation, greening capacities, pigment precursors and critical metabolites, enzyme and genes involved in glutathione and NADPH metabolism of garlic stored at five temperatures (4, 8, 16, 24 and 30 ℃) were analyzed. Results showed that garlic pre-stored at 4, 8 and 16 ℃ were more likely to green than ones at 24 and 30 ℃ after pickling. After 25 days, more S-1-propenyl-l-cysteine sulfoxide (1-PeCSO) were detected in garlic stored at 4, 8 and 16 ℃ (753.60, 921.85 and 756.75 mAU, respectively) than that at 24 and 30 ℃ (394.35 and 290.70 mAU). Pigment precursors' accumulation in garlic was mainly realized by glutathione and NADPH metabolism under low-temperature storage, through enhancements of activities or expressions for GR (GSR), GST (GST), γ-GT (GGT1, GGT2), 6PGDH (PGD) and ICDHc (IDH1). This study enriched the mechanism of garlic greening.

Sex Differences in the Relationship between Abdominal Obesity and Cardiovascular Death in Elderly Patients with Permanent Pacemakers Implantation: A Retrospective Cohort Study.

Objectives: This study aims to investigate the association between waist circumference (WC) and cardiovascular death in patients with permanent pacemakers (PPMs). Methods: This is a retrospective cohort study that enrolled patients who underwent PPM implantation in Fuwai Hospital from May 2010 to April 2014, according to the BIOTRONIK Home Monitoring database. The WC was treated as sex-specific quartiles, and patients were divided into three groups according to body mass index (BMI): normal (≤22.9 kg/m2), overweight (23-24.9 kg/m2), and obese (≥25 kg/m2). Cox proportional hazards models were used to calculate hazard ratios and 95% confidence intervals for cardiovascular death according to WC and BMI in patients. Results: 492 patients with PPMs implantation were analyzed (mean age: 71.9 ± 10.8 years; 55.1% men (n = 271)). Data showed that after a mean follow-up 67.2 ± 17.5 months, 24 (4.9%) patients had experienced cardiovascular death and 71 (14.4%) were cases of all-cause mortality. Men in the third quartile of WC had an HR of 10.67 (Model 4, 95% CI: 1.00-115.21, p trend = 0.04) for cardiovascular death. However, the association disappeared in female patients (Model 4, HR = 3.99, 95% CI: 0.37-42.87, p trend = 0.25). There was no association between BMI and cardiovascular death or all-cause mortality in both male and female patients. Conclusions: Abdominal obesity was associated with an increased risk of cardiovascular death in patients with PPMs, and this relationship was only in male patients.

Diterpenoids inhibit ox-LDL-induced foam cell formation in RAW264.7 cells by promoting ABCA1 mediated cholesterol efflux.

Introduction: Atherosclerosis is the main cause of many cardiovascular diseases and contributes to morbidity and mortality worldwide. The formation of macrophage-derived foam cells plays a critical role in the early stage of atherosclerosis pathogenesis. Diterpenoids found in the flowers of Callicarpa rubella Lindl., a traditional Chinese medicine, have been reported to have anti-inflammatory activity. However, little is known about the effects of these diterpenoids on macrophage foam cell formation. Methods: A macrophage-derived foam cell formation model was established by treating RAW264.7 cells with oxidized low-density lipoprotein (ox-LDL) for 24 h. Oil red O staining were used to detect the intracellular lipids. The cholesterol efflux capacity was assayed by labeling cells with 22-NBD-cholesterol. Western blots and real-time PCRs were performed to quantify protein and mRNA expressions. Results: Two diterpenoid molecules, 14α-hydroxyisopimaric acid (C069002) and isopimaric acid (C069004), extracted from the flowers of Callicarpa rubella Lindl., significantly attenuated ox-LDL-induced foam cell formation in RAW264.7 macrophages. Further investigation showed that these two diterpenoids could promote cholesterol efflux from RAW264.7 macrophages to apolipoprotein A-I or high-density lipoproteins, which was associated with upregulated expression of ATP-binding cassette A1/G1 (ABCA1/G1), liver X receptor-α (LXRα), and peroxisome proliferator-activated receptor-γ (PPARγ). Unexpectedly, the diterpenoids C069002 and C069004 failed to enhance the mRNA transcription of the ABCG1 gene in macrophage-derived foam cells induced by ox-LDL. To evaluate the effects of diterpenoids on macrophage foam cell formation and determine the underlying mechanism, two drugs (lovastatin and rosiglitazone) were used as positive controls. Although both drugs could reduce macrophage foam cell formation and promote cholesterol efflux, they each had distinctive abilities to modulate the expression of cholesterol efflux-related genes. In contrast to lovastatin, rosiglitazone showed a similar influence on the expression of cholesterol efflux-related genes (including ABCA1, LXRα, and PPARγ) as the diterpenoids regardless of the presence or absence of ox-LDL, implying a similar mechanism by which they may exert atheroprotective effects. Conclusion: Our research indicates that diterpenoids effectively inhibit ox-LDL-induced macrophage foam cell formation by promoting cholesterol efflux from macrophages via the PPARγ-LXRα-ABCA1 pathway. Further investigation of diterpenoids as potential drugs for the treatment of atherosclerosis is warranted.

Protective effects of glutamine on lipopolysaccharide/D-galactosamine-induced fulminant hepatitis in mice.

Fulminant hepatitis remains a critical health problem owing to its high mortality rate and the lack of effective therapies. An increasing number of studies have shown that glutamine supplementation provides protective benefits in inflammation-related disorders, but the pharmacological significance of glutamine in lipopolysaccharide (LPS)/D-galactosamine (D-Gal)-induced fulminant hepatitis remains unclear. In the present study, the potential effects of glutamine on LPS/D-Gal-induced fulminant hepatitis were investigated. Pretreatment with glutamine decreased plasma activities of alanine and aspartate aminotransferases, and ameliorated hepatic morphological abnormalities in LPS/D-Gal-exposed mice. Glutamine pretreatment also inhibited LPS/D-Gal-induced tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6) production. In addition, glutamine pretreatment decreased the level of cleaved cysteinyl aspartate-specific proteinase 3 (caspase-3), suppressed the activities of caspase-3, caspase-8, and caspase-9, and reduced the number of cells positive for TdT-mediated dUTP nick-end labeling in LPS/D-Gal-challenged mice. Interestingly, post-treatment with glutamine also provided protective benefits against LPS/D-Gal-induced acute liver injury, although these effects were less robust than those of glutamine pre-treatment. Thus, glutamine may have potential value as a pharmacological intervention in fulminant hepatitis.

Effect of combined ultrasonic and enzymatic extraction technique on the quality of noni (Morinda citrifolia L.) juice.

In order to obtain noni juice with high yield and good quality, the effect of combined extraction technique of enzymatic treatment (EZ) and ultrasonication (US) on the overall quality of noni juice was investigated. Moreover, the extraction performance of the EZ-US combined extraction technique was compared with that of EZ-based extraction and the US-based extraction. Response surface methodology (RSM) was designed to optimize the parameters of ultrasonic treatment, by taking consideration of the extraction efficiency, quality parameters and bioactive ingredients of noni juice. The results indicated that combined ultrasonic and enzymatic treatment achieved a synergistic effect on promoting the quality of noni juice. The maximum juice yield of 67.95 % was obtained under ultrasonication for 10 min at 600 W after enzymatic treatment (EZU). In addition, EZU-treated juice exhibited the highest contents of total phenolic and flavonoid, which were 148.19 ± 2.53 mg gallic acid/100 mL and 47.19 ± 1.22 mg rutin/100 mL, respectively, thus contributing to better antioxidant activity. Moreover, the EZU treatment significantly reduced the particle size of noni juice, and improved its suspension stability and rheological properties. FTIR results indicated that the treatments did not bring major changes in the chemical structure and the functional groups of compounds in noni juice. Therefore, EZU treatment can be successfully applied to the extraction of noni juice with better nutritional properties and overall quality.

Analysis of 12 Chemical Compounds And Pattern Recognition of Different Parts of Angelicae Sinensis Radix by Liquid Chromatography-Tandem Mass Spectrometry And Chemometrics Methods.

To evaluate the quality and quantify bioactive constituents in different parts of Angelicae Sinensis Radix, an efficient, high-speed, high-sensitivity high-performance liquid chromatography and triple quadrupole mass spectrometry method was used for simultaneous detection of 12 chemical compounds including L-tryptophan, chlorogenic acid, caffeic acid, ferulic acid, isoferulic acid, senkyunolide I, guanosine, proline, L-glutamine, γ-aminobutyric acid, glutamic acid, and arginine in 52 batches of Angelicae Sinensis Radix from Gansu, China. The established methods were validated by good linearity (R2≥0.9921), limits of detection (0.0001-0.0156 µg/mL), limits of quantitation (0.0006-0.0781 µg/mL), stability (RSD≤7.77%), repeatability (RSD≤6.79%), intra- and interday precisions (RSD≤6.00% and RSD≤6.39%, respectively) and recovery (90.90-107.16%). According to the quantitative results, the contents of the hydrophilic compounds were higher in the head, while the medium and weak polar components were mainly concentrated in the tail. Finally, principal component analysis results revealed that Angelicae Sinensis Radix could be divided into different medicinal sites based on polar components such as amino acids, nucleosides. The combination of liquid chromatography-tandem mass spectrometry and principal component analysis is a simple and reliable method for pattern recognition and quality evaluation of Angelicae Sinensis Radix.

The traditional chinese medicine monomer Ailanthone improves the therapeutic efficacy of anti-PD-L1 in melanoma cells by targeting c-Jun.

BACKGROUND: C-Jun, a critical component of AP-1, exerts essential functions in various tumors, including melanoma, and is believed to be a druggable target for cancer therapy. Unfortunately, no effective c-Jun inhibitors are currently approved for clinical use. The advent of immune checkpoint inhibitor (ICI) has brought a paradigm shift in melanoma therapy, but more than half of patients fail to exhibit clinical responses. The exploration of new combination therapies has become the current pursuit of melanoma treatment strategy. This study aims to screen out Chinese herbal monomers that can target c-Jun, explore the combined effect of c-Jun inhibitor and ICI, and further clarify the related molecular mechanism.  METHODS: We adopted a combinatorial screening strategy, including molecular docking, ligand-based online approaches and consensus quantitative structure-activity relationship (QSAR) model, to filter out c-Jun inhibitors from a traditional Chinese medicine (TCM) library. A mouse melanoma model was used to evaluate the therapeutic efficacy of monotherapy and combination therapy. Multicolor flow cytometry was employed to assess the tumor microenvironment (TME). Multiple in vitro assays were performed to verify down-streaming signaling pathway. CD4 + T-cell differentiation assay was applied to investigate Treg differentiation in vitro. RESULTS: Ailanthone (AIL) was screened out as a c-Jun inhibitor, and inhibited melanoma cell growth by directly targeting c-Jun and promoting its degradation. Surprisingly, AIL also facilitated the therapeutic efficacy of anti-programmed death ligand-1 (PD-L1) in melanoma cells by reducing the infiltration of Tregs in TME. Additionally, AIL treatment inhibited c-Jun-induced PD-L1 expression and secretion. As a consequence, Treg differentiation was attenuated after treatment with AIL through the c-Jun/PD-L1 axis. CONCLUSION: Our findings identified AIL as a novel c-Jun inhibitor, and revealed its previously unrecognized anti-melanoma effects and the vital role in regulating TME by Treg suppression, which provides a novel combination therapeutic strategy of c-Jun inhibition by AIL with ICI. AIL down-regulates c-Jun by reducing its stability, and inhibits the function of Tregs via AIL-c-Jun-PD-L1 pathway, ultimately suppressing melanoma progression and enhancing the efficacy of anti-PD-L1.

Comparative transcriptome and proteome profiles reveal the regulation mechanism of low temperature on garlic greening.

Garlic stored at low temperature (0-13 ℃) for some times and subsequently crushed and placed at room temperature would turn green, while the one stored at high temperature (30 ℃) would not. In order to elucidate the regulatory mechanism of low temperature on garlic greening, transcriptome and proteome profiles of garlic stored at 4 ℃ and 30 ℃ were explored by RNA-seq and iTRAQ techniques. Principal component analysis showed that garlic at different storage temperatures were of significant differences on both gene and protein levels. 14,381 and 861 differential expression genes (DEGs) and proteins (DEPs) were identified respectively, in which 268 factors were shared according to their joint analysis, including 186 (144) up-regulated genes (proteins) and 82 (124) down-regulated genes (proteins) in comparing garlic stored at 4 ℃ with ones at 30 ℃. These 268 factors were mainly attributed to biological process (metabolic process) and molecular function (catalytic activity, binding) categories by Gene Ontology classification. The KEGG (Kyoto Encyclopedia of Genes and Genomes) pathways enrichment of DEGs and DEPs revealed that GSSG production, GSH degradation, amino acid biosynthesis (cysteine and methionine) and energy metabolism (TCA and HMP cycles) were promoted by low-temperature storage to responding to oxidative stress and prepared for pigment synthesis in garlic. These results provide valuable information for the regulation of garlic greening during processing.

The role of metabolic reprogramming in cancer metastasis and potential mechanism of traditional Chinese medicine intervention.

Metabolic reprogramming is one of the most prominent features underlying cancer cells progression and metastasis.Traditional Chinese medicine (TCM) has been widely used in the clinical treatment of cancer, with the advantages of multi-pathway, multi-target, multi-component anti-tumor pharmacological effects and low risk of adverse effects. However, the mechanisms underlying the anti-tumor effects of TCM are not fully understood, especially on cellular metabolic reprogramming. In this review, we summarize the role of glucose, lipid and amino acid metabolism in cancer metastasis, which is key in cancer cells and tumor micro-environment (TME) cell metabolism. Furthermore, we reviewed the potential mechanisms by which, most bioactive TCM compounds suppress cancer metastasis by regulating metabolic reprogramming and the possibility of sensitizing other anti-tumor drugs. TCM and its bioactive compounds have huge prospects for clinical application in the treatment of cancer metastasis. Unfortunately, little is currently known about the regulatory effects of Chinese herbal medicines and their bioactive compounds on the metabolic reprogramming of cancer cells and the combination therapy for cancers. This review provides novel insights into the regulation of metabolic reprogramming by TCM in combination with other anti-tumor drugs against cancer metastasis and the possibility of becoming sensitizers for other anti-tumor drugs.

Amphiphilic nano-delivery system based on modified-chitosan and ovalbumin: Delivery and stability in simulated digestion.

Nano-delivery systems play an important role in the development of nutritional supplements due to their efficient encapsulation and delivery properties for nutrients. Herein, we prepared protein-polysaccharide nanoparticles as a novel amphiphilic nano-delivery system based on gallic acid modified chitosan (GCS) and ovalbumin (OVA) by pH-driven and calcium ion crosslinking. The nanoparticles loaded with hydrophilic riboflavin (Rib) and hydrophobic quercetin (Que) as nutrient models were abbreviated as GCS-OVA-Rib NPs and GCS-OVA-Que NPs, respectively. Their encapsulation efficiencies for Rib and Que. were 66.36 % and 96.61 %, respectively. In addition, GCS-OVA-Rib NPs and GCS-OVA-Que NPs showed antioxidant activity as well as good stability and delivery capacity for Rib and Que. in simulated digestion with release ratios of 78.38 % and 84.15 %, respectively. More importantly, GCS-OVA-Rib/Que. NPs performed good biocompatibility for further applications. Overall, this work provides some useful insights for the design of novel amphiphilic nano-delivery systems based on polysaccharides and proteins.

Rod-like hybrid nanomaterial with tumor targeting and pH-responsive for cancer chemo/photothermal synergistic therapy.

The development of chemo/photothermal nanotherapeutic systems with excellent photothermal performance, stable drug loading, tumor targeting and strong membrane penetration still remains a challenge. To address this problem, herein a rod-like nanocomposite system (AuNR@FA-PR/PEG) forming from folic acid (FA) terminated carboxylated cyclodextrin (CD) pseudopolyrotaxane (FA-PR) and polyethylene glycol (PEG) modifying gold nanorods (AuNR) was reported. Cisplatin (CDDP) was loaded in AuNR@FA-PR/PEG via coordination bonds to prepare a rod-like pH-responsive nanosystem (AuNR@FA-PR/PEG/CDDP) with chemotherapy/photothermal therapy. The rod-like morphology of AuNR@FA-PR/PEG was characterized by transmission electron microscope. In vitro drug release experiments showed the pH-responsive of AuNR@FA-PR/PEG/CDDP. In vivo real-time imaging assays proved AuNR@FA-PR/PEG/CDDP could rapidly enrich in the tumor area and stay for a long time because of folate targeting and their rod-like morphology. In vivo photothermal imaging assays showed AuNR@FA-PR/PEG/CDDP excellent photothermal performance, the average temperature of tumor region could reach 63.5 °C after 10 min irradiation. In vitro and in vivo experiments also demonstrated that the combined therapy of chemotherapy and photothermal therapy had an outstandingly synergistic effect and improved the therapeutic efficacy comparing with chemotherapy and photothermal therapy alone. Therefore, the prepared rod-like AuNR@FA-PR/PEG/CDDP will provide a new strategy for the effective treatment of cancer.

Precisely NIR-II-activated and pH-responsive cascade catalytic nanoreactor for controlled drug release and self-enhanced synergetic therapy.

Mesoporous polydopamine (MPDA) and MPDA-based nanosystems have been widely used in the field of photothermal therapy (PTT) and drug delivery. However, synthesis of the corresponding nanoplatforms for efficient PTT and controlled drug release simultaneously in the second near infrared (NIR-II) region remains a great challenge. Herein, a NIR-II and pH dual-responsive HMPDA@Cu2-xSe cascade catalytic nanoplatform was constructed by assembling hollow mesoporous polydopamine (HMPDA) with ultra-small Cu2-xSe, which could compensate the inadequate NIR-II-induced PTT effect of HMPDA and enhance the efficacy of chemodynamic therapy (CDT) simultaneously under NIR-II laser irradiation. Meanwhile, doxorubicin (DOX) and glucose oxidase (GOx) were encapsulated into the synthesized HMPDA@Cu2-xSe using the photothermal-induced phase change material (PCM) tetradecyl (1-TD) as a gatekeeper to achieve the controlled release of the cargo. Under 1064 nm laser, the generated heat could cause 1-TD melting, resulting in the release of large amounts of DOX and GOx. The released GOx could further catalyze glucose to H2O2 and gluconic acid, which in turn promoted the effects of PTT/CDT and the release of drugs. In vitro and in vivo experiments showed that the synthesized HMPDA@Cu2-xSe-DOX-GOx@PCM (HMPC-D/G@PCM) nanosystem exhibited a significant tumor cell inhibition effect by combining different treatment modes. Thus, this smart nanoplatform with multiple stimuli-activated cascade reactions provided a new idea for designing effective multi-modal combination therapy for tumors.

Danlou Tablet Improves Chronic Intermittent Hypoxia-Induced Dyslipidemia and Arteriosclerosis by HIF-1α-Angptl4 mRNA Signaling Pathway.

OBJECTIVE: To detect whether Danlou Tablet (DLT) regulates the hypoxia-induced factor (HIF)-1α-angiopoietin-like 4 (Angptl4) mRNA signaling pathway and explore the role of DLT in treating chronic intermittent hypoxia (CIH)-induced dyslipidemia and arteriosclerosis. METHODS: The mature adipocytes were obtained from 3T3-L1 cell culturation and allocated into 8 groups including control groups (Groups 1 and 5, 0.1 mL of cell culture grade water); DLT groups (Groups 2 and 6, 0.1 mL of 1,000 µg/mL DLT submicron powder solution); dimethyloxalylglycine (DMOG) groups (Groups 3 and 7, DMOG and 0.1 mL of cell culture grade water); DMOG plus DLT groups (Groups 4 and 8, DMOG and 0.1 mL of 1,000 µg/mL DLT submicron powder solution). Groups 1-4 used mature adipocytes and groups 5-8 used HIF-1 α-siRNA lentivirus-transfected mature adipocytes. After 24-h treatment, real-time polymerase chain reaction and Western blot were employed to determine the mRNA and protein expression levels of HIF-1 α and Angptl4. In animal experiments, the CIH model in ApoE-/- mice was established. Sixteen mice were complete randomly divided into 4 groups including sham group, CIH model group [intermittent hypoxia and normal saline (2 mL/time) gavage once a day]; Angptl4 Ab group [intermittent hypoxia and Angptl4 antibody (30 mg/kg) intraperitoneally injected every week]; DLT group [intermittent hypoxia and DLT (250 mg/kg) once a day], 4 mice in each group. After 4-week treatment, enzyme linked immunosorbent assay was used to detect the expression levels of serum total cholesterol (TC) and triglyceride (TG). Hematoxylin-eosin and CD68 staining were used to observe the morphological properties of arterial plaques. RESULTS: Angptl4 expression was dependent on HIF-1 α, with a reduction in mRNA expression and no response in protein level to DMOG or DLT treatment in relation to siHIF-1 α -transfected cells. DLT inhibited HIF-1 α and Angptl4 mRNA expression (P<0.05 or P<0.01) and reduced HIF-1 α and Angptl4 protein expressions with DMOG in mature adipocytes (all P<0.01), as the effect on HIF-1 α protein also existed in the presence of siHIF-1 α (P<0.01). ApoE-/- mice treated with CIH had increased TG and TC levels (all P<0.01) and atherosclerotic plaque. Angptl4 antibody and DLT both reduce TG and TC levels (all P<0.01), as well as reducing atherosclerotic plaque areas, narrowing arterial wall thickness and alleviating atherosclerotic lesion symptoms to some extent. CONCLUSION: DLT had positive effects in improving dyslipidemia and arteriosclerosis by inhibiting Angptl4 protein level through HIF-1 α-Angptl4 mRNA signaling pathway.

Combination of targeted UVB phototherapy and calcipotriene versus targeted UVB alone in psoriasis: systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Targeted UVB and topical calcipotriene have frequently been used in the treatment of psoriasis, but the joint effect of calcipotriene and targeted UVB has been controversial. OBJECTIVES: The purpose of this study was to systematically evaluate whether the efficacy of the combined use of targeted UVB and calcipotriene is superior to the targeted UVB alone. METHODS: We performed systematic review and meta-analysis of randomized controlled trials (RCTs) in patients with plaque-type psoriasis through searching the defined key words in the PubMed, EMBase, and Cochrane Central Register databases. Pooled mean difference of the Psoriasis Area and Severity Index (PASI) relative change (%) was estimated using a random effect model. The quality of included studies and publication bias were assessed using the Jadad scale and the Egger's test, respectively. RESULTS: A total of five RCTs including 182 patients were included in the systematic review. The mean difference of the PASI relative change (%) between the combined therapy versus the targeted UVB alone was -22.68 (95%CI: -37.12 to -8.24; p = .002). Publication bias was not supported by the Egger's test (p = .424). CONCLUSION: Addition of calcipotriene ointment may improve the efficacy of the targeted UVB phototherapy in the treatment of plaque-type psoriasis.

A multifunctional nanoamplifier with self-enhanced acidity and hypoxia relief for combined photothermal/photodynamic/starvation therapy.

Phototherapies, including photothermal therapy (PTT) and photodynamic therapy (PDT) have been potential noninvasive therapeutic modality with high efficiency, however, there still exist some intrinsic limitations that impede their clinical applications. Herein, taking the advantages of the synergistic effect and high reactivity of manganese dioxide (MnO2) nanosheets and glucose oxidase (GOx), multifunctional MPDA@MnO2-MB-GOx nanoamplifier was constructed for enhanced PTT, PDT, and starvation therapy. In tumor microenvironment (TME), MnO2 nanosheets on the surface of mesoporous polydopamine (MPDA) could react with endogenous hydrogen peroxide (H2O2) and generate oxygen (O2) to relieve tumor hypoxia, thus enhancing the efficacy of PDT and GOx catalysis. Glucose consumption under the catalysis of GOx will enhance the acidity of TME and increase intracellular H2O2 concentration, which in turn promotes the production of O2 by MnO2 nanosheets, thus forming efficient cascade reaction and maximizing the efficacy of the functional agents. Furthermore, the heat generated by MPDA under the irradiation of 808 nm laser can accelerate chemical reactions, thus further enhancing synergistic therapeutic efficacy. In vitro/vivo results emphasize that enhanced cancer cell death and tumor inhibition are gained by modulating unfavorable TME with the functional nanosystem, which highlights the promise of the synthesized MPDA@MnO2-MB-GOx nanomaterial to overcome the limitations of phototherapy.

Chinese Herbal Medicines Prevent and Treat Atopic Dermatitis by Improving Skin Barrier： A Review / 中国实验方剂学杂志

Atopic dermatitis is a chronic， refractory and inflammatory skin disease with the clinical manifestations of severe pruritus and recurrent attacks. It has a high incidence and is closely correlated with other allergic， autoimmune or infectious diseases， which can cause a variety of secondary diseases and mental and psychological disorders， seriously affecting the life quality of patients. Chinese herbal medicines have been used for the prevention and treatment of atopic dermatitis for thousands of years， and many Chinese herbal medicines （including compound prescriptions） effective for this disease have been recorded. These medicines generally have little adverse reactions and the treated patients have low recurrence rate of atopic dermatitis. According to the evidence of modern medicine， the onset of atopic dermatitis is related to the impairment of skin barrier function， abnormal immune response， and abnormal differentiation of mast cells， antigen-presenting cells， and eosinophils. Additionally， it is associated with mental， endocrine， metabolic and other factors. The defect of skin barrier function and the dysfunction of immune system are the main pathogenesis of atopic dermatitis. In recent years， scientists have achieved certain progress in improving skin barrier function with Chinese herbal medicines. This paper systematically summarizes the studies about the application of Chinese herbal medicines in regulating the expression of epidermal proteins， epidermal lipids， aquaporins， tight junction proteins， and antimicrobial peptides in recent 10 years， aiming to clarify the pathological mechanism and provide reference for the clinical research and application of Chinese herbal medicines in the treatment of atopic dermatitis.