Xiaoer niuhuang qingxin powder alleviates influenza a virus infection by inhibiting the activation of the TLR4/MyD88/NF-κB signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Xiaoer Niuhuang Qingxin Powder (XNQP) is a classic traditional Chinese medicine formula with significant clinical efficacy for treating febrile convulsions and influenza. AIM OF THE STUDY: This study aims to explore the potential mechanisms of XNQP in combating combating the influenza A virus, providing a theoretical basis for its clinical application. MATERIALS AND METHODS: The present investigation employed network pharmacology and bioinformatics analysis to determine the TLR4/MyD88/NF-κB signaling pathway as a viable target for XNQP intervention in IAV infection.Subsequently, a mouse model of influenza A virus infection was established, and different doses of XNQP were used for intervention. The protein expression levels of TLR4/MyD88/NF-κB were detected using HE staining, Elisa, immunohistochemistry, immunofluorescence, and western blot. RESULTS: The results showed that treatment with XNQP after IAV infection reduced the mortality and prolonged the survival time of infected mice. It reduced the release of TNF-α and IFN-γ in the serum and alleviated pathological damage in the lung tissue following infection. Additionally, the levels of TLR4, MyD88, NF-κB, and p-NF-κB P65 proteins were significantly reduced in lung tissue by XNQP. The inhibitory effect of XNQP on the expression of MyD88 and NF-κB was antagonized when TLR4 signaling was overexpressed. Consequently, the expression levels of MyD88, NF-κB, and p-NF-κB P65 were increased in lung tissue. Conversely, the expression levels of the proteins MyD88, NF-κB, and p-NF-κB P65 were downregulated when TLR4 signaling was inhibited. CONCLUSIONS: XNQP alleviated lung pathological changes, reduced serum levels of inflammatory factors, reduced mortality, and prolonged survival time in mice by inhibiting the overexpression of the TLR4/MyD88/NF-κB signaling pathway in lung tissues after IAV infection.

An inorganic-organic-polymeric nanovehicle for targeting delivery of doxorubicin: Rational assembly, pH-stimulus release, and dual hyperthermia/chemotherapy of hepatocellular carcinoma.

Efficiently synergistic therapy of hepatocellular carcinoma (HCC) by chemotherapeutic drug and photothermal agent remains a considerable challenge. Here, we report a nanodrug that integrates specific hepatoma-targeted delivery, pH-triggered drug release, and cooperative photothermal-chemotherapy function. By grafting the easily self-assembled CuS@polydopamine (CuS@PDA) nanocapsulation with polyacrylic acid (PAA), an inorganic-organic-polymeric hybrid nanovehicle was developed as a dual photothermal agent and carrier for loading antitumor drug-doxorubicin (DOX) through electrostatic adsorption and chemical linking antibody against GPC3 commonly overexpressed in HCC, resulting in the nanodrug, CuS@PDA/PAA/DOX/GPC3. The multifunctional nanovehicle had excellent biocompatibility, stability, and high photothermal conversion efficiency, due to the rationally designed binary CuS@PDA photothermal agent. The 72-h accumulative drug release in pH 5.5 tumor microenvironment can reach up to 84%, far higher than 15% measured in pH 7.4 condition. Notably, in contrast to the merely 20% survival rate of H9c2 and HL-7702 cells exposed to free DOX, their viabilities in the nanodrug circumstance can maintain 54% and 66%, respectively, suggesting the abated toxicity to the normal cell lines. When exposed to the hepatoma-targeting nanodrug, the viability of HepG2 cells was found to be 36%, which further drastically declined to 10% plus 808-nm NIR irradiation. Moreover, the nanodrug is potent to cause tumor ablation in HCC-modeled mice, and the therapeutic efficacy can be greatly enhanced under NIR stimulus. Histology analyses reveal that the nanodrug can effectively alleviate the chemical damage to heart and liver, as compared to free DOX. This work thus offers a facile strategy for design of targeting anti-HCC nanodrug toward combined photothermal-chemotherapy.

Natural Compound Allicin Containing Thiosulfinate Moieties as Transmembrane Protein 16A (TMEM16A) Ion Channel Inhibitor for Food Adjuvant Therapy of Lung Cancer.

Cancer is one of the most serious malignant diseases, and chemotherapy is cancer's main clinical treatment method. However, chemotherapy inevitably produces drug resistance, and side effects accompany them. Adjuvant therapy is an effective way to enhance chemotherapeutic drug sensitivity and reduce side effects. This study found allicin, garlic's active ingredient, is an inhibitor of transmembrane protein 16A (TMEM16A), a novel drug target of lung adenocarcinoma. Allicin concentration-dependently inhibited TMEM16A currents with an IC50 of 24.35 ± 4.14 µM. Allicin thiosulfinate moieties bound with R535A/E624A/E633A residues of TMEM16A blocked the ion transport function and downregulated TMEM16A protein expression affecting the mitogen-activated protein kinase signal transduction. Then, allicin reduced the viability and migration of LA795 cells, and induced cell apoptosis. Moreover, multitarget combination administration results indicated that the therapeutic effect of 3.56 mg/kg allicin and 3 mg/kg cisplatin combined administration was superior to the superposition of the two drugs alone, demonstrating that the anticancer effects of allicin and cisplatin were synergistic. In addition, low-concentration combined administration also avoided the side effects of cisplatin in mice. Based on the good tumor suppressor effect and high biosafety of allicin and cisplatin combination in vivo, allicin can be used for food adjuvant therapy of cisplatin chemotherapy.

A Two-Pronged Strategy for Enhanced Deep-Tumor Penetration and NIR-II Multimodal Imaging-Monitored Photothermal Therapy.

The second near-infrared (NIR-II)-induced photothermal therapy (PTT) has attracted a great deal of attention in recent years due to its non-invasiveness and because it uses less energy. However, the penetration of photothermal agents into solid tumors is seriously impeded by the dense-tumor extracellular matrix (ECM) containing cross-linked hyaluronic acid (HA), thereby compromising the ultimate therapeutic effects. Herein, acid-labile metal-organic frameworks were employed as nanocarriers to efficiently mineralize hyaluronidase (HAase) and encapsulate Ag2S nanodots by a one-pot approach under mild conditions. The obtained nanocomposites (AHZ NPs) maintained enzyme activity and changed in size to prolong blood circulation and complete delivery of the cargo to the tumor. Moreover, the released HAase could specifically break out the HA to loosen ECM and enable the Ag2S nanodots to breeze through the tumor matrix space and gain access to the deep tumor. Under near-infrared laser irradiation, the AHZ NPs displayed remarkable fluorescence, outstanding photoacoustic signals, and excellent photothermal properties in the whole tumor. This work offers a promising two-pronged strategy via a decrease in nanoparticle size and the degradation of dense ECM for NIR-II multimodal imaging-guided PTT of deep tumors.

Caffeic Acid, an Active Ingredient in Coffee, Combines with DOX for Multitarget Combination Therapy of Lung Cancer.

Adjuvant diet therapy is an important means of comprehensive treatment of cancer. It is recognized by patients for its high safety, painlessness, and ease to operate. However, the development of adjuvant dietary therapy is limited by unclear targets and unclear anticancer mechanisms. In this work, caffeic acid was found as an inhibitor of TMEM16A with an IC50 of 29.47 ± 3.19 µM by fluorescence quenching and whole-cell patch-clamp experiments. Caffeic acid regulated the proliferation, migration, and apoptosis of lung cancer cells targeting TMEM16A, which was detected by CCK-8, colony formation, wound healing, and Annexin V assays. In addition, molecular docking combined with site-directed mutagenesis confirmed that the binding sites of caffeic acid to TMEM16A were D439, E448, and R753. Western blot results indicated that caffeic acid regulated the growth of lung cancer through the MAPK pathway. In vitro experiments showed that the inhibitory effect of caffeic acid combined with hydroxydaunorubicin (DOX) on lung cancer cell growth was better than a double concentration of any single dose. In vivo pharmacokinetic experiments and tumor xenograft experiments indicated that the combination of 5.4 mg/kg caffeic acid and 4.1 mg/kg DOX achieved 85.6% tumor suppression rate and offset the side effects. Therefore, caffeic acid is a safe and efficient antitumor active ingredient of food that can enhance the antitumor effect of DOX.

Rational assembly of RGD/MoS2/Doxorubicin nanodrug for targeted drug delivery, GSH-stimulus release and chemo-photothermal synergistic antitumor activity.

Herein, we present the facile design and construction of a nanodrug system integrating targeted drug delivery and synergistic chemo-photothermal antitumor activity. MoS2 nanosheets were synthesized and modified by ανß3 integrin binding peptide (Arg-Gly-Asp, RGD) using lipoic acid functionalized polyethylene glycol (LA-PEG-COOH), forming a well dispersed and targeted delivery nanocarrier. Further, covalent coupling of antitumor drug, thiolated doxorubicin (DOX) via disulfide linkage resulted in a novel nanodrug, RGD/MoS2/DOX. The prepared nanocarrier showed favorable stability, biocompatibility and photothermal conversion efficiency. Fluorescence imaging revealed that Hela cells could endocytose far more nanodrug than H9c2 normal myocardial cells due to the targeted delivery characteristic. Particularly, GSH-induced disulfide bond cleavage facilitated the effective release of DOX from the nanodrug in the tumor microenvironment. The survival rate of Hela cells incubated with the nanodrug for 48 h was 22.2 ± 1.2%, which dramatically reduced to 8.9 ± 1.4% in combination with 808 nm NIR irradiation, demonstrating powerful photothermal induced tumor-killing efficacy. In contrast, the survival rates of H9c2 cells treated by the nanodrug and free DOX were 68.5 ± 2.6% and 6.7 ± 2.6%, respectively, an indication of the notably alleviated cardiotoxicity of the designed nanodrug. The cell apoptosis experiment further verified the synergistic chemo-photothermal effect, thus paving a way toward design of high-efficiency and low-toxicity antitumor nanodrug.

Levels of trace blood elements associated with severe sleep disturbance in maintenance hemodialysis patients.

PURPOSE: Sleep disturbance is frequently observed in patients on maintenance hemodialysis (MHD), and this population usually presents imbalances in trace elements. We investigated the association between blood trace element levels and sleep quality in patients on MHD. METHODS: This cross-sectional and single-center study was performed in September 2019. Patients regularly undergoing hemodialysis for > 3 months at our center were recruited, and demographic, clinical, and laboratory parameters were recorded. The Pittsburgh Sleep Quality Index (PSQI) was applied to define sleep disturbance. Blood trace element (zinc, manganese, copper, selenium, and lead) levels were measured using an inductively coupled plasma mass spectrometer. RESULTS: In total, 121 patients on MHD (male/female = 68:53) were enrolled in the study (mean age 63.7 ± 13.9 years, median dialysis vintage 38.0 [20.0, 60.0] months). According to PSQI, 56 (46%) patients experienced severe sleep disturbance. These patients were characterized by older age, higher serum parathyroid hormone levels, and lower blood selenium levels (all P < 0.05). No significant differences in blood zinc, manganese, copper, and lead levels were observed between groups. Univariate binary logistic regression showed that lower blood selenium levels were associated with severe sleep disturbance (odds ratio = 0.976, 95% confidence interval: 0.954-0.999, P = 0.038). Multivariate analyses also confirmed the results after adjusting for confounding factors. CONCLUSION: Our study indicated an association between lower blood selenium levels and the occurrence of severe sleep disturbances in patients on MHD. However, a prospective study with a larger sample size and assessing the importance of selenium supplementation are needed to confirm the results.

Antioxidant and Inflammatory Effects of Nelumbo nucifera Gaertn. Leaves.

This study is aimed at identifying the bioactive components in lotus leaf flavonoid extract (LLFE) and analyzing the antioxidant and anti-inflammatory activities of LLFE in vitro and in vivo. The flavonoids in LLFE were determined by UHPLC-MS/MS. The effect of LLFE on damaged 293T cells (H2O2, 0.3 mmol/L) was determined by MTT assay, and the activity of antioxidant enzymes was measured by kits. We studied the antioxidant and anti-inflammatory effects of LLFE on D-Gal/LPS (30 mg/kg·bw and 3 µg/kg·bw)-induced aging mice. We also evaluated the main organ index, pathological changes in the liver, lung, and kidney, liver function index, biochemical index, cytokine level, and mRNA expression level in serum and liver. The results showed that LLFE contains baicalein, kaempferol, kaempferid, quercetin, isorhamnetin, hyperoside, lespenephryl, and rutin. LLFE reduced the oxidative damage sustained by 293T cells, increased the levels of SOD, CAT, GSH, and GSH-Px, and decreased the level of MDA. The animal studies revealed that LLFE reduced oxidative damage and inflammation in injured mice, inhibited increases in AST, ALT, MDA, and NO, increased SOD, CAT, GSH, and GSH-Px levels, upregulated anti-inflammatory cytokines IL-10 and IL-12, and downregulated proinflammatory cytokines IL-6, IL-1ß, TNF-α, and IFN-γ. Furthermore, the expression of antioxidant- and anti-inflammatory-related mRNA was consistent with the above results.

Parthenolide, an NF-κB inhibitor, alleviates peritoneal fibrosis by suppressing the TGF-ß/Smad pathway.

Transforming growth factor (TGF)-ß/Smad signalling plays a central role in the pathogenesis of peritoneal fibrosis related to peritoneal dialysis (PD). Parthenolide (PTL), a naturally occurring phytochemical, is isolated from the shoots of feverfew (Tanacetum parthenium) and displays analgesia, anti-inflammation and anticancer activities. In this study, we examined the therapeutic potential of PTL on PD-related peritoneal fibrosis induced by daily intraperitoneal injection of 4.25% dextrose-containing PD fluid (PDF) in vivo and TGF-ß1-induced epithelial-mesenchymal transition (EMT) in vitro. PTL was administered daily before PDF injection or after 14 days of PDF injection. Both PTL treatments showed a protective effect on peritoneal fibrosis and prevented peritoneal dysfunction. Similarly, PTL suppressed the expression of fibrotic markers (fibronectin and collagen I) and restored the expression of the epithelial marker (E-cadherin) in TGF-ß1-treated HMrSV5 cells. Furthermore, PTL inhibited TGF-ß1-induced Smad2 and Smad3 phosphorylation and nuclear translocation but did not influence Smad1/5/9 phosphorylation or activate other downstream signalling pathways of TGF-ß1, including AKT, extracellular signal-regulated kinase (ERK) or p38. In conclusion, PTL treatment may represent an effective and novel therapy for PD-associated peritoneal fibrosis by suppressing the TGF-ß/Smad pathway.

Micheliolide ameliorates diabetic kidney disease by inhibiting Mtdh-mediated renal inflammation in type 2 diabetic db/db mice.

Diabetic kidney disease (DKD) is the principal cause of end-stage renal disease worldwide and few treatments are available. Because immunomodulators are pivotal to DKD pathophysiology, anti-inflammatory agents may be useful for treating DKD. This study was conducted to investigate the effect of micheliolide (MCL), a novel guaianolide sesquiterpene lactone with well-known anti-inflammatory effects, on DKD. Treatment with dimethylaminomicheliolide (DMAMCL), the pro-drug of MCL currently under clinical trial in oncology, protected the kidneys against proteinuria, renal failure, histopathological injury, and inflammation in db/db mice. This effect was associated with metadherin (Mtdh) downregulation. We observed aberrant upregulation of Mtdh in the kidneys of db/db mice and high-glucose (HG)-induced mouse tubular epithelial cells (mTECs). Downregulation of Mtdh obviously inhibited nuclear factor-κB signaling activation and suppressed its downstream inflammatory cytokines, such as monocyte chemotactic peptide-1, interleukin-1ß, tumor necrosis factor-α, and interleukin-6 in HG-induced mTECs, which was similar to the effect of MCL. Mtdh overexpression largely reversed the anti-inflammatory role of MCL. Moreover, MCL downregulated Mtdh by both inhibiting the transcription level and promoting ubiquitin-mediated degradation. These findings suggest that DMAMCL is a promising anti-inflammatory agent useful for preventing renal injury in DKD by inhibiting Mtdh-mediated renal inflammation.

Dimethylaminomicheliolide ameliorates peritoneal fibrosis through the activation of autophagy.

Peritoneal fibrosis (PF) is a major cause of ultrafiltration failure in patients receiving long-term peritoneal dialysis (PD), and effective prevention and treatment strategies are urgently needed. The dimethylamino Michael adduct of a natural product-derived micheliolide (MCL), dimethylaminomicheliolide (DMAMCL), is a new lead compound with the advantages of high stability, low toxicity, and sustainable release of MCL. This study aimed to investigate the protective effect of DMAMCL against PD-related PF and the mechanisms involved. In this study, we found that DMAMCL significantly decreased PD-induced extracellular matrix (ECM) deposition in a mouse model of PD, and that delayed DMAMCL administration halted the progression of PF in an established PD model. In addition, rapamycin administration induced autophagy and significantly ameliorated PF. The protective effect of DMAMCL against PF was weakened when co-administered with DMAMCL and 3-methyladenine. Inducing autophagy by rapamycin decreased transforming growth factor-ß1-induced ECM accumulation in vitro. MCL promoted autophagy and inhibited ECM deposition. The anti-fibrotic effect of MCL was eliminated when knocking down ATG7 by siRNA. Taken together, DMAMCL might prevent against PF through activating autophagy. The anti-fibrotic effect of DMAMCL may be a new candidate for the treatment in patients with PD-related PF. KEY MESSAGES: Dimethylaminomicheliolide, the pro-drug of micheliolide, protects against peritoneal fibrosis in a mouse peritoneal dialysis model. Micheliolide inhibits TGF-ß1-induced extracellular matrix accumulation in vitro. Autophagy plays a protective role against peritoneal fibrosis. The antifibrogenic effect of dimethylaminomicheliolide may be due to the activation of autophagy.

Gender differences in anomalous subcortical morphology for children with ADHD.

Although studies showed subtle reductions in brain volume in fronto-striatial regions in children with ADHD, there have been limited investigations of volume and lateralizaton in subcortical structures and a paucity of exploration of the influence of gender on these findings. This study aims to examine morphology of subcortical structures and their association with ADHD symptoms in boys and girls as compared to their typically-developing (TD) peers. One hundred and eighty five children aged 7-14 years with and without ADHD were included from ADHD-200 Consortium. Results showed that compared to TD boys, boys with ADHD had reduced accumbens, amygdala and hippocampus volumes. There were no volumetric differences in any structure between ADHD and TD girls. Asymmetry analysis revealed right lateralization compressions within the thalamus in ADHD boys relative to TD boys. The findings suggest a gender dimorphic pattern of differences in subcortical structures in children with ADHD, and a possible neurobiological mechanism where boys with ADHD demonstrate increasing difficulties with hyperactivity/impulsivity.