[Mechanism of Biejiajian Pills against non-alcoholic steatohepatitis based on lipidomics].

This study aims to explore the potential mechanism of Biejiajian Pills in the treatment of non-alcoholic steatohepatitis(NASH) based on lipidomics. A mouse model of NASH was induced by high-fat/high cholesterol diet, and the mice of the normal group were fed with a normal diet. The therapeutic efficacy of Biejiajian Pills against NASH was evaluated through biochemical indexes in both of serum and liver, as well as the hepatic histopathology. Lipid metabolites in the liver were detected by ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry(UPLC-Q-TOF-MS)-based lipidomics. Then the partial least-squares discriminant analysis, t-test and receiver operating characteristic curve analysis were performed to screen the differential lipid metabolites and the main biomarkers. The proteins and genes involved in the lipid metabolism and inflammatory response were detected by Western blot and qPCR. The results demonstrated that Biejiajian Pills notably lowered the levels of alanine aminotransferase(ALT), aspartate aminotransferase(AST), and alkaline phosphatase(ALP) in the serum and the levels of triglyceride(TG) and total cholesterol(TC) in the liver tissue. In addition, Biejiajian Pills alleviated the lipid accumulation, hepatocyte ballooning, and liver fibrosis. Lipidomics revealed that Biejiajian Pills regulated the content of 11 biomarkers including phosphatidyl choline(PC), phosphatidyl ethanolamine(PE), sphingomyelin(SM), and ceramide(Cer). The results of Western blot and qPCR demonstrated that Biejiajian Pills regulated the expression of sterol regulatory element-binding protein 1(SREBP1), peroxisome proliferator-activated receptor gamma(PPARγ) and phospho-AMP-activated protein kinase(p-AMPK), and the mRNA level of fatty acid translocase 36 gene(Cd36), Pparγ, cardiolipin synthase 1 gene(Crls1), and phospholipase Cß2 gene(Plcß2). Furthermore, Biejiajian Pills displayed inhibitory effects on phospho-p38 MAPK(p-p38 MAPK) and phospho-ERK1/2(p-ERK1/2) and the mRNA levels of interleukin-6 gene(Il-6), interleukin-1ß gene(Il-1ß) and tumor necrosis factor-α gene(Tnf-α). In conclusion, Biejiajian Pills could alleviate the lipid metabolism disorders and regulate the expression of SREBP1, PPARγ, and p-AMPK and the mRNA levels of pro-inflammatory cytokines.

Distinct Assembly Patterns of Soil Antibiotic Resistome Revealed by Land-Use Changes over 30 Years.

Compared with the ever-growing information about the anthropogenic discharge of nutrients, metals, and antibiotics on the disturbance of antibiotic resistance genes (ARGs), less is known about how the potential natural stressors drive the evolutionary processes of antibiotic resistance. This study examined how soil resistomes evolved and differentiated over 30 years in various land use settings with spatiotemporal homogeneity and minimal human impact. We found that the contents of soil organic carbon, nitrogen, soil microbial biomass, and bioavailable heavy metals, as well as related changes in the antibiotic resistome prevalence including diversity and abundance, declined in the order of grassland > cropland > bareland. Sixty-nine remaining ARGs and 14 mobile genetic elements (MGEs) were shared among three land uses. Multiple factors (i.e., soil properties, heavy metals, bacterial community, and MGEs) contributed to the evolutionary changes of the antibiotic resistome, wherein the resistome profile was dominantly driven by MGEs from both direct and indirect pathways, supported by a partial least-squares path model analysis. Our results suggest that pathways to mitigate ARGs in soils can coincide with land degradation processes, posing a challenge to the common goal of managing our environment sustainably.

[Effect of Naotaifang on microglial polarization and glial scar following cerebral ischemia reperfusion injury].

This study aims to investigate the effect of Naotaifang(NTF) on the proteins associated with microglial polarization and glial scar in the rat model of cerebral ischemia reperfusion injury(CIRI). The CIRI model was established by middle cerebral artery occlusion/reperfusion. The 48 successfully modeled rats were randomized into model 7 d, model 14 d, NTF 7 d, and NTF 14 d groups(n=12). In addition, 12 SD rats were selected as the sham group. The NTF group was administrated with NTF suspension at 27 g·kg~(-1)·d~(-1) by gavage, and the sham, model 7 d, and model 14 d groups were administrated with the same volume of normal saline every day by gavage for 7 and 14 days, respectively. After the intervention, Longa score was evaluated. The infarct volume was measured by 2,3,5-triphenyl-2H-tetrazolium chloride(TTC) staining. Morris water maze and open field tests were carried out to evaluate the spatial learning, memory, cognitive function, and anxiety degree of rats. Hematoxylin-eosin(HE) staining was employed to observe the morphological structure and damage of the brain tissue. The immunofluorescence assay was employed to measure the expression of glial fibrillary acidic protein(GFAP) and glial scar. Western blot was employed to determine the protein levels of GFAP, neurocan, phosphacan, CD206, arginase-1(Arg-1), interleukin(IL)-1ß, IL-6, and IL-4. Compared with the sham, model 7 d and model 14 d groups showed cerebral infarction of different degrees, severe pathological injury of cerebral cortex and hippocampus, neurological impairment, reduced spatial learning and memory, cognitive dysfunction, severe anxiety, astrocyte hyperplasia, thickening penumbra glial scar, and up-regulated protein levels of IL-1ß, IL-6, GFAP, neurocan, phosphacan, CD206, and Arg-1(P<0.01). Compared with the model group, NTF 7 d and NTF 14 d groups improved spatial learning, memory, and cognitive function, reduced anxiety, improved nerve function, reduced cerebral infarction volume, reduced astrocyte hyperplasia, thinned penumbra glial scar, down-regulated the protein levels of GFAP, neurocan, phosphacan, IL-6, and IL-1ß, and up-regulated the protein levels of IL-4, CD206, and Arg-1(P<0.05 or P<0.01). NTF exerts a neuroprotective effect on CIRI by inducing the M2 polarization of microglia, inhibiting inflammatory response, and reducing the formation of glial scar.

Influence of blood glucose fluctuations on chemotherapy efficacy and safety in type 2 diabetes mellitus patients complicated with lung carcinoma.

BACKGROUND: Patients with type 2 diabetes mellitus (T2DM) have large fluctuations in blood glucose (BG), abnormal metabolic function and low immunity to varying degrees, which increases the risk of malignant tumor diseases and affects the efficacy of tumor chemotherapy. Controlling hyperglycemia may have important therapeutic implications for cancer patients. AIM: To clarify the influence of BG fluctuations on chemotherapy efficacy and safety in T2DM patients complicated with lung carcinoma (LC). METHODS: The clinical data of 60 T2DM + LC patients who presented to the First Affiliated Hospital of Ningbo University between January 2019 and January 2021 were retrospectively analyzed. All patients underwent chemotherapy and were grouped as a control group (CG; normal BG fluctuation with a mean fluctuation < 3.9 mmol/L) and an observation group (OG; high BG fluctuation with a mean fluctuation ≥ 3.9 mmol/L) based on their BG fluctuations, with 30 cases each. BG-related indices, tumor markers, serum inflammatory cytokines and adverse reactions were comparatively analyzed. Pearson correlation analysis was performed to analyze the correlation between BG fluctuations and tumor markers. RESULTS: The fasting blood glucose and 2-hour postprandial blood glucose levels in the OG were notably elevated compared with those in the CG, together with markedly higher mean amplitude of glycemic excursions (MAGE), mean of daily differences, largest amplitude of glycemic excursions and standard deviation of blood glucose (P < 0.05). In addition, the OG exhibited evidently higher levels of carbohydrate antigen 19-9, carbohydrate antigen 125, carcinoembryonic antigen, neuron-specific enolase, cytokeratin 19, tumor necrosis factor-α, interleukin-6, and high-sensitivity C-reactive protein than the CG (P < 0.05). Pearson analysis revealed a positive association of MAGE with serum tumor markers. The incidence of adverse reactions was significantly higher in the OG than in the CG (P < 0.05). CONCLUSION: The greater the BG fluctuation in LC patients after chemotherapy, the more unfavorable the therapeutic effect of chemotherapy; the higher the level of tumor markers and inflammatory cytokines, the more adverse reactions the patient experiences.

Ascorbic acid potentiates photodynamic inactivation mediated by octyl gallate and blue light for rapid eradication of planktonic bacteria and biofilms.

This study reported for the first time that Ascorbic acid (AA) could appreciably boost the efficiency of Octyl gallate (OG)-mediated photodynamic inactivation (PDI) on Escherichia coli and Staphylococcus aureus in planktonic and biofilm states. The combination of OG (0.075 mM) and AA (200 mM) with 420 nm blue light (212 mW/cm2) led to a >6 Log killing within only 5 min for E. coli and S. aureus and rapid eradication of biofilms. The mechanism of action appears to be the generation of highly toxic hydroxyl radicals (•OH) via photochemical pathways. OG was exposed to BL irradiation to generate various reactive oxygen radicals (ROS) and the addition of AA could transform singlet oxygen (1O2) into hydrogen peroxide (H2O2), which could further react with AA to generate enormous •OH. These ROS jeopardized bacteria and biofilms by nonspecifically attacking various biomacromolecules. Overall, this PDI strategy provides a powerful microbiological decontamination modality to guarantee safe food products.

A dual data stream hybrid neural network for classifying pathological images of lung adenocarcinoma.

Lung cancer has seriously threatened human health due to its high lethality and morbidity. Lung adenocarcinoma, in particular, is one of the most common subtypes of lung cancer. Pathological diagnosis is regarded as the gold standard for cancer diagnosis. However, the traditional manual screening of lung cancer pathology images is time consuming and error prone. Computer-aided diagnostic systems have emerged to solve this problem. Current research methods are unable to fully exploit the beneficial features inherent within patches, and they are characterized by high model complexity and significant computational effort. In this study, a deep learning framework called Multi-Scale Network (MSNet) is proposed for the automatic detection of lung adenocarcinoma pathology images. MSNet is designed to efficiently harness the valuable features within data patches, while simultaneously reducing model complexity, computational demands, and storage space requirements. The MSNet framework employs a dual data stream input method. In this input method, MSNet combines Swin Transformer and MLP-Mixer models to address global information between patches and the local information within each patch. Subsequently, MSNet uses the Multilayer Perceptron (MLP) module to fuse local and global features and perform classification to output the final detection results. In addition, a dataset of lung adenocarcinoma pathology images containing three categories is created for training and testing the MSNet framework. Experimental results show that the diagnostic accuracy of MSNet for lung adenocarcinoma pathology images is 96.55 %. In summary, MSNet has high classification performance and shows effectiveness and potential in the classification of lung adenocarcinoma pathology images.

Four New Species and One New Record of Thelephora from China.

Species of the genus Thelephora (Thelephorales, Thelephoraceae) are ectomycorrhizal symbionts of coniferous and broad-leaved plants, and some of them are well-known edible mushrooms, making it an exceptionally important group ecologically and economically. However, the diversity of the species from China has not been fully elucidated. In this study, we conducted a phylogenetic analysis based on the internal transcribed spacer (ITS) regions, using Maximum Likelihood and Bayesian analyses, along with morphological observations of this genus. Four new species from China are proposed, viz., T. dactyliophora, T. lacunosa, T. petaloides, and T. pinnatifida. In addition, T. sikkimensis originally described from India is reported for the first time from China. Thelephora dactyliophora, T. pinnatifida, and T. sikkimensis are distributed in subtropical forests and mainly associated with plants of the families Fagaceae and Pinaceae. Thelephora lacunosa and T. petaloides are distributed in tropical to subtropical forests. Thelephora lacunosa is mainly associated with plants of the families Fagaceae and Pinaceae, while T. petaloides is mainly associated with plants of the family Fagaceae. Line drawings of microstructures, color pictures of fresh basidiomes, and detailed descriptions of these five species are provided.

Mechanisms for the biological activity of Gastrodia elata Blume and its constituents: A comprehensive review on sedative-hypnotic, and antidepressant properties.

BACKGROUND: Insomnia and depressive disorder are two common symptoms with a reciprocal causal relationship in clinical practice, which are usually manifested in comorbid form. Several medications have been widely used in the treatment of insomnia and depression, but most of these drugs show non-negligible side effects. Currently, many treatments are indicated for insomnia and depressive symptom, including Chinese herbal medicine such as Gastrodia elata Blume (G. elata), which has excellent sedative-hypnotic and antidepressant effects in clinical and animal studies. PURPOSE: To summarize the mechanisms of insomnia and depression and the structure-activity mechanism for G. elata to alleviate these symptoms, particularly by hypothalamic-pituitary-adrenal (HPA) axis and intestinal flora, aiming to discover new approaches for the treatment of insomnia and depression. METHODS: The following electronic databases were searched from the beginning to November 2023: PubMed, Web of Science, Google Scholar, Wanfang Database, and CNKI. The following keywords of G. elata were used truncated with other relevant topic terms, such as depression, insomnia, antidepressant, sedative-hypnotic, neuroprotection, application, safety, and toxicity. RESULTS: Natural compounds derived from G. elata could alleviate insomnia and depressive disorder, which is involved in monoamine neurotransmitters, inflammatory response, oxidative stress, and gut microbes, etc. Several clinical trials showed that G. elata-derived natural compounds that treat depression and insomnia have significant and safe therapeutic effects, but further well-designed clinical and toxicological studies are needed. CONCLUSION: G. elata exerts a critical role in treating depression and insomnia due to its multi-targeting properties and fewer side effects. However, more clinical and toxicological studies should be performed to further explore the sedative-hypnotic and antidepressant mechanisms of G. elata and provide more evidence and recommendations for its clinical application. Our review provides an overview of G. elata treating insomnia with depression for future research direction.

The Interplay between Mitochondrial Dysfunction and Ferroptosis during Ischemia-Associated Central Nervous System Diseases.

Cerebral ischemia, a leading cause of disability and mortality worldwide, triggers a cascade of molecular and cellular pathologies linked to several central nervous system (CNS) disorders. These disorders primarily encompass ischemic stroke, Alzheimer's disease (AD), Parkinson's disease (PD), epilepsy, and other CNS conditions. Despite substantial progress in understanding and treating the underlying pathological processes in various neurological diseases, there is still a notable absence of effective therapeutic approaches aimed specifically at mitigating the damage caused by these illnesses. Remarkably, ischemia causes severe damage to cells in ischemia-associated CNS diseases. Cerebral ischemia initiates oxygen and glucose deprivation, which subsequently promotes mitochondrial dysfunction, including mitochondrial permeability transition pore (MPTP) opening, mitophagy dysfunction, and excessive mitochondrial fission, triggering various forms of cell death such as autophagy, apoptosis, as well as ferroptosis. Ferroptosis, a novel type of regulated cell death (RCD), is characterized by iron-dependent accumulation of lethal reactive oxygen species (ROS) and lipid peroxidation. Mitochondrial dysfunction and ferroptosis both play critical roles in the pathogenic progression of ischemia-associated CNS diseases. In recent years, growing evidence has indicated that mitochondrial dysfunction interplays with ferroptosis to aggravate cerebral ischemia injury. However, the potential connections between mitochondrial dysfunction and ferroptosis in cerebral ischemia have not yet been clarified. Thus, we analyzed the underlying mechanism between mitochondrial dysfunction and ferroptosis in ischemia-associated CNS diseases. We also discovered that GSH depletion and GPX4 inactivation cause lipoxygenase activation and calcium influx following cerebral ischemia injury, resulting in MPTP opening and mitochondrial dysfunction. Additionally, dysfunction in mitochondrial electron transport and an imbalanced fusion-to-fission ratio can lead to the accumulation of ROS and iron overload, which further contribute to the occurrence of ferroptosis. This creates a vicious cycle that continuously worsens cerebral ischemia injury. In this study, our focus is on exploring the interplay between mitochondrial dysfunction and ferroptosis, which may offer new insights into potential therapeutic approaches for the treatment of ischemia-associated CNS diseases.

Ultraefficient OG-Mediated Photodynamic Inactivation Mechanism for Ablation of Bacteria and Biofilms in Water Augmented by Potassium Iodide under Blue Light Irradiation.

While photodynamic inactivation (PDI) has emerged as a novel sterilization strategy for drinking water treatment that recently attracted tremendous attention, its efficiency needs to be further improved. In this study, we aimed to clarify the ultraefficient mechanism by which potassium iodide (KI) potentiates octyl gallate (OG)-mediated PDI against bacteria and biofilms in water. When OG (0.15 mM) and bacteria were exposed to blue light (BL, 420 nm, 210 mW/cm2), complete sterilization (>7.5 Log cfu/mL of killing) was achieved by the addition of KI (250 mM) within only 5 min (63.9 J/cm2). In addition, at lower doses of OG (0.1 mM) with KI (100 mM), the biofilm was completely eradicated within 10 min (127.8 J/cm2). The KI-potentiated mechanism involves in situ rapid photogeneration of a multitude of reactive oxygen species, especially hydroxyl radicals (•OH), reactive iodine species, and new photocytocidal substances (quinone) by multiple photochemical pathways, which led to the destruction of cell membranes and membrane proteins, the cleavage of genomic DNA and extracellular DNA within biofilms, and the degradation of QS signaling molecules. This multitarget synergistic strategy provided new insights into the development of an environmentally friendly, safe, and ultraefficient photodynamic drinking water sterilization technology.

Magnetic biochar/quaternary phosphonium salt reduced antibiotic resistome and pathobiome on pakchoi leaves.

Antibiotic resistance genes (ARGs) and human pathogenic bacteria (HPB) in leafy vegetable is a matter of concern as they can be transferred from soil, atmosphere, and foliar sprays, and poses a potential risk to public health. While traditional disinfection technologies are effective in reducing the presence of ARGs and HPB in soil. A new technology, foliar spraying with magnetic biochar/quaternary ammonium salt (MBQ), was demonstrated and applied to the leaf surface. High-throughput quantitative PCR targeting 96 valid ARGs and 16 S rRNA sequencing were used to assess its efficacy in reducing ARGs and HPB. The results showed that spraying MBQ reduced 97.0 ± 0.81% of "high-risk ARGs", associated with seven classes of antibiotic resistance in pakchoi leaves within two weeks. Water washing could further reduce "high-risk ARGs" from pakchoi leaves by 19.8%- 24.6%. The relative abundance of HPB closely related to numerous ARGs was reduced by 15.2 ± 0.23% with MBQ application. Overall, this study identified the potential risk of ARGs from leafy vegetables and clarified the significant implications of MBQ application for human health as it offers a promising strategy for reducing ARGs and HPB in leafy vegetables.

SIX1 induced HULC modulates neuropathic pain and Schwann cell oxidative stress after sciatic nerve injury.

Neuropathic pain is a severe and debilitating condition caused by damage to the peripheral nerve or central nervous system. Although several mechanisms have been identified, the underlying pathophysiology of neuropathic pain is still not fully understood. Unfortunately, few effective therapies are available for this condition. Therefore, there is an urgent need to investigate the underlying mechanisms of neuropathic pain to develop more effective treatments. Long non-coding RNAs (lncRNAs) have recently gained attention due to their potential to modulate protein expression through various mechanisms. LncRNAs have been implicated in many diseases, including neuropathic pain. This study aimed to identify a novel lncRNA involved in neuropathic pain progression. The lncRNA microarray analysis showed that lncRNA Upregulated in Liver Cancer (HULC) was significantly upregulated in spinal cord tissue of sciatic nerve injury (SNI) rats. Further experiments confirmed that HULC promoted neuropathic pain progression and aggravated H2O2-induced Schwann cell injury. Mechanistically, Sine Oculis Homeobox 1 (SIX1) regulated the transcriptional expression of HULC, and both SIX1 and HULC were involved in neuropathic pain and Schwann cell injury. The results of our research indicate the existence of a previously unknown SIX1/HULC axis that plays a significant role in the development and progression of neuropathic pain, shedding light on the complex mechanisms that underlie this debilitating condition. These findings offer novel insights into the molecular pathways involved in neuropathic pain. This study underscores the potential of targeting lncRNAs as a viable approach to alleviate the suffering of patients with neuropathic pain.

Structural Evolution of Giant Polyoxometalate: From "Keplerate" to "Lantern" Type Mo132 for Improved Oxidation Catalysis.

Structural variants of high-nuclearity clusters are extremely important for their modular assembly study and functional expansion, yet the synthesis of such giant structural variants remains a great challenge. Herein, we prepared a lantern-type giant polymolybdate cluster (L-Mo132 ) containing equal metal nuclearity with the famous Keplerate type Mo132 (K-Mo132 ). The skeleton of L-Mo132 features a rare truncated rhombic triacontrahedron, which is totally different with the truncated icosahedral K-Mo132 . To the best of our knowledge, this is the first time to observe such structural variants in high-nuclearity cluster built up of more than 100 metal atoms. Scanning transmission electron microscopy reveals that L-Mo132 has good stability. More importantly, because the pentagonal [Mo6 O27 ]n- building blocks in L-Mo132 are concave instead of convex in the outer face, it contains multiple terminal coordinated water molecules on its outer surface, which make it expose more active metal sites to display superior phenol oxidation performance, which is more higher than that of K-Mo132 coordinated in M=O bonds on the outer surface.

Regulated High-Spin State and Constrained Charge Behavior of Active Cobalt Sites in Covalent Organic Frameworks for Promoting Electrocatalytic Oxygen Reduction.

A novel type of covalent organic frameworks has been developed by assembling definite cobalt-nitrogen-carbon configurations onto carbon nanotubes using linkers that have varying electronic effects. This innovative approach has resulted in an efficient electrocatalyst for oxygen reduction, which is understood by a combination of in situ spectroelectrochemistry and the bond order theorem. The strong interaction between the electron-donating carbon nanotubes and the electron-accepting linker mitigates the trend of charge loss at cobalt sites, while inducing the generation of high spin state. This enhances the adsorption strength and electron transfer between the cobalt center and reactants/intermediates, leading to an improved oxygen reduction capability. This work not only presents an effective strategy for developing efficient non-noble metal electrocatalysts through reticular chemistry, but also provides valuable insights into regulating the electronic configuration and charge behavior of active sites in designing high-performance electrocatalysts.

Azidobenziodazolones as Azido Sources for the Enantioselective Copper-Catalyzed Azidation of N-Unprotected 3-Trifluoromethylated Oxindoles.

Both azido (N3) and trifluoromethyl (CF3) groups are key moieties of numerous valuable molecules that are extensively applied in drug discovery, chemical biology, and synthetic chemistry. However, the asymmetric construction of chiral quaternary stereocenters bearing both N3 and CF3 groups is still unexplored. Herein, we report a kind of bench-stable and easily adjustable benziodazolone-based azidating reagents. These reagents were used to achieve an enantioselective copper-catalyzed azidation of N-unprotected 3-trifluoromethylated oxindoles to provide diverse enantioenriched 3-N3-3-CF3 oxindoles.

[Effect of a novel phosphodiesterase 5 inhibitor, CPD1, on renal interstitial fibrosis after unilateral renal ischemia-reperfusion injury].

This study was designed to evaluate the protective effect of CPD1, a novel phosphodiesterase 5 inhibitor, on renal interstitial fibrosis after unilateral renal ischemia-reperfusion injury (UIRI). Male BALB/c mice were subjected to UIRI, and treated with CPD1 once daily (i.g, 5 mg/kg). Contralateral nephrectomy was performed on day 10 after UIRI, and the UIRI kidneys were harvested on day 11. Hematoxylin-eosin (HE), Masson trichrome and Sirius Red staining methods were used to observe the renal tissue structural lesions and fibrosis. Immunohistochemical staining and Western blot were used to detect the expression of proteins related to fibrosis. HE, Sirius Red and Masson trichrome staining showed that CPD1-treated UIRI mice had lower extent of tubular epithelial cell injury and deposition of extracellular matrix (ECM) in renal interstitium compared with those in the fibrotic mouse kidneys. The results from immunohistochemistry and Western blot assay indicated significantly decreased protein expressions of type I collagen, fibronectin, plasminogen activator inhibitor-1 (PAI-1) and α-smooth muscle actin (α-SMA) after CPD1 treatment. In addition, CPD1 dose-dependently inhibited the expression of ECM-related proteins induced by transforming growth factor ß1 (TGF-ß1) in normal rat kidney interstitial fibroblasts (NRK-49F) and human renal tubular epithelial cell line (HK-2). In summary, the novel PDE inhibitor, CPD1, displays strong protective effects against UIRI and fibrosis by suppressing TGF-ß signaling pathway and regulating the balance between ECM synthesis and degradation through PAI-1.

A rapid approach to capture the potential bioactive compounds from Rhizoma Drynariae, utilizing disease-associated mutation in calcium sensing receptor to alter the binding affinity for agonists.

Rhizoma Drynariae (RD) was used clinically to treat osteoporosis in China due to stimulating bone formation and inhibiting bone resorption, however, the bioactive constituents with the dual effect on bone are still unknown exactly. Disease-causing mutations in calcium sensing receptor (CaSR) can alter parathyroid hormone secretion and affect Ca2+ release from bone and Ca2+ reabsorption from kidney, which gives an indication that CaSR is a potential target for developing therapeutics to manage osteoporosis. Herein, a chromatographic approach was established, by immobilizing the mutant CaSR onto the surface of silica gels as stationary phase in a one-step procedure and then adding the different amino acids into mobile phase as competitors, for exploring the binding features of the known agonists and further screening ligands from RD. The mutant CaSR-coated column was prepared rapidly without the complicated purification and separation of the receptor, which had the large capacity of 13.1 mg CaSR /g silica gels and kept a good stability and specificity for at least 35 days. The CaSR mutation can weaken the binding affinities for three agonists, and the largest decreases occurred on the mutational site Thr151Met for neomycin, on the two sites of Asn118Lys and Glu191Lys for gentamicin-C, and on the site Phe612Ser for kanamycin, which gained new insights into their structure-function relationship. The potential bioactive compounds from RD were screened using the mutant CaSR-coated column and were recognized as coumaric acid 4-O-ß-D-glucopyranoside, caffeic acid, and naringin using UPLC-MS. Among them, naringin targeting CaSR gives a possible explanation that RD could manage osteoporosis. These results indicated that, such a rapid and simple method, utilizing disease-associated mutation in CaSR to alter the binding affinity for agonists, can be applied in capturing the potential bioactive compounds efficiently from complex matrices like herb medicines.

Tongguanteng injection reverses paclitaxel resistance via upregulation of TAB1 expression in ovarian cancer in vitro and in vivo.

ETHNOPHARMACOLOGICAL RELEVANCE: Tongguanteng injection (TGT), the water extract from the stem of the Traditional Chinese hebal medicine of Marsdenia tenacissima (Roxb.) Wight et Arn. has been used as anticancer remedy for decades. TGT was not only used in the treatment of many malignant cancers extensively, but also an adjuvant anticancer drug with chemotherapeutics clinically. AIM OF THE STUDY: To evaluate the effects of TGT on reversing paclitaxel (PTX) resistance and investigate the potential mechanism related to TAB1 in ovarian cancer (OC) in vitro and in vivo. MATERIALS AND METHODS: The synergistic effect and reversal ratio were determined by CCK8 assay and median-effect principle after the combination of TGT and PTX in OC A2780 and its PTX-resistant (A2780/T) cells. The biological functions in cell apoptosis, migration and invasion of A2780/T cells treated by PTX 4 µM with TGT 20, 40, 80 mg⋅mL-1 for 24 h were evaluated by colony formation, flow cytometry, wound healing and transwell assays. Proteomics technique and bioinformatic analysis were used to indentify the change of TAB1 expression in A2780/T cells induced by TGT. The association between TAB1 expression and human OC was analyzed by gene expression databases. In A2780/T cells, western blotting and colony formation assays were used to investigate the relationship between TAB1 expression and PTX resistance after TAB1 overexpression by TAB1 plasmids. The mechanism of TGT and PTX regulating TAB1 and its related proteins were explored by western blotting and flow cytometry assays after TAB1 knock-down using siTAB1. Moreover, TUNEL staining, immunohistochemistry (IHC) and histopathology were used to observe the antitumor effects, TAB1 and p-p38 expression and the tissues impairments in nude mice xenograft model established by A2780/T cells after the co-treatment with TGT and PTX by in vivo. RESULTS: TGT combined with PTX showed the synergistic effect (CI<1), which could reverse the IC50 values of PTX in OC A2780 and A2780/T cells about 23.50 and 6.44 times, respectively. Besides, TGT combined with PTX could significantly inhibit the migration, invasion and promote apoptosis of A2780/T cells. We identified that TGT could induce TAB1 expression in A2780/T cells by proteomics analysis. TAB1 downregulation was significantly associated with tumorigenesis and poor prognosis in OC patients and PTX resistance in A2780/T cells. Furthermore, TGT could activate TAB1/TAK1/p38 MAPK signaling pathway targeting TAB1 and regulate the expression of Bax, Bcl-2 proteins to improve the sensitivity of A2780/T cells to PTX. TGT combined with PTX also showed a greater inhibition in tumor growth than PTX monotherapy in vivo. These promising results show the efficacy of TGT in reversing PTX resistance and provide a potential strategy that targeting TAB1/TAK1/p38 MAPK signaling pathway may improve the chemotherapy sensitivity in OC. CONCLUSIONS: Our results revealed that Tongguanteng injection could reverse paclitaxel resistance and the potential mechanism might be associated with the activation of TAB1/TAK1/p38 MAPK signaling pathway in OC in vitro and in vivo. TAB1 might be a pivotal target for reversing PTX resistance. This study will provide a theoretical basis for the combination of Tongguanteng injection and paclitaxel in clinic.

Manure- and straw-derived biochars reduce the ecological risk of PBDE and promote nitrogen cycling by shaping microbiomes in PBDE-contaminated soil.

Pyrolysis of agricultural waste into biochar for soil remediation is a useful solid waste management strategy. However, it is still unclear how different agricultural feedstocks affect the properties of biochars and their effectiveness in remediation of PBDE-contaminated soil. In this study, we systematically investigated dynamic alterations of soil properties, microbial communities, and PBDE dissipation and bioavailability induced by the application of biochars from manure (MBC) and straw (SBC) to PBDE-contaminated soil. The results showed that soil properties, microbial community structure, and diversity changed differently with the incorporation of the two biochars. MBC had a larger surface area (17.4 m2/g) and a higher nutrient content (45.1% ash content), making it more suitable for use as a soil additive to improve soil quality and nutrient conditions, as well as to stimulate microbial growth. SBC showed higher adsorption capacity for 2,2',4,4'-Tetrabromodiphenyl Ether (BDE-47) (26.73 ± 0.65 mg/g), thus lowering the bioavailability and ecological risk of BDE-47 in soil. BDE-47 was stepwise debrominated into lower brominated PBDE by PBDE-degrading bacteria. MBC accelerated the debromination of BDE-47 (10.1%) by promoting PBDE-degrading microorganisms, while this was inhibited by SBC (3.5%) due to strong adsorption of BDE-47. In addition, we found that both types of biochar favored Nitrospirae bacteria and promoted N cycling. Overall, biochars from manure and straw can positively shape soil microbial communities differently by altering soil properties, soil fertility and nutrient availability, and the fate and the effects of contaminants, which ultimately led to a difference in the potential of biochars for their use in soil remediation.