Remediation of cadmium contaminated soil using electrokinetic-phytoremediation system with rotary switching electrodes.

Considering both electrokinetic remediation and phytoremediation have limitations, an electrokinetic phytoremediation (EP) system was constructed to obtain efficient and environmentally friendly remediation results. This study indicates that the electric field can promote the absorption of Cd by ryegrass with little impact on soil physicochemical properties under the condition of rotary switching electrodes, and the accumulation of Cd in the aboveground and underground parts of ryegrass increased by 145.2% and 93.7%, respectively. The DC electric field combined with ryegrass under rotary switching electrode mode proved to be the optimal condition for the remediation of Cd contaminated soil with a remediation efficiency of 66.7%. Moreover, the rotary switching of the electrodes alleviated the suppression of the growth of ryegrass by the DC electric field. During the EP remediation process, the electric field promoted the transformation of the residue state of Cd to the other forms, which accelerated the desorption rate of Cd from the soil and facilitated the migration of Cd into plants. In conclusion, EP is a green and efficient remediation technology for heavy metal contaminated soil with good application prospects.

A meta-analysis of the risk factors for lateral epicondylitis.

BACKGROUND: Very few meta-analyses discussed risk factors for lateral epicondylitis (LE), and previous meta-analyses reached conflicting conclusions with each other on some specific risk factors. PURPOSE: To investigate the risk factors for LE through meta-analysis. STUDY DESIGN: Meta-analysis. METHODS: PubMed, Embase, and Web of Science databases were searched for relevant studies in January 2022. Raw data were extracted into a predefined worksheet, and quality analysis was conducted by the Quality in Prognosis Studies (QUIPS) tool. Pooled effect sizes and 95% confidence intervals were calculated. R package "meta" was used for statistical analysis. RESULTS: 22 studies were included in the meta-analysis. Female sex (odds ratio [OR]=1.33 and p-value<0.05), smoking history (OR=1.46 and p-value<0.001), manual labor (OR=2.39 and p-value<0.001), and hypercholesterolemia (OR=1.67 and p-value<0.05) were significant risk factors for LE. CONCLUSIONS: Female gender, smoking history, manual labor, and hypercholesterolemia could increase the risk of LE. According to an additional literature review, statin treatment for hypercholesterolemia is described as potentially related to the development of LE.

Properties and mechanisms of steel slag strengthening microbial cementation of cyanide tailings.

The advantages of microbial induced carbonate precipitation (MICP) as bio-cementation technology for tailings-solidification are under extensive investigation. In order to improve performance of bio-cementation, many strengthening materials were applied to the bio-cementation of tailings. Steel slag (SS) is a kind of industrial solid waste, its chemical composition and mineral composition are similar to cement, and it has a certain application prospect as an auxiliary cementing material. In this study, the properties and mechanism of SS strengthening MICP cementation of cyanide tailings (CT) were investigated. The results showed that Sporosarcina pasteurii growth is not inhibited by SS, and Sporosarcina pasteurii can promote the hydration reaction of SS, providing a suitable alkaline environment and Ca2+, promoting the production of more CaCO3 in the MICP process. When 200 mL of CT leachate was added 1.4 g SS (200-400 mesh), the adsorption of Cu, Pb, Zn, Cd, total cyanide (T-CN), and free cyanide (F-CN) reached 48.05%, 44.28%, 36.25%, 16.67%, 79.05%, and 67.20%, respectively. The maximum unconfined compressive strength（UCS） of the cemented body (with 5%, 150 mesh SS) was 1.97 MPa, which was 3.396 times as high as that without SS. The cemented body with the addition of SS (5%, 150 mesh) contained more carbonate bound Cu (2.75%), Pb (4.89%), Zn (5.37%), and Cd (5.75%), and less exchangeable Cu (3.65%), Pb (6.85%), Zn (2.27%), and Cd (4.42%) than that without SS. In summary, the addition of SS improved the UCS of cemented bodies and the stability of heavy metals and cyanide, reduced the environmental risks existing in the process of CT storage. Meanwhile, it also provides new ideas for resource utilization of industrial solid waste SS and improvement of mine filling materials.

Sulfidated nanoscale zero valent iron for in situ immobilization of hexavalent chromium in soil and response of indigenous microbes.

This study aimed to investigate the immobilization efficiency of sulfidated nanoscale zero valent iron on Cr(VI) in soil. Reactions between sulfidated nanoscale zero valent iron and Cr(VI) in soil system and effects of sulfidated nanoscale zero valent iron on microbes had been demonstrated. Solid characterization results confirmed the incorporation of sulfur into nanoscale zero valent iron. Furthermore, the main oxidation products of iron after the reactions were magnetite, goethite and lepidocrocite. Fe-Cr complexes indicated that Cr(VI) was reduced to Cr(III). The results of 16 S rRNA gene analysis indicated that the sulfidated nanoscale zero valent iron had a limited bactericidal effect but further stimulated the sulfite reductase gene population, representing its positive effect for the soil remediation. The study showed that some microflora such as Protobacteria were promoted, while others community such as Firmicutes, were depressed. Furthermore, Cr mainly converted from a high toxic state such as exchangeable (EX) to less bioavailable state such as iron-manganese oxides bound (OX) and organic matter-bound (OM), thus reducing the toxicity of Cr when sulfidated nanoscale zero valent iron was added. High immobilization efficiency of the Cr(VI) compared to nanoscale zero valent iron indicated an improvement on selectivity and reactivity after sulfidation. Overall, sulfidated nanoscale zero valent iron was promising for the immobilization of Cr(VI) immobilization soil.

Efficient Removal of Antimony(V) from Antimony Mine Wastewater by Micrometer Zero-Valent Iron.

This paper investigates the effectiveness of two commercial micron zero-valent irons (mZVIs) in removing Sb(V) from antimony mine wastewater. The wastewater contains a range of complex components and heavy metal ions, including As(V), which can impact the removal efficiency of mZVI. The study aims to provide insights into actual working conditions and focuses on influencing factors and standard conditions. The results demonstrate that mZVI can reduce Sb(V) concentration in the mine wastewater from 3875.7 µg/L to below the drinking water standard of 5 µg/L within 2 h. Adding a small amount of mZVI every 30 min helps to maintain a high removal rate. The study confirms the existence of a reduction reaction by changing the atmospheric conditions of the reaction, and the addition of 1,10-phenanthroline highlights the important role of active Fe(II) in the adsorption and removal of Sb(V) by mZVI. Additionally, the paper presents an innovative experimental method of acid treatment followed by alkali treatment, which proves the interfacial reaction between mZVI and Sb(V). Overall, the study demonstrates that the removal of Sb(V) by mZVI entails a dual function of reduction and adsorption, highlighting the potential of mZVI in repairing Sb(V) in antimony mine wastewater.

Long-term effectiveness of conservative management for lateral epicondylitis: a meta-analysis.

OBJECTIVE: To investigate the long-term (>12 months) effectiveness of conservative management for lateral epicondylitis. DATA SOURCES: PubMed and Embase databases were searched for relevant studies from inception to March 2023. STUDY SELECTION AND DATA EXTRACTION: Only English-written randomized controlled trial (RCT) with data download as well as follow up ≥12 months were acceptable. Raw data were extracted into a predefined worksheet, and quality analysis was conducted based on the Cochrane risk-of-bias tool version 2 (RoB2). DATA SYNTHESIS: The standardized mean difference (SMD) with 95% confidence interval (CI) were calculated. RESULTS: Extracorporeal shock wave therapy (ESWT) could significantly relive pain for lateral epicondylitis patients in the long term (SMD: -0.19, 95% CI [-0.36, -0.02]); however, there was no significant difference between ESWT and control groups in long-term function outcome (SMD: 0.24, 95% CI [-0.02, -0.49]). No significant difference could be observed between (1) exercise and control groups in pain (SMD: -0.21, 95% CI [-0.60, 0.18]) or function (SMD: 0.06, 95% CI [-0.11, 0.23]), (2) corticosteroids and placebo groups in pain (SMD: 0.70, 95% CI [-0.43, 1.82]) or function (SMD: -0.02, 95% CI [-0.36, 0.31]), and (3) platelet-rich plasma (PRP) in pain (SMD: -0.30, 95% CI [-0.85, 0.25]) and function (SMD: -0.08, 95% CI [-0.78, 0.62]). CONCLUSION: The present conventional conservative management for lateral epicondylitis, with the exception of ESWT, a lack adequate evidence supporting their long-term effectiveness.

Effect and mechanism of kaolinite loading amorphous zero-valent iron to stabilize cadmium in soil.

Amorphousness effectively improves the electron transfer rate of zero-valent iron. In this study, a novel kaolinite loading amorphous zero-valent iron composite (K-AZVI) was prepared and applied to the remediation of soils with cadmium (Cd) pollution concentrations of 20, 50, and 100 mg/kg respectively. The results showed that the application of K-AZVI increased the pH and cation exchange capacity (CEC) of soil, and decreased the dissolved organic carbon (DOC) and organic matter (OM) of soil, thus indirectly promoting the adsorption of Cd in the soil. After 28 days of stabilization, the stabilizing efficiency of K-AZVI on the water-soluble Cd content in soil reached 98.72 %. Under the amendment of 0.25 %-1.0 % (w/w), the available Cd content in 20-100 mg/kg contaminated soil decreased by 46.47 %-62.23 %, 24.10 %-41.52 %, and 16.09 %-30.51 % respectively compared with CK. More importantly, the addition of K-AZVI promoted the transformation of 33.18 %-48.42 % exchangeable fraction (EXC) to 10.09 %-20.14 % residual fraction (RES), which increased the abundance and diversity of soil bacterial communities. Comprehensive risk assessment showed that adding 1.0 % K-AZVI provided the best remediation on contaminated soil. In addition, the results of scanning electron microscopy (SEM), X-ray diffraction (XRD), and X-ray photoelectron spectroscopy (XPS) of K-AZVI before and after the reaction showed that the stabilization mechanism of K-AZVI to Cd in soil is mainly the stable metal species (Cd(OH)2, CdO and CdFe2O4) formed by the direct complexation and coprecipitation of a large number of iron oxides formed by the rapid corrosion of amorphous zero-valent iron (AZVI). Overall, this work provides a promising approach to the remediation of Cd-contaminated soil using K-AZVI composites.

Blocking LTB4 signaling-mediated TAMs recruitment by Rhizoma Coptidis sensitizes lung cancer to immunotherapy.

BACKGROUND: Immune checkpoint blockade (ICB) induces durable immune responses across a spectrum of advanced cancers and revolutionizes the oncology field. However, only a subset of patients achieves long-lasting clinical benefits. Tumor-associated macrophages (TAMs) usually secrete immunosuppressive cytokines and contribute to the failure of ICB therapy. Therefore, it is crucial to mechanically manipulate the abundance and function of TAMs in the tumor microenvironment (TME), which can offer a promising molecular basis to improve the clinical response efficacy of ICB in cancer patients. PURPOSE: This study aims to investigate TAMs in the immunosuppressive microenvironment to identify new therapeutic targets, improve the ability to predict and guide responses to clinical immunotherapy, and develop new strategies for immunotherapy of lung tumors. METHODS: Lewis lung carcinoma (LLC) xenograft-bearing mouse models were established to analyze the antitumor activity of Rhizoma Coptidis (RC) in vivo. A systems pharmacology strategy was used to predict the correlation between RC and M2 macrophages. The effect of RC on the abundance of M2 macrophages was analyzed by flow cytometry of murine samples. Western blot was performed to analyze the expression of Leukotriene A4 hydrolase (LTA4H) and LTB4 receptor 1 (BLT1) in harvested lung cancer tissues. The impact of blocking leukotriene B4 (LTB4) signaling by RC on the recruitment of M2 macrophages was assessed in vitro and in vivo. Transwell migration assays were conducted to clarify the inhibition of macrophage migration by blocking LTB4. Lta4h-/- mice were used to investigate the sensitivity of immunotherapy to lung cancer by blocking the LTB4 signaling. RESULTS: Here, we report that RC, an herbal medicine from the family Ranunculaceae, suppresses the recruitment and immunosuppressive function of TAMs, which in turn sensitizes lung cancer to ICB therapy. Firstly, a systems pharmacology strategy was proposed to identify combinatorial drugs for ICB therapy with a systems biology perspective of drug-target-pathway-TME phenotype. We predicted and verified that RC significantly inhibits tumor growth and the infiltration of M2-TAMs into TME of LLC tumor-bearing mice. Then, RC inhibits the recruitment of macrophages to the tumor TME via blocking LTB4 signaling, and suppresses the expression of immunosuppressive factors (IL-10, TGF-ß and VEGF). As a result, RC enables CD8+ T cells to retain their proliferative and infiltrative abilities within the TME. Ultimately, these events promote cytotoxic T-cell-mediated clearance of tumor cells, which is further enhanced by the addition of anti-PD-L1 therapy. Furthermore, we employed LTA4H deficient mice (Lta4h-/- mice) to evaluate the antitumor efficiency, the results showed that the efficacy of immunotherapy was enhanced due to the synergistic effect of LTB4 signaling blockage and ICB inhibition, leading to remarkable inhibition of tumor growth in a mouse model of lung adenocarcinoma. CONCLUSIONS: Taken together, these findings suggest that RC enhances antitumor immunity, providing a rationale for combining RC with immunotherapies as a potential anti-cancer treatment strategy.

Physicochemical Effects of Sulfur Precursors on Sulfidated Amorphous Zero-Valent Iron and Its Enhanced Mechanisms for Cr(VI) Removal.

Amorphous zerovalent iron (AZVI) has gained considerable attention due to its remarkable reactivity, but there is limited research on sulfidated amorphous zerovalent iron (SAZVI) and the influence of different sulfur precursors on its reactivity remains unclear. In this study, SAZVI materials with an amorphous structure were synthesized using various sulfur precursors, resulting in significantly increased specific surface area and hydrophobicity compared to AZVI. The Cr(VI) removal efficiency of SAZVI-Na2S, which exhibited the most negative free corrosion potential (-0.82 V) and strongest electron transfer ability, was up to 8.5 times higher than that of AZVI. Correlation analysis revealed that the water contact angle (r = 0.87), free corrosion potential (r = -0.92), and surface Fe(II) proportion (r = 0.98) of the SAZVI samples played crucial roles in Cr(VI) removal. Furthermore, the enhanced elimination ability of SAZVI-Na2S was analyzed, primarily attributed to the adsorption of Cr(VI) by the FeSx shell, followed by the rapid release of internal electrons to reduce Cr(VI) to Cr(III). This process ultimately led to the precipitation of FeCr2O4 and Cr2S3 on the surface of SAZVI-Na2S, resulting in their removal from the water. This study provides insights into the influence of sulfur precursors on the reactivity of SAZVI and offers a new strategy for designing highly active AZVI for efficient Cr(VI) removal.

Fabricating Amorphous Zero-Valent Iron for Cr(VI) Efficient Reduction: Unveiling the Effect of Ethylenediamine on Physicochemical Properties.

Amorphous zero-valent iron (AZVI) has attracted wide attention due to its high-efficiency reduction ability. However, the effect of different EDA/Fe(II) molar ratios on the physicochemical properties of the synthesized AZVI requires further investigation. Herein, series of AZVI samples were prepared by changing the molar ratio of EDA/Fe(II) to 1/1 (AZVI@1), 2/1 (AZVI@2), 3/1 (AZVI@3), and 4/1 (AZVI@4). When the EDA/Fe(II) ratio increased from 0/1 to 3/1, the Fe0 proportion on the AZVI surface increased from 26.0 to 35.2% and the reducing ability was enhanced. As for AZVI@4, the surface was severely oxidized to form a large amount of Fe3O4, and the Fe0 content was only 74.0%. Moreover, the removal ability of Cr(VI) was in the order AZVI@3 > AZVI@2 > AZVI@1 > AZVI@4. The isothermal titration calorimetry results revealed that the increase of the molar ratio of EDA/Fe(II) would lead to the stronger complexation of EDA with Fe(II), which resulted in the gradual decrease of the yield of AZVI@1 to AZVI@4 and the gradual deterioration of water pollution after the synthesis. Therefore, based on the evaluation of all indicators, AZVI@2 was the optimal material, not only because its yield was as high as 88.7% and the secondary water pollution level was low, but most importantly, the removal efficiency of Cr(VI) by AZVI@2 was excellent. Furthermore, the actual Cr(VI) wastewater with the concentration of 14.80 mg/L was treated with AZVI@2, and the removal rate of 97.0% was achieved after only a 30 min reaction. This work clarified the effect of different ratios of EDA/Fe(II) on the physicochemical properties of AZVI, which provided insights for guiding the reasonable synthesis of AZVI and is also conducive to investigating the reaction mechanism of AZVI in Cr(VI) remediation.

Treatment outcomes of tendinitis of long head of the biceps brachii tendon by different surgeries based on the concept of enhanced recovery after surgery.

OBJECTIVES: This study aims to evaluate the therapeutic effects of tenotomy and tenodesis of the long head of the biceps brachii tendon (LHBT) under shoulder arthroscopy based on the concept of enhanced recovery after surgery (ERAS) on long head of the biceps (LHB) tendinitis. PATIENTS AND METHODS: Between January 2019 and January 2021, a total of 80 LHB tendinitis patients (44 males, 36 females; mean age: 55.3±4.5 years; range, 45 to 72 years) were included. The patients were randomly divided into the group of tenotomy of LHBT under shoulder arthroscopy (tenotomy group, n=40) and group of tenodesis of LHBT under shoulder arthroscopy (tenodesis group, n=40). Tenotomy group was randomly subdivided into Tenotomy-1 and Tenotomy-2 groups including 20 patients in each group to receive conventional treatment and treatment plan guided by ERAS concept, respectively. Similarly, the tenodesis group was randomly subdivided into Tenodesis-1 and Tenodesis-2 groups including 20 patients in each group. Their postoperative shoulder joint functions and pain were compared. RESULTS: The Visual Analog Scale score showed a significant difference between Tenotomy-1 group and Tenodesis-1 group at one, three, and six months after surgery (p<0.05). However, there was no significant difference at nine months after surgery (p>0.05). In the tenotomy group, although the operation time was shorter, the patients were more prone to develop Popeye deformity after surgery. The American Shoulder and Elbow Surgeon score, Western Ontario Rotator Cuff Index, Constant-Murley shoulder score had no significant differences between the tenotomy and tenodesis groups; however, there was a significant difference between the conventional treatment group (Tenotomy-1 group and Tenodesis-1 group) and ERAS treatment group (Tenotomy-2 group and Tenodesis-2 group) (p<0.05). CONCLUSION: The clinical efficacy is similar between tenotomy and tenodesis of LHBT under shoulder arthroscopy. While selecting surgical approaches, comprehensive assessment should be performed based on all conditions of patients. Besides, therapeutic schedules should be upgraded and optimized with the help of the ERAS concept after admission to minimize the pain of patients, reduce the potential risk of surgery, and help patients recover quickly.

Circ_0062582 promotes osteogenic differentiation of human bone marrow mesenchymal stem cells in vitro by elevating SMAD5 expression through sponging miR-197-3p.

Circular RNAs (circRNAs) play crucial roles in many human diseases. However, the functions of circRNAs in osteoporosis (OP) are barely reported. In this study, we aimed to explore the function of circ_0062582 in osteogenic differentiation of human bone marrow mesenchymal stem cells (hBMSCs) in vitro. Circ_0062582 and SMAD5 were downregulated and miR-197-3p was upregulated in OP patients and increased in osteoblast medium (OM)-induced hBMSCs in vitro. Circ_0062582 knockdown inhibited the viability and osteogenic differentiation of hBMSCs. Circ_0062582 directly targeted miR-197-3p and miR-197-3p inhibition reversed the effects of circ_0062582 on hBMSC viability and osteogenic differentiation. SMAD5 was the target gene of miR-197-3p. SMAD5 overexpression promoted the viability and osteogenic differentiation of hBMSCs and attenuated miR-197-3p-mediated suppressive roles in hBMSC viability and osteogenic differentiation. In conclusion, circ_0062582 sponged miR-197-3p to elevate SMAD5 expression, thereby inducing hBMSC proliferation and osteogenic differentiation in vitro.

Platycodon grandiflorum Triggers Antitumor Immunity by Restricting PD-1 Expression of CD8+ T Cells in Local Tumor Microenvironment.

In the tumor microenvironment (TME), the activation of programmed death-1 (PD-1)-programmed death ligand-1 (PD-L1) pathway is one of the main signals of immune escape and tumor deterioration. Clinically, the application of monoclonal antibodies slows down the progression of various malignancies and prolongs the survival of patients effectively. However, these treatments result in serious immune-related adverse events (irAEs) owning to systemic immune activation. Therefore, to achieve long-term therapeutic effects and low side effects, it is necessary to find drugs inhibiting the local PD-1/PD-L1 signaling pathway of the TME. Here, we discovered that Platycodon grandiflorum (PG), a medicine and food homology herb, reduced the expression of PD-1 on the surface of CD8+ T cells to exert antitumor effects in non-small cell lung cancer (NSCLC). Firstly, by combining systems pharmacology strategies and clinical data analysis, we found that PG has the potential to immunomodulate T cells and suppress tumors. Secondly, in vivo and in vitro experiments have confirmed the antitumor effect of the combination of Platycodin D and Platycodin D3, which is preferred and representative of the compounds. Mechanistically, PG increased the infiltration and killing activity of CD8+ T cells, which was related to the decrease of PD-1+ CD8+ T cells. Furthermore, we confirmed that PG regulated the expression of PD-1 on the surface of CD8+ T cells via reducing the secretion of VEGF-A regulated by the level of P-STAT3 in tumor cells. Additionally, PG also positively impacted the biological processes downstream of STAT3. Overall, we demonstrated that PG-mediated downregulation of PD-1 on the surface of CD8+ T cells represents a promising strategy to locally enhance T-cell responses and improve antitumor immunity.

Licorice extract inhibits growth of non-small cell lung cancer by down-regulating CDK4-Cyclin D1 complex and increasing CD8+ T cell infiltration.

BACKGROUND: Targeting tumor microenvironment (TME) may provide therapeutic activity and selectivity in treating cancers. Therefore, an improved understanding of the mechanism by which drug targeting TME would enable more informed and effective treatment measures. Glycyrrhiza uralensis Fisch (GUF, licorice), a widely used herb medicine, has shown promising immunomodulatory activity and anti-tumor activity. However, the molecular mechanism of this biological activity has not been fully elaborated. METHODS: Here, potential active compounds and specific targets of licorice that trigger the antitumor immunity were predicted with a systems pharmacology strategy. Flow cytometry technique was used to detect cell cycle profile and CD8+ T cell infiltration of licorice treatment. And anti-tumor activity of licorice was evaluated in the C57BL/6 mice. RESULTS: We reported the G0/G1 growth phase cycle arrest of tumor cells induced by licorice is related to the down-regulation of CDK4-Cyclin D1 complex, which subsequently led to an increased protein abundance of PD-L1. Further, in vivo studies demonstrated that mitigating the outgrowth of NSCLC tumor induced by licorice was reliant on increased antigen presentation and improved CD8+ T cell infiltration. CONCLUSIONS: Briefly, our findings improved the understanding of the anti-tumor effects of licorice with the systems pharmacology strategy, thereby promoting the development of natural products in prevention or treatment of cancers.

Predicting the herbal medicine triggering innate anti-tumor immunity from a system pharmacology perspective.

Although the main focus of immuno-oncology has been manipulating the adaptive immune system, tumor associated macrophages (TAMs) are the main infiltrating component in the tumor microenvironment (TME) and play a critical role in cancer progression. TAMs are mainly divided into two different subtypes: macrophages with antitumor or killing activity are called M1 while tumor-promoting or healing macrophages are named M2. Therefore, controlling the polarization of TAMs is an important strategy for cancer treatment, but there is no particularly effective means to regulate the polarization process. Here, combined systems pharmacology targets and pathways analysis strategy, we uncovered Scutellariae Radix (SR) has the potential to regulate TAMs polarization to inhibit the growth of non-small cell lung cancer (NSCLC). Firstly, systems pharmacology approach was used to reveal the active components of SR targeting macrophages in TME through compound target prediction and target-microenvironment phenotypic association analysis. Secondly, in vitro experiment verified that WBB (wogonin, baicalein and baicalin), major active ingredients of SR are significantly related to macrophages and survival, initiated macrophages programming to M1-like macrophages to promoted the apoptosis of tumor cells. Finally, we evidenced that WBB effectively inhibited tumor growth in LLC (Lewis lung carcinoma) tumor-bearing mice and increased the infiltration of M1-type macrophages in TME. Overall, the systems pharmacology strategy offers a paradigm to understand the mechanism of polypharmacology of natural products targeting TME.

Systems pharmacology: a combination strategy for improving efficacy of PD-1/PD-L1 blockade.

Targeting tumor microenvironment (TME), such as immune checkpoint blockade (ICB), has achieved increased overall response rates in many advanced cancers, such as non-small cell lung cancer (NSCLC), however, only in a fraction of patients. To improve the overall and durable response rates, combining other therapeutics, such as natural products, with ICB therapy is under investigation. Unfortunately, due to the lack of systematic methods to characterize the relationship between TME and ICB, development of rational immune-combination therapy is a critical challenge. Here, we proposed a systems pharmacology strategy to identify resistance regulators of PD-1/PD-L1 blockade and develop its combinatorial drug by integrating multidimensional omics and pharmacological methods. First, a high-resolution TME cell atlas was inferred from bulk sequencing data by referring to a high-resolution single-cell data and was used to predict potential resistance regulators of PD-1/PD-L1 blockade through TME stratification analysis. Second, to explore the drug targeting the resistance regulator, we carried out the large-scale target fishing and the network analysis between multi-target drug and the resistance regulator. Finally, we predicted and verified that oxymatrine significantly enhances the infiltration of CD8+ T cells into TME and is a powerful combination agent to enhance the therapeutic effect of anti-PD-L1 in a mouse model of lung adenocarcinoma. Overall, the systems pharmacology strategy offers a paradigm to identify combinatorial drugs for ICB therapy with a systems biology perspective of drug-target-pathway-TME phenotype-ICB combination.

NOGEA: A Network-oriented Gene Entropy Approach for Dissecting Disease Comorbidity and Drug Repositioning.

Rapid development of high-throughput technologies has permitted the identification of an increasing number of disease-associated genes (DAGs), which are important for understanding disease initiation and developing precision therapeutics. However, DAGs often contain large amounts of redundant or false positive information, leading to difficulties in quantifying and prioritizing potential relationships between these DAGs and human diseases. In this study, a network-oriented gene entropy approach (NOGEA) is proposed for accurately inferring master genes that contribute to specific diseases by quantitatively calculating their perturbation abilities on directed disease-specific gene networks. In addition, we confirmed that the master genes identified by NOGEA have a high reliability for predicting disease-specific initiation events and progression risk. Master genes may also be used to extract the underlying information of different diseases, thus revealing mechanisms of disease comorbidity. More importantly, approved therapeutic targets are topologically localized in a small neighborhood of master genes in the interactome network, which provides a new way for predicting drug-disease associations. Through this method, 11 old drugs were newly identified and predicted to be effective for treating pancreatic cancer and then validated by in vitro experiments. Collectively, the NOGEA was useful for identifying master genes that control disease initiation and co-occurrence, thus providing a valuable strategy for drug efficacy screening and repositioning. NOGEA codes are publicly available at https://github.com/guozihuaa/NOGEA.

Systems pharmacology dissection of Epimedium targeting tumor microenvironment to enhance cytotoxic T lymphocyte responses in lung cancer.

The clinical notably success of immunotherapy fosters an enthusiasm in developing drugs by enhancing antitumor immunity in the tumor microenvironment (TME). Epimedium, is a promising herbal medicine for tumor immunotherapy due to the pharmacological actions in immunological function modulation and antitumor. Here, we developed a novel systems pharmacology strategy to explore the polypharmacology mechanism of Epimedium involving in targeting TME of non-small cell lung cancer (NSCLC). This strategy integrates the active compounds screening, target predicting, network pharmacology analysis and onco-immune interacting to predict the potential active compounds that trigger the antitumor immunity. Icaritin (ICT), a major active ingredient of Epimedium, was predicted to have good drug-like properties and target immune microenvironment in NSCLC via regulating multiple targets and pathways. Then, we evidenced that the ICT effectively inhibited tumor growth in LLC tumor-bearing mice and increases the infiltration of CD8+ T cells in TME. In addition, we demonstrated that ICT promotes infiltration of CD8+ T cells in TME by downregulating the immunosuppressive cytokine (TNF-α, IL10, IL6) and upregulating chemotaxis (CXCL9 and CXCL10). Overall, the systems pharmacology strategy offers an important paradigm to understand the mechanism of polypharmacology of natural products targeting TME.

Systems pharmacology unravels the synergic target space and therapeutic potential of Rhodiola rosea L. for non-small cell lung cancer.

BACKGROUND: Lung cancer is the most common and mortal cancer worldwide. Rhodiola rosea L. (RR), a well-known traditional Chinese medicine (TCM), has been turned out to be effective in anti-lung cancer therapy, but its molecular mechanism of action has not been clearly understood. PURPOSE: In this study, we aimed to elucidate the possible molecular mechanism underlying the effect of RR against non-small cell lung cancer (NSCLC) by systems pharmacology. METHODS: The effects of RR on NSCLC were examined in Lewis lung carcinoma (LLC) tumor-bearing mice models. The possible molecular mechanism was unraveled by systems pharmacology, which includes pharmacokinetics evaluation, active compounds screening, target prediction and network analysis. Cell proliferation was examined by cell counting kit-8 (CCK-8) assay; cell apoptosis was detected by flow cytometry; protein and proinflammatory cytokines expression were evaluated by Western blot and qRT-PCR. RESULTS: In vivo, RR significantly inhibited the tumor growth and prolonged the survival of the tumor bearing mice. In silico, we identified 19 potential active molecules (e.g., salidroside and rhodiosin), 112 targets (e.g., COX-2 and AKT) and 27 pathways (e.g., PI3K/AKT signaling pathway and NF-κB signaling pathway) for RR. Additionally, targets analysis and networks construction further revealed that RR exerted anti-cancer effects by regulating apoptosis, angiogenesis and inflammation. In vitro, salidroside could significantly decrease expression of pro-angiogenic factors (e.g., VEGF and eNOS) and proinflammatory cytokines (e.g., COX-2, iNOS and TNF-α). Also, Bcl-2, an anti-apoptotic protein was decreased whereas Bax, a pro-apoptotic protein, was increased. Further flow cytometry analysis showed that salidroside could induce apoptosis in H1975 cells. CONCLUSIONS: Mechanistically, the antitumor effect of RR on NSCLC was responsible for the synergy among anti-inflammatory, anti-angiogenic and pro-apoptotic.

Effect of pH on the adsorption of arsenic(V) and antimony(V) by the black soil in three systems: Performance and mechanism.

Arsenic (As) and antimony (Sb) are listed as the priority pollutants by the U.S. Environmental Protection Agency (EPA) and the European Union (EU) due to their toxicity and potential carcinogenicity. It is necessary to investigate their adsorption over soil as such a behavior affects their mobility and bioavailability. In this study, the effect of pH on the adsorption of As(V) and Sb(V) by the black soil was investigated with three systems: the Single system, Binary system, and Sequence system. The operating pH was set at 4.0, 7.0 and 10.0. Based on the Langmuir isothermal and the pseudo-second-order kinetic models, the adsorption for As(V) was always better than Sb(V) in the whole pH range; the best adsorption performance for the two sorbates was achieved at pH of 4.0, followed by 7.0 and 10.0 in the three systems. The reasons could be that the atomic radius of arsenic is smaller than that of antimony, and the positively charged functional groups carried by the inorganic colloids in the soil contributed to binding with the negatively charged As(V)/Sb(V). A lower pH promoted the inorganic colloids to carry more positive charges. Compared to Single system, the maximum adsorption capacity (qm) and the initial adsorption rates (k2qe,cal2) of As(V) and Sb(V) in Binary system decreased obviously, suggesting competitive adsorption occurred when As(V) and Sb(V) coexisted. The findings of this workimprove the understanding of As(V)/Sb(V) adsorption behavior in soil under different situations and would facilitate a comprehensive evaluation on the risk assessment of arsenic and antimony.