Intriguing steroid glycosides for cancer therapy by suppressing the DNA damage response and mTOR/S6K signaling pathways.

Two rare 8-hydroxysteroid glycosides (6-7), and their downstream metabolites (1-5) with an unprecedented 6/6/5/5/5-pentacyclic scaffold, together with seven known analogues (8-14) were isolated from the twigs and leaves of Strophanthus divaricatus. Their structures were fully assigned by analysis of the spectroscopic and ECD data, NMR calculations, X-ray crystallographic study, and chemical methods. In addition, the inhibitory effects of 1-14 on liver and lung cancer cell lines were evaluated, and preliminary structure-activity relationship was discussed. Data-independent acquisition (DIA)-based quantitative proteomic analysis and biological verification of H1299 cells suggested that this family of compounds may play an anticancer role by suppressing both DNA damage response (DDR) and mTOR/S6K signaling pathways.

Suppressing Wnt signaling of the blood‒tumor barrier to intensify drug delivery and inhibit lipogenesis of brain metastases.

Lipogenesis is often highly upregulated in breast cancer brain metastases to adapt to intracranial low lipid microenvironments. Lipase inhibitors hold therapeutic potential but their intra-tumoral distribution is often blocked by the blood‒tumor barrier (BTB). BTB activates its Wnt signaling to maintain barrier properties, e.g., Mfsd2a-mediated BTB low transcytosis. Here, we reported VCAM-1-targeting nano-wogonin (W@V-NPs) as an adjuvant of nano-orlistat (O@V-NPs) to intensify drug delivery and inhibit lipogenesis of brain metastases. W@V-NPs were proven to be able to inactivate BTB Wnt signaling, downregulate BTB Mfsd2a, accelerate BTB vesicular transport, and enhance tumor accumulation of O@V-NPs. With the ability to specifically kill cancer cells in a lipid-deprived environment with IC50 at 48 ng/mL, W@V-NPs plus O@V-NPs inhibited the progression of brain metastases with prolonged survival of model mice. The combination did not induce brain edema, cognitive impairment, and systemic toxicity in healthy mice. Targeting Wnt signaling could safely modulate the BTB to improve drug delivery and metabolic therapy against brain metastases.

See farther and more: a master-slave UAVs based synthetic optical aperture imaging system with wide and dynamic baseline.

An open challenge remained in designing an optical system to capture the aerial image with a wide field of view (FoV) and high resolution. The optical system of one camera from a single unmanned aerial vehicle (UAV) can hardly promise the FoV and resolution. The conventional swarm UAVs can form the camera array with a short or fixed baseline. They can capture the images with a wide FoV and high resolution, but the cost is the requirement of many UAVs. We aim to design a camera array with a wide and dynamic baseline to reduce the demand for UAVs to organize a synthetic optical aperture. In this thought, we propose a master-slave UAVs-based synthetic optical aperture imaging system with a wide and dynamic baseline. The system consists of one master UAV and multiple slave UAVs. Master and slave UAVs provide the global and local FoVs, respectively, and improve the efficiency of image acquisition. In such a system, fusing UAV images becomes a new challenge due to two factors: (i) the small FoV overlap of slave UAVs and (ii) the gap in resolution scale from slave to master UAV images. To deal with it, a coarse-to-fine stitching method is proposed to stitch up the multi-view images into one to obtain a wide FoV with high resolution. A video stabilization method has also been designed for the proposed imaging system. Challenges caused by wide and dynamic baselines can thus be solved by the above methods. Actual data experiments demonstrate that the proposed imaging system achieves high-quality imaging results.

Celecoxib attenuates interleukin 33-induced expression of vascular cell adhesion molecule-1 in human ovarian endometriotic stromal cells.

OBJECTIVE: Endometriosis is an estrogen-dependent chronic inflammatory disease in women of reproductive age. A review of the literature revealed that cytokines and inflammatory factors are associated with endometriosis-associated infertility. Interleukin 33 (IL-33) is a strong inducer of other pro-inflammatory cytokines. Vascular cell adhesion molecule-1 (VCAM-1) plays a central role in recruiting inflammatory cells, whose expression facilitates leukocyte adhesion and is rapidly induced by pro-inflammatory cytokines. Many studies have indicated that VCAM-1 expression is high in endometriosis; however, whether the expression of VCAM-1 is related to IL-33 is unclear. MATERIALS AND METHODS: Human ovarian endometriotic stromal cells (hOVEN-SCs) were treated with IL-33 to enable investigation of cell characterization, gene and protein expression, and signal pathways. Proliferation potential was measured using an MTT assay. Gene expression was analyzed using reverse transcription-polymerase chain reaction. Protein expression assay was performed using western blot analysis. RESULTS: This study investigated the effects of IL-33 on VCAM-1 and COX-2 expression in hOVEN-SCs. First, the results revealed that the IL-33/ST2/mitogen-activated protein kinase (MAPK) signaling pathway could increase the expression of VCAM-1 and COX-2 in hOVEN-SCs. Second, we discovered that COX-2 expression was essential for IL-33-induced VCAM-1 expression because the effects could be negated through NS398, a selective COX-2 inhibitor. Finally, treatment of IL-33-treated hOVEN-SCs with celecoxib significantly and dose-responsively decreased VCAM-1 expression. CONCLUSION: Taken together, these results indicate that IL-33 can upregulate VCAM-1 expression in hOVEN-SCs through the IL-33/ST2/MAPK/COX-2 signaling pathway and thereby contribute to endometriosis.

Efficacy and Safety of Mazdutide in Chinese Patients With Type 2 Diabetes: A Randomized, Double-Blind, Placebo-Controlled Phase 2 Trial.

OBJECTIVE: We conducted a randomized, double-blind, placebo-controlled phase 2 trial to evaluate the efficacy and safety of mazdutide, a once-weekly glucagon-like peptide 1 and glucagon receptor dual agonist, in Chinese patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: Adults with type 2 diabetes inadequately controlled with diet and exercise alone or with stable metformin (glycated hemoglobin A1c [HbA1c] 7.0-10.5% [53-91 mmol/mol]) were randomly assigned to receive 3 mg mazdutide (n = 51), 4.5 mg mazdutide (n = 49), 6 mg mazdutide (n = 49), 1.5 mg open-label dulaglutide (n = 50), or placebo (n = 51) subcutaneously for 20 weeks. The primary outcome was change in HbA1c from baseline to week 20. RESULTS: Mean changes in HbA1c from baseline to week 20 ranged from -1.41% to -1.67% with mazdutide (-1.35% with dulaglutide and 0.03% with placebo; all P < 0.0001 vs. placebo). Mean percent changes in body weight from baseline to week 20 were dose dependent and up to -7.1% with mazdutide (-2.7% with dulaglutide and -1.4% with placebo). At week 20, participants receiving mazdutide were more likely to achieve HbA1c targets of <7.0% (53 mmol/mol) and ≤6.5% (48 mmol/mol) and body weight loss from baseline of ≥5% and ≥10% compared with placebo-treated participants. The most common adverse events with mazdutide included diarrhea (36%), decreased appetite (29%), nausea (23%), vomiting (14%), and hypoglycemia (10% [8% with placebo]). CONCLUSIONS: In Chinese patients with type 2 diabetes, mazdutide dosed up to 6 mg was generally safe and demonstrated clinically meaningful HbA1c and body weight reductions.

Inhibition of SOCS3 signaling in the nucleus tractus solitarii and retrotrapezoid nucleus alleviates hypoventilation in diet-induced obese male mice.

The central leptin signaling system has been found to facilitate breathing and is linked to obesity-related hypoventilation. Activation of leptin signaling in the nucleus tractus solitarii (NTS) and retrotrapezoid nucleus (RTN) enhances respiratory drive. In this study, we investigated how medullary leptin signaling contributes to hypoventilation and whether respective deletion of SOCS3 in the NTS and RTN could mitigate hypoventilation in diet-induced obesity (DIO) male mice. Our findings revealed a decrease in the number of CO2-activated NTS neurons and downregulation of acid-sensing ion channels in DIO mice compared to lean control mice. Moreover, NTS leptin signaling was disrupted, as evidenced by the downregulation of phosphorylated STAT3 and the upregulation of SOCS3 in DIO mice. Importantly, deleting SOCS3 in the NTS and RTN significantly improved the diminished hypercapnic ventilatory response in DIO mice. In conclusion, our study suggests that disrupted medullary leptin signaling contributes to obesity-related hypoventilation, and inhibiting the upregulated SOCS3 in the NTS and RTN can alleviate this condition.

Ag(I)-Mediated Annulation of 2-(2-Enynyl)pyridines and Propargyl Amines to Access 1-(2H-Pyrrol-3-yl)indolizines.

An effective Ag(I)-mediated annulation of 2-(2-enynyl)pyridines and propargyl amines was developed, unexpectedly affording a broad range of functionalized 1-(2H-pyrrol-3-yl)indolizines in moderate to excellent yields. The developed method is characterized by operational simplicity, ready availability of starting materials, high regioselectivity, and broad substrate scope under mild reaction conditions. The Ag(I)-promoted cyclization of 2-(2-enynyl)pyridines and propargyl amines possibly results in the formation of the spiroindolizine, the ring-opening rearrangement of which may give the 1-(2H-pyrrol-3-yl)indolizine. Furthermore, a gram-scale reaction and synthetic transformations are also studied.

Mechanism of synergistic remediation of soil phenanthrene contamination in paddy fields by rice-crab coculture and bioaugmentation with Pseudomonas sp.

Polycyclic aromatic hydrocarbons (PAHs) are persistent and harmful pollutants with high priority concern in agricultural fields. This work constructed a rice-crab coculture and bioaugmentation (RCM) system to remediate phenanthrene (a model PAH) contamination in rice fields. The results showed that RCM had a higher remediation performance of phenanthrene in rice paddy compared with rice cultivation alone, microbial addition alone, and crab-rice coculture, reaching a remediation efficiency of 88.92 % in 42 d. The concentration of phenanthrene in the rice plants decreased to 6.58 mg/kg, and its bioconcentration effect was efficiently inhibited in the RCM system. In addition, some low molecular weight organic acids of rice root increased by 12.87 %∼73.87 %, and some amino acids increased by 140 %∼1150 % in RCM. Bioturbation of crabs improves soil aeration structure and microbial migration, and adding Pseudomonas promoted the proliferation of some plant growth-promoting rhizobacteria (PGPRs), which facilitated the degradation of phenanthrene. This coupling rice-crab coculture with bioaugmentation had favorable effects on soil enzyme activity, microbial community structure, and PAH degradation genes in paddy fields, enhancing the removal of and resistance to PAH contamination in paddy fields and providing new strategies for achieving a balance between production and remediation in contaminated paddy fields.

Tafolecimab in Chinese patients with non-familial hypercholesterolemia (CREDIT-1): a 48-week randomized, double-blind, placebo-controlled phase 3 trial.

Background: Tafolecimab, a fully human proprotein convertase subtilisin/kexin type 9 (PCSK9) monoclonal antibody developed for the treatment of hypercholesterolemia, demonstrated robust lipid-lowering efficacy and favorable safety in previous short-term studies. We aimed to assess the long-term efficacy and safety of tafolecimab in Chinese non-familial hypercholesterolemia (non-FH) patients. Methods: Non-FH patients at high or very-high cardiovascular risk with screening low-density lipoprotein cholesterol (LDL-C) level ≥1.8 mmol/L or non-FH patients with screening LDL-C level ≥3.4 mmol/L and on stable lipid-lowering therapy for at least 4 weeks, were randomized in a 2:2:1:1 ratio to receive subcutaneous tafolecimab 450 mg Q4W, tafolecimab 600 mg Q6W, placebo 450 mg Q4W, or placebo 600 mg Q6W, respectively, in the 48-week double-blind treatment period. The primary endpoint was the percent change from baseline to week 48 in LDL-C levels. Findings: A total of 618 patients were randomized and 614 patients received at least one dose of tafolecimab (n = 411) or placebo (n = 203). At week 48, tafolecimab induced significant reductions in LDL-C levels (treatment differences versus placebo [on-treatment estimand]: -65.0% [97.5% CI: -70.2%, -59.9%] for 450 mg Q4W; -57.3% [97.5% CI: -64.0%, -50.7%] for 600 mg Q6W; both P < 0.0001). Significantly more patients treated with tafolecimab achieved ≥50% LDL-C reductions, LDL-C < 1.8 mmol/L, and LDL-C < 1.4 mmol/L than placebo group at both dose regimens (all P < 0.0001). Furthermore, tafolecimab significantly reduced non-HDL-C, apolipoprotein B, and lipoprotein(a) levels. The most commonly-reported treatment emergent adverse events in the tafolecimab groups included upper respiratory infection, urinary tract infection and hyperuricemia. Interpretation: Tafolecimab dosed at 450 mg Q4W and 600 mg Q6W was safe and showed superior lipid-lowering efficacy versus placebo, providing a novel treatment option for Chinese hypercholesterolemia patients. Funding: This study was sponsored by Innovent Biologics, Inc.

UAV-YOLOv8: A Small-Object-Detection Model Based on Improved YOLOv8 for UAV Aerial Photography Scenarios.

Unmanned aerial vehicle (UAV) object detection plays a crucial role in civil, commercial, and military domains. However, the high proportion of small objects in UAV images and the limited platform resources lead to the low accuracy of most of the existing detection models embedded in UAVs, and it is difficult to strike a good balance between detection performance and resource consumption. To alleviate the above problems, we optimize YOLOv8 and propose an object detection model based on UAV aerial photography scenarios, called UAV-YOLOv8. Firstly, Wise-IoU (WIoU) v3 is used as a bounding box regression loss, and a wise gradient allocation strategy makes the model focus more on common-quality samples, thus improving the localization ability of the model. Secondly, an attention mechanism called BiFormer is introduced to optimize the backbone network, which improves the model's attention to critical information. Finally, we design a feature processing module named Focal FasterNet block (FFNB) and propose two new detection scales based on this module, which makes the shallow features and deep features fully integrated. The proposed multiscale feature fusion network substantially increased the detection performance of the model and reduces the missed detection rate of small objects. The experimental results show that our model has fewer parameters compared to the baseline model and has a mean detection accuracy higher than the baseline model by 7.7%. Compared with other mainstream models, the overall performance of our model is much better. The proposed method effectively improves the ability to detect small objects. There is room to optimize the detection effectiveness of our model for small and feature-less objects (such as bicycle-type vehicles), as we will address in subsequent research.

Tafolecimab in Chinese Patients With Hypercholesterolemia (CREDIT-4): A Randomized, Double-Blind, Placebo-Controlled Phase 3 Trial.

Background: Tafolecimab is a novel fully human proprotein convertase subtilisin/kexin type 9 (PCSK9) monoclonal antibody, developed for the treatment of hypercholesterolemia. Objectives: The purpose of this study was to assess the efficacy and safety of tafolecimab in Chinese patients at high or very high cardiovascular risk with hypercholesterolemia. Methods: Patients with diagnoses of heterozygous familial hypercholesterolemia (HeFH) by the Simon Broome criteria or at high or very high cardiovascular risk with nonfamilial hypercholesterolemia, with screening low-density lipoprotein cholesterol (LDL-C) level ≥1.8 mmol/L, were randomized 2:1 to receive tafolecimab or placebo 450 mg every 4 weeks (Q4W) in the 12-week double-blind treatment period. The primary endpoint was the percent change from baseline to week 12 in LDL-C levels. Results: A total of 303 patients were enrolled and received at least 1 dose of tafolecimab (n = 205) or placebo (n = 98). The least squares mean percent change in LDL-C level from baseline to week 12 was -68.9% (SE 1.4%) in the tafolecimab group and -5.8% (1.8%) in the placebo group (difference: -63.0%; [95% CI: -66.5% to -59.6%]; P < 0.0001). More patients treated with tafolecimab achieved ≥50% LDL-C reductions, LDL-C <1.8 mmol/L, and LDL-C <1.4 mmol/L at week 12 than did those in the placebo group (all P < 0.0001). Furthermore, tafolecimab markedly reduced non-HDL-C, apolipoprotein B, and lipoprotein(a) levels. During the double-blind treatment period, the most commonly reported adverse events included urinary tract infection (5.9% with tafolecimab vs 4.1% with placebo) and hyperuricemia (3.4% vs 4.1%). Conclusions: Tafolecimab was safe and showed robust lipid-lowering efficacy in Chinese patients at high or very high cardiovascular risk with hypercholesterolemia. (A Study of IBI306 in Participants With Hypercholesterolemia; NCT04709536).

Cinobufagin: a promising therapeutic agent for cancer.

OBJECTIVES: Cinobufagin is a natural active ingredient isolated from the traditional Chinese medicine Venenum Bufonis (Chinese: Chansu), which is the dried secretion of the postauricular gland or skin gland of the Bufo gargarizans Cantor or Bufo melanostictus Schneider. There is increasing evidence indicating that cinobufagin plays an important role in the treatment of cancer. This article is to review and discuss the antitumor pharmacological effects and mechanisms of cinobufagin, along with a description of its toxicity and pharmacokinetics. METHODS: The public databases including PubMed, China National Knowledge Infrastructure and Elsevier were referenced, and 'cinobufagin', 'Chansu', 'Venenum Bufonis', 'anticancer', 'cancer', 'carcinoma', and 'apoptosis' were used as keywords to summarize the comprehensive research and applications of cinobufagin published up to date. KEY FINDINGS: Cinobufagin can induce tumour cell apoptosis and cycle arrest, inhibit tumour cell proliferation, migration, invasion and autophagy, reduce angiogenesis and reverse tumour cell multidrug resistance, through triggering DNA damage and activating the mitochondrial pathway and the death receptor pathway. CONCLUSIONS: Cinobufagin has the potential to be further developed as a new drug against cancer.

A non-genetic engineering platform for rapidly generating and expanding cancer-specific armed T cells.

BACKGROUND: Cancer-specific adoptive T cell therapy has achieved successful milestones in multiple clinical treatments. However, the commercial production of cancer-specific T cells is often hampered by laborious cell culture procedures, the concern of retrovirus-based gene transfection, or insufficient T cell purity. METHODS: In this study, we developed a non-genetic engineering technology for rapidly manufacturing a large amount of cancer-specific T cells by utilizing a unique anti-cancer/anti-CD3 bispecific antibody (BsAb) to directly culture human peripheral blood mononuclear cells (PBMCs). The anti-CD3 moiety of the BsAb bound to the T cell surface and stimulated the differentiation and proliferation of T cells in PBMCs. The anti-cancer moiety of the BsAb provided these BsAb-armed T cells with the cancer-targeting ability, which transformed the naïve T cells into cancer-specific BsAb-armed T cells. RESULTS: With this technology, a large amount of cancer-specific BsAb-armed T cells can be rapidly generated with a purity of over 90% in 7 days. These BsAb-armed T cells efficiently accumulated at the tumor site both in vitro and in vivo. Cytotoxins (perforin and granzyme) and cytokines (TNF-α and IFN-γ) were dramatically released from the BsAb-armed T cells after engaging cancer cells, resulting in a remarkable anti-cancer efficacy. Notably, the BsAb-armed T cells did not cause obvious cytokine release syndrome or tissue toxicity in SCID mice bearing human tumors. CONCLUSIONS: Collectively, the BsAb-armed T cell technology represents a simple, time-saving, and highly safe method to generate highly pure cancer-specific effector T cells, thereby providing an affordable T cell immunotherapy to patients.

Effect of humic acid-modified attapulgite on polycyclic aromatic hydrocarbon adsorption and release from paddy soil into the overlying water in a rice-crab coculture paddy ecosystem and the underlying process.

Phenanthrene (Phe), a typical polycyclic aromatic hydrocarbon (PAH) pollutant, poses an enormous safety risk to rice-crab coculture (RC) paddy ecosystems. In this study, humic acid-modified purified attapulgite (HA-ATP) with a composite structure was successfully fabricated to adsorb PAHs released from paddy soil to overlying water in RC paddy ecosystems in Northeast China. The maximum crab bioturbation intensities for dissolved Phe and particulate Phe were 64.83nullng/L·(cm2·d) and 214.29nullng/L·(cm2·d), respectively. The highest concentration of dissolved Phe released from paddy soil to overlying water due to crab bioturbation reached 80.89nullng/L, while the corresponding concentration of particulate Phe reached 267.36nullng/L. The dissolved organic carbon (DOC) and total suspended solid (TSS) concentrations in overlying water increased correspondingly and were strongly correlated with dissolved Phe and particulate Phe concentrations, respectively (P < 0.05). When 6% HA-ATP was added to the surface layer of paddy soil, the efficiency of the adsorption of Phe release was 24.00%-36.38% for particulate Phe and 89.99%-91.91% for dissolved Phe. Because HA-ATP has a large adsorption pore size (11.33 nm) and surface area (82.41nullm2/g) as well as many HA functional groups, it provided multiple hydrophobic adsorption sites for dissolved Phe, which was conducive to competitive adsorption with DOC in the overlying water. In contrast to that adsorbed by DOC, the average proportion of dissolved Phe adsorbed by HA-ATP reached 90.55%, which reduced the dissolved Phe concentration in the overlying water. Furthermore, even though the particulate Phe was resuspended by crab bioturbation, HA-ATP immobilized particulate Phe due to its capacity to inhibit desorption, which achieved the goal of reducing the Phe concentration in the overlying water. This result was confirmed by research on the adsorption-desorption characteristics of HA-ATP. This research provides an environmentally friendly in situ remediation method for reducing agricultural environmental risks and improving rice crop quality.

Efficacy and safety of tafolecimab in Chinese patients with heterozygous familial hypercholesterolemia: a randomized, double-blind, placebo-controlled phase 3 trial (CREDIT-2).

BACKGROUND: Heterozygous familial hypercholesterolemia (HeFH) is largely underdiagnosed and undertreated in China where few patients achieved recommended target levels of low density lipoprotein cholesterol (LDL-C). We conducted the first randomized, placebo-controlled clinical trial in Chinese patients with HeFH to assess the efficacy and safety of tafolecimab, a novel fully human proprotein convertase subtilisin/kexin type 9 (PCSK9) monoclonal antibody. METHODS: Patients diagnosed with HeFH by Simon Broome criteria and on a stable lipid-lowering therapy for at least 4 weeks were randomized 2:2:1:1 to receive subcutaneous tafolecimab 150 mg every 2 weeks (Q2W), tafolecimab 450 mg every 4 weeks (Q4W), placebo Q2W or placebo Q4W in the 12-week double-blind treatment period. After that, participants received open-label tafolecimab 150 mg Q2W or 450 mg Q4W for 12 weeks. The primary endpoint was the percent change from baseline to week 12 in LDL-C levels. Secondary endpoints included proportion of participants achieving ≥50% LDL-C reductions and proportion of participants with LDL-C <1.8 mmol/L at week 12 and 24, the change from baseline to week 12 in non-high density lipoprotein cholesterol (non-HDL-C), apolipoprotein B and lipoprotein(a) levels, as well as the change from baseline to week 24 in lipid levels. RESULTS: In total, 149 participants were randomized and 148 received at least one dose of the study treatment. At week 12, tafolecimab treatment induced significant reductions in LDL-C levels (treatment difference versus placebo [on-treatment estimand]: -57.4% [97.5% CI, -69.2 to -45.5] for 150 mg Q2W; -61.9% [-73.4 to -50.4] for 450 mg Q4W; both P <0.0001). At both dose regimens, significantly more participants treated with tafolecimab achieved ≥50% LDL-C reductions or LDL-C <1.8 mmol/L at week 12 as compared with corresponding placebo groups (all P <0.0001). Meanwhile, non-HDL-C, apolipoprotein B and lipoprotein(a) levels were significantly reduced in the tafolecimab groups at week 12. The lipid-lowering effects of tafolecimab were maintained till week 24. During the double-blind treatment period, the most commonly-reported adverse events in the tafolecimab groups included upper respiratory tract infection, increased blood creatine phosphokinase, increased alanine aminotransferase, increased aspartate aminotransferase and hypertension. CONCLUSIONS: Tafolecimab administered either 150 mg Q2W or 450 mg Q4W yielded significant and persistent reductions in LDL-C levels and showed a favorable safety profile in Chinese patients with HeFH. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04179669.

Natural products targeting macrophages in tumor microenvironment are a source of potential antitumor agents.

BACKGROUND: Macrophages are one of the major cell types in the immune system and are closely related to tumor development, which can be polarized into M1 type with anti-tumor activity or M2 type with pro-tumor activity. The infiltration of more macrophages into tumor predicts poorer prognosis due to their more exhibition of M2 phenotype under the influence of many factors in the tumor microenvironment (TME). Therefore, reverse of M2 macrophage polarization in TME is conducive to the suppression of tumor deterioration and understanding the influencing factors of macrophage polarization is helpful to provide new ideas for the subsequent targeting macrophages for tumor therapy. PURPOSE: This review summarizes the effects of TME on macrophage polarization and natural products against M2 macrophage polarization, which may provide some directions for tumor therapy. METHODS: The search of relevant literature was conducted using the PubMed, Science Direct, CNKI and Web of Science databases with the search terms "macrophage", "tumor microenvironment", "natural product" and "tumor". RESULTS: The mutual transformation of M1 and M2 phenotypes in macrophages is influenced by many factors. Tumor cells affect the polarization of macrophages by regulating the expression of genes and proteins and the secretion of cytokines. The expression of some genes or proteins in macrophages is also related to their own polarization. Many natural products can reverse M2 polarization of macrophages which has been summarized in this review. CONCLUSION: Regulation of macrophage polarization in TME can inhibit tumor development, and natural products have the potential to impede tumor development by regulating macrophage polarization.

Comparing the Therapeutic Mechanism and Immune Response of Human and Mouse Mesenchymal Stem Cells in Immunocompetent Mice With Acute Liver Failure.

Current mesenchymal stem cell (MSC) research is based on xenotransplantation of human MSCs (hMSCs) in immunodeficient mice and cannot comprehensively predict MSC repair mechanisms and immunomodulatory effects in damaged tissue. This study compared the therapeutic efficacy, mechanisms, and immune response of hMSCs and mouse MSCs (mMSCs) in immunocompetent mice with CCl4-induced acute liver failure. mMSCs maintained F4/80+ hepatic macrophage recruitment into the damaged liver region, increased IL-6-dependent hepatocyte proliferation, and reduced inflammatory TNF-α cytokine secretion. Moreover, mMSCs reduced α-SMA+ myofibroblast activation by lowering TGF-ß1 accumulation in damaged liver tissue. In contrast, hMSCs lowered TNF-α and TGF-ß1 by reducing the recruitment of F4/80+ hepatic macrophages, which lost the ability to remove debris and induce IL-6 liver regeneration. Finally, hMSCs, but not mMSCs, caused a significant antibody response in immunocompetent mice; therefore, hMSCs are unsuitable for long-term MSC studies. This comparative study provides reference information for further MSC studies of immunocompetent mice.

Oct-4 induces cisplatin resistance and tumor stem cell-like properties in endometrial carcinoma cells.

OBJECTIVE: Research has suggested that tumor-initiating tumor stem cells are derived from normal stem cells and that tumor cells undergo progressive de-differentiation to achieve a stem cell-like state. Tumor stem cells are characterized by high proliferation ability, high plasticity, expression of multi-drug resistance proteins, and the ability to seed new tumors. Octamer-binding transcription factor 4 (Oct-4) and its activation targets are overexpressed in the tumor stem cells of various types of tumors, and this expression is associated with the pathogenesis, development, and poor prognosis of tumors. The primary objective of this study was to test if a stably transfected with Oct-4 gene cell line, RL95-2/Oct-4, has the characteristics of tumor stem cells. MATERIALS AND METHODS: Human endometrial carcinoma cells (RL95-2) were transfected with a plasmid carrying genes for Oct-4 and green fluorescent protein (GFP). The stably transfected cells, RL95-2/Oct-4, were selected using G418 and observed to express the GFP reporter gene under the control of the Oct-4 promoter. GFP expression levels of RL95-2/Oct-4 cells were measured using flow cytometry. The proliferation potential of cells was determined according to cumulative population doubling and colony-formation efficiency. Gene expression was analyzed using reverse transcription-polymerase chain reaction. RESULTS: RL95-2/Oct-4 cells not only exhibited increased expression of the three most important stem cell genes, Oct-4, Nanog, and Sox2, but also had increased expression of the endometrial tumor stem cell genes CD133 and ALDH1. Furthermore, enhanced expression of these genes in the RL95-2/Oct-4 cells was associated with higher colony-forming ability and growth rate than in parental RL95-2 cells. We also observed that cisplatin induced less cell death in RL95-2/Oct-4 cells than in RL95-2 cells, indicating that RL95-2/Oct-4 cells were more resistant to chemotherapeutic agents. CONCLUSION: The study findings contribute to investigate the effects of Oct-4 on tumor stem cell origins.

Forsythiasides: A review of the pharmacological effects.

Forsythiasides are a kind of phenylethanol glycosides existing in Forsythia suspensa (Thunb.) Vahl, which possesses extensive pharmacological activities. According to the different groups connected to the nucleus, forsythiasides can be divided into A-K. In recent years, numerous investigations have been carried out on forsythiasides A, B, C, D, E, and I, which have the effects of cardiovascular protection, anti-inflammation, anti-oxidation, neuroprotection, et al. Mechanistically, forsythiasides regulate toll-like receptor 4 (TLR4)/myeloid differentiation factor 88 (MyD88)/nuclear factor kappaB (NF-κB), nuclear factor-erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) and other signaling pathways, as well as the expression of related cytokines and kinases. Further exploration and development may unearth more treatment potential of forsythiasides and provide more evidence for their clinical applications. In summary, forsythiasides have high development and application value.

Bie-Jia-Ruan-Mai-Tang, a Chinese Medicine Formula, Inhibits Retinal Neovascularization in Diabetic Mice Through Inducing the Apoptosis of Retinal Vascular Endothelial Cells.

Proliferative diabetic retinopathy (PDR) is one of the main complications of diabetes, mainly caused by the aberrant proliferation of retinal vascular endothelial cells and the formation of new blood vessels. Traditional Chinese medicines possess great potential in the prevention and treatment of PDR. Bie-Jia-Ruan-Mai-Tang (BJ), a Chinese medicine formula, has a good therapeutic effect on PDR clinically; however, the mechanism of action involved remains unclear. Therefore, we investigated the effect of BJ on PDR through in vitro and in vivo experiments. A diabetic mouse model with PDR was established by feeding a high-fat-high-glucose diet combined with an intraperitoneal injection of streptozotocin (STZ), while high-glucose-exposed human retinal capillary endothelial cells (HRCECs) were employed to mimic PDR in vitro. The in vivo experiments indicated that BJ inhibited the formation of acellular capillaries, decreased the expression of VEGF, and increased the level of ZO-1 in diabetic mice retina. In vitro experiments showed that high glucose significantly promoted cell viability and proliferation. However, BJ inhibited cell proliferation by cycle arrest in the S phase, thus leading to apoptosis; it also increased the production of ROS, decreased the mitochondrial membrane potential, reduced the ATP production, and also reduced the expressions of p-PI3K, p-AKT, and Bcl-xL, but increased the expressions of Bax and p-NF-κB. These results suggest that BJ induces the apoptosis of HRCECs exposed to high glucose through activating the mitochondrial death pathway by decreasing the PI3K/AKT signaling and increasing the NF-κB signaling to inhibit the formation of acellular capillaries in the retina, thus impeding the development of PDR.