Characterisation of new in vitro models and identification of potentially active drugs in angiosarcoma.

Angiosarcoma is a rare soft tissue sarcoma originating from endothelial cells. Given that current treatments for advanced disease have shown limited efficacy, alternative therapies need to be identified. In rare diseases, patient-derived cell models are crucial for screening anti-tumour activity. In this study, cell line models were characterised in 2D and 3D cultures. The cell lines' growth, migration and invasion capabilities were explored, confirming them as useful tools for preclinical angiosarcoma studies. By screening a drug library, we identified potentially effective compounds: 8-amino adenosine impacted cell growth and inhibited migration and invasion at considerably low concentrations as a single agent. No synergistic effect was detected when combining with paclitaxel, gemcitabine or doxorubicin. These results suggest that this compound could be a potentially useful drug in the treatment of AGS.

Diagnosis, toxicological mechanism, and detoxification for hepatotoxicity induced by pyrrolizidine alkaloids from herbal medicines or other plants.

Pyrrolizidine alkaloids (PAs) are one type of phytotoxins distributed in various plants, including many medicinal herbs. Many organs might suffer injuries from the intake of PAs, and the liver is the most susceptible one. The diagnosis, toxicological mechanism, and detoxification of PAs-induced hepatotoxicity have been studied for several decades, which is of great significance for its prevention, diagnosis, and therapy. When the liver was exposed to PAs, liver sinusoidal endothelial cells (LSECs) loss, hemorrhage, liver parenchymal cells death, nodular regeneration, Kupffer cells activation, and fibrogenesis occurred. These pathological changes classified the PAs-induced liver injury as acute, sub-acute, and chronic type. PAs metabolic activation, mitochondria injury, glutathione (GSH) depletion, inflammation, and LSECs damage-induced activation of the coagulation system were well recognized to play critical roles in the pathological process of PAs-induced hepatotoxicity. A lot of natural compounds like glycyrrhizic acid, (-)-epicatechin, quercetin, baicalein, chlorogenic acid, and so on were demonstrated to be effective in alleviating PAs-induced liver injury, which rendered them huge potential to be developed into therapeutic drugs for PAs poisoning in clinics. This review presents updated information about the diagnosis, toxicological mechanism, and detoxification studies on PAs-induced hepatotoxicity.

LPS/TLR4 Pathway Regulates IgA1 Secretion to Induce IgA Nephropathy.

Context: Studies have reported that the incidence and severity of IgA nephropathy (IgAN) are closely related to the imbalance of the intestinal flora. Imbalance of the intestinal flora may cause abnormalities, such as intestinal mucosal immunity or mesenteric B1 lymphocyte subsets. These can lead to an increase in immunoglobulin A (IgA) production and IgA structural changing, which can eventually cause IgA1 deposition in the glomerular mesangial area and nephritis. Objective: The study intended to explore whether the LPS/TLR4 pathway regulates mesenteric B cells, secreting Gd-IgA1 to induce IgA nephropathy. Design: The research team designed an animal study. Setting: The study took place at Department of Nephrology, Minhang Hospital, Fudan University. Animals: The animals were 60 specific pathogen free (SPF) C57BL/6 (B6, H-2b) male mice from that were 6-8 weeks old and weighed 20-25 grams. Intervention: The research team established a mouse model of IgA nephropathy. The team created five groups of mice: (1) the NC group, a normal negative control group without induced nephropathy and with no treatments; (2) the IgA nephropathy (IgAN) group, a positive control group with induced nephropathy and with no treatments; (3) the IgAN+anti-TLR4 group, an intervention group, with induced nephropathy and with a TLR4-antibody (anti-TLR4) treatment; (4) the IgAN+GEC group, an intervention group, with induced nephropathy and with treatment with glutamine enteric-coated capsules (GEC); and (5) the IgAN+anti-TLR4+GEC group, an intervention group, with induced nephropathy and with treatment with anti-TLR4 and GEC. Outcome Measures: The research team collected the blood and urine of all the mice and used an enzyme-linked immunoassay (ELISA) to analyze the levels of blood creatinine, urine protein, and urea nitrogen (BUN). The team also used the ELISA to analyze signal molecules for serum inflammation: interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-α), monocyte chemotactic protein 1 (MCP-1), cyclooxygenase-2 (COX2), and galactose-deficient IgA1(Gd-IgA1). The team analyzed the distribution and content of IgA+B220+B lymphocytes in the intestinal tissues of all the mice, using tissue immunofluorescence tracking technology, and used hematoxylin-eosin (HE) staining to analyze the pathological damage in the kidney tissue. For analysis of glomerular IgA deposition, the team used a tissue immunofluorescence technique, and for detection of protein expression-toll-like receptor 4 (TLR4), B-cell activating factor (BAFF), and a proliferation-inducing ligand (APRIL)-in mesenteric lymphoid tissues, the team used western blot analysis. Results: For the five groups of mice, the amount or degree of the physiological indicators and inflammatory factors that ELISA detected, the B lymphocytes and IgA sedimentation that immunofluorescence tracing measured, the kidney pathological that HE staining detected, and the expression of immune-related proteins that western blotting measured, all showed a common trend: IgAN group> IgAN+ glomerular endothelial cells (GEC) group> IgAN+anti-TLR4 group> IgAN+anti-TLR4+GEC group> NC group. Conclusions: The TLR4 antibody and GEC for the treatment of the intestinal tract can regulate and repair intestinal function, so that IgAN can also be relieved at the same time. The results supported the hypothesis that a relationship exists between IgAN and the LPS/TLR4 pathway that regulates mesenteric B cells to secrete low-glycosylated poly-IgA1, which provides a new potential therapeutic plan for IgA nephritis.

Research Progress of Inflammatory Factors in Chronic Obstructive Pulmonary Disease with Pulmonary Hypertension at High Altitude.

Chronic obstructive pulmonary disease (COPD) is currently one of the highest morbidity and mortality worldwide, a serious public health problem. Pulmonary hypertension is a common complication of COPD. At present, the pathogenesis of pulmonary hypertension is not clear. A concise overview of the known factors contributing to pulmonary hypertension in COPD includes hypoxia and inflammation. Hypoxia, resulting from lung damage and inadequate oxygen supply, can lead to pulmonary vasoconstriction and increased vascular resistance, thus contributing to the development of pulmonary hypertension in COPD patients. Inflammation also plays a significant role in the progression of pulmonary hypertension. COPD patients exhibit inflammatory responses in their lung tissues, with the release of various inflammatory mediators. These mediators can stimulate abnormal proliferation of endothelial cells and smooth muscle cells within the pulmonary arteries, leading to vascular wall thickening and restricted blood flow. This paper focuses on the pathogenesis of four inflammatory factors, namely interleukin (IL-1ß), IL-6, IL-8, and tumor necrosis factor (TNF)-α, in pulmonary hypertension. IL-1ß, IL-6, IL-8, and TNF-α are known as pro-inflammatory cytokines that play crucial roles in the inflammatory response. In the context of pulmonary hypertension, these inflammatory factors have been implicated in the remodeling of the pulmonary vasculature, leading to increased vascular resistance and impaired blood flow. The research presented in this paper will delve into the current scientific knowledge surrounding IL-1ß, IL-6, IL-8, and TNF-α, and their roles in pulmonary vascular remodeling, endothelial dysfunction, smooth muscle cell proliferation, and inflammation. The goal is to provide a comprehensive overview of their involvement in pulmonary hypertension and how these factors may be influenced by the hypoxic environment prevalent in high-altitude regions. By focusing on the relevance of these inflammatory factors in high-altitude areas, we hope to contribute valuable insights that can inform clinical management strategies, prevention approaches, and potential therapeutic interventions for individuals residing in such regions who are at an increased risk of developing pulmonary hypertension.

Ulmus davidiana 60% edible ethanolic extract for prevention of pericyte apoptosis in diabetic retinopathy.

Diabetic retinopathy (DR) is a disease that causes visual deficiency owing to vascular leakage or abnormal angiogenesis. Pericyte apoptosis is considered one of the main causes of vascular leakage in diabetic retina, but there are few known therapeutic agents that prevent it. Ulmus davidiana is a safe natural product that has been used in traditional medicine and is attracting attention as a potential treatment for various diseases, but its effect on pericyte loss or vascular leakage in DR is not known at all. In the present study, we investigated on the effects of 60% edible ethanolic extract of U. davidiana (U60E) and catechin 7-O-ß-D-apiofuranoside (C7A), a compound of U. davidiana, on pericyte survival and endothelial permeability. U60E and C7A prevented pericyte apoptosis by inhibiting the activation of p38 and JNK induced by increased glucose and tumor necrosis factor alpha (TNF-α) levels in diabetic retina. Moreover, U60E and C7A reduced endothelial permeability by preventing pericyte apoptosis in co-cultures of pericytes and endothelial cells. These results suggest that U60E and C7A could be a potential therapeutic agent for reducing vascular leakage by preventing pericyte apoptosis in DR.

Dahuang Zhechong pill attenuates hepatic sinusoidal capillarization in liver cirrhosis and hepatocellular carcinoma rat model via the MK/integrin signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Dahuang Zhechong pill (DHZCP), a traditional Chinese medicine, was derived from the famous book Unk "Synopsis of Prescriptions of the Golden Chamber" during the Han dynasty. Owing to its ability to invigorate the circulation of blood in Chinese medicine, DHZCP is usually used for treating liver cirrhosis (LC) and hepatocellular carcinoma (HCC). Clinical application have shown that DHZCP exhibits satisfactory therapeutic effects in HCC adjuvant therapy; however, little is known about its underlying mechanisms. AIM OF THE STUDY: We aimed to clarify the mechanism of DHZCP against hepatic sinusoidal capillarization in rats with LC and HCC by inhibiting the MK/integrin signaling pathway of liver sinusoidal endothelial cells (LSECs). MATERIALS AND METHODS: The contents of 29 characteristic components in DHZCP were determined by ultraperformance liquid chromatography-tandem mass spectrometry. DEN (Diethylnitrosamine)-induced LC and HCC rat models were constructed, and DHZCP was administered when the disease entered the LC stage. After 4 or 12 weeks of administration, hematoxylin and eosin staining, Masson staining, Metavir score, and SSCP (Single strand conformation polymorphism) gene mutation detection were used to confirm tissue fibrosis and cancer. The levels of NO, ET-1 and TXA2, which can regulate vasomotor functions and activate the MK/Itgα6/Src signaling pathway were evaluated by using immunohistochemistry, chemiluminescence, immunofluorescence, Western blot analysis, and enzyme-linked immunosorbent assay (ELISA). Similar methods were also used to evaluate the levels of VEGF, VEGFR, Ang-2 and Tie, which can promote pathological angiogenesis and activate the MK/Itgα4/NF-κB signaling pathway. In vitro cell experiments were performed using potential pharmacodynamic molecules targeting integrins in DHZCP were selected by molecular docking, and the effects of these molecules on the function of LSECs were studied by Itgα4+ and Itgα6+ cell models. RESULTS: At the stage of LC, the animal experiments demonstrated that DHZCP mainly inhibited the MK/Itgα6 signaling pathway to increase the number and size of hepatic sinus fenestration, reversed the ET-1/NO and TXA2/NO ratios, regulated hepatic sinus relaxation and contraction balance, reduced the portal vein pressure, and inhibited cirrhotic carcinogenesis. At the HCC stage, DHZCP could also significantly inhibit the MK/Itgα4 signaling pathway, reduce pathological angiogenesis, and alleviate disease progression. The results of the cell experiments showed that Rhein, Naringenin, Liquiritin and Emodin-8-O-ß-D-glucoside (PMEG) were involved in vascular regulation by affecting the MK/integrin signaling pathway. Liquiritin and PMEG mainly blocked the MK/α6 signal, which is important in regulating the vasomotor function of the liver sinus. Naringenin and Rhein mainly acted by blocked the signaling of MK/α4 action signal, which are potent molecules that inhibit pathological angiogenesis. CONCLUSIONS: DHZCP could improve the hepatic sinusoidal capillarization of LC and HCC by inhibiting the MK/Itgα signaling pathway and inhibited disease progression. Rhein, Naringenin, Liquiritin and PMEG were the main active molecules that affected the MK/Itgα signaling pathway.

Intravascular papillary endothelial hyperplasia of the spleen in a child: a case report.

BACKGROUND: Intravascular papillary endothelial hyperplasia (IPEH) is a vascular tumor characterized by the proliferation of endothelial cells with papillary formation. It is a rare benign condition affecting the head and neck. Currently, no cases of IPEH of the spleen have been reported. Here, we report a case of IPEH of the spleen in a child and discuss its clinical manifestations, imaging features, and surgical treatment. CASE PRESENTATION: A 5-year-old female presented with a 4-month-old tumor in the left upper abdomen, abdominal pain, and constipation. She underwent radiography, barium enema, US, and MRI. A solid space-occupying mass was found in the left abdominal cavity on preoperative imaging, and it was diagnosed as angiosarcoma. The lesion was surgically resected. Histopathological analysis was consistent with IPEH. CONCLUSION: Clinicians should consider the possibility of IPEH in patients presenting with tumors in the spleen, which is curable by surgical resection. Malignant vascular tumors must be excluded in the differential diagnosis of IPEH to prevent misdiagnosis and inappropriate overtreatment.

New insights into antiangiogenic therapy resistance in cancer: Mechanisms and therapeutic aspects.

Angiogenesis is a hallmark of cancer and is required for tumor growth and progression. Antiangiogenic therapy has been revolutionarily developing and was approved for the treatment of various types of cancer for nearly two decades, among which bevacizumab and sorafenib continue to be the two most frequently used antiangiogenic drugs. Although antiangiogenic therapy has brought substantial survival benefits to many cancer patients, resistance to antiangiogenic drugs frequently occurs during clinical treatment, leading to poor outcomes and treatment failure. Cumulative evidence has demonstrated that the intricate interplay among tumor cells, bone marrow-derived cells, and local stromal cells critically allows for tumor escape from antiangiogenic therapy. Currently, drug resistance has become the main challenge that hinders the therapeutic efficacies of antiangiogenic therapy. In this review, we describe and summarize the cellular and molecular mechanisms conferring tumor drug resistance to antiangiogenic therapy, which was predominantly associated with redundancy in angiogenic signaling molecules (e.g., VEGFs, GM-CSF, G-CSF, and IL17), alterations in biological processes of tumor cells (e.g., tumor invasiveness and metastasis, stemness, autophagy, metabolic reprogramming, vessel co-option, and vasculogenic mimicry), increased recruitment of bone marrow-derived cells (e.g., myeloid-derived suppressive cells, tumor-associated macrophages, and tumor-associated neutrophils), and changes in the biological functions and features of local stromal cells (e.g., pericytes, cancer-associated fibroblasts, and endothelial cells). We also review potential biomarkers to predict the response to antiangiogenic therapy in cancer patients, which mainly consist of imaging biomarkers, cellular and extracellular proteins, a certain type of bone marrow-derived cells, local stromal cell content (e.g., pericyte coverage) as well as serum or plasma biomarkers (e.g., non-coding RNAs). Finally, we highlight the recent advances in combination strategies with the aim of enhancing the response to antiangiogenic therapy in cancer patients and mouse models. This review introduces a comprehensive understanding of the mechanisms and biomarkers associated with the evasion of antiangiogenic therapy in cancer, providing an outlook for developing more effective approaches to promote the therapeutic efficacy of antiangiogenic therapy.

Chemical composition and protective effect of cerebrospinal fluid of Dan-Deng-Tong-Nao capsules on brain microvascular endothelial cells injured by OGD/R.

ETHNOPHARMACOLOGICAL RELEVANCE: Dan-Deng-Tong-Nao Capsules (DDTNC) is a Chinese patent medicine and has been used in treating cerebral ischemic stroke (IS) for a long time in China, protection of brain microvascular endothelial cells (BMECs) is the main treatment strategy. But the holistic chemical information and potential bioactive components of DDTNC on protecting BMECs and its underlying mechanism is still unclear. AIM OF THE STUDY: To identify the active ingredients of DDTNC and to explore the protective effects of DDTNC on BMECs associated with Wnt/ß-catenin pathway. MATERIALS AND METHODS: The components of DDTNC and cerebrospinal fluid containing composition of DDTNC (DDTNC-CSF) were detected by High performance liquid chromatography combined with Diode array detector (HPLC-DAD) and Ultra-high performance liquid chromatography with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS), respectively. The experiment rat model was established with middle cerebral artery occlusion (MCAO), the therapeutic effects of DDTNC were assessed by Longa assay and TTC staining. The cerebral micro vessel density was determined by immunofluorescence staining. The injured BMECs caused by oxygen-glucose deprivation and reperfusion (OGD/R) was used to evaluate the protective effect of cerebrospinal fluid containing composition of DDTNC (DDTNC-CSF). The cell survival rate was detected by the method of CCK-8, the intracellular Ca2+ and reactive oxygen species (ROS) was estimated by Fluo-3. Moreover, the proteins of Bax, Bcl-2, Wnt, ß-catenin, GSK-3ß was determined by Western blotting. RESULTS: The RSD values of all methodological studies were less than 3.0%. A total of 20 compounds were detected under the optimized HPLC-DAD chromatographic condition. In the UPLC-Q-TOF-MS negative mode, peak 1 and peak 2 were detecteted in DDTNC-CSF and was identified as Danshensu and Puerarin, respectively. In the UPLC-Q-TOF-MS positive mode, peak 1 and peak 3 were detecteted in DDTNC-CSF and was identified as Danshensu and Scutellarin, respectively. DDTNC significantly decreased the Longa values and infarct volume and significantly increased the cerebral microvessel density of the MCAO rats. The accumulation of intracellular Ca2+ and ROS in BMECs injured by OGD/R decreased significantly in DDTNC-CSF group. The expression of Bcl-2, ß-catenin, wnt-1 was upregulated by DDTNC-CSF and the level of Bax and GSK3ß could be downregulated by DDTNC-CSF. CONCLUSION: The present study provided a scientific basis for revealing the mechanism of DDTNC in the treatment of IS and DDTNC is expected to be an effective drug for the treatment of IS.

Dynamic Role of Macrophage Sub Types on Development of Atherosclerosis and Potential Use of Herbal Immunomodulators as Imminent Therapeutic Strategy.

Atherosclerosis, a major contributor to cardiovascular disease, is a global alarm causing mortality worldwide. Being a progressive disease in the arteries, it mainly causes the recruitment of monocytes to the inflammatory sites and subsides pathological conditions. Monocyte-derived macrophage mainly acts in foam cell formation by engorging the LDL molecules, oxidizes it into Ox-LDL and leads to plaque deposit development. Macrophages in general differentiate, proliferate and undergo apoptosis at the inflammatory site. Frequently two subtypes of macrophages M1 and M2 have to act crucially in balancing the micro-environmental conditions of endothelial cells in arteries. The productions of pro-inflammatory mediators like IL-1, IL-6, TNF-α by M1 macrophage have atherogenic properties majorly produced during the early progression of atherosclerotic plaques. To counteract cytokine productions and M1-M2 balance, secondary metabolites (phytochemicals) from plants act as a therapeutic agent in alleviating atherosclerosis progression. This review summarizes the fundamental role of the macrophage in atherosclerotic lesion formation along with its plasticity characteristic as well as recent therapeutic strategies using herbal components and anti-inflammatory cytokines as potential immunomodulators.

Treatment of hepatocellular carcinoma with autologous platelets encapsulating sorafenib or lenvatinib: A novel therapy exploiting tumor-platelet interactions.

Hepatocellular carcinoma (HCC) activates platelets through the action of adjacent sinusoidal cells. Activated platelets bind to tumor-associated endothelial cells and release growth factors that promote tumor progression. We hypothesized that platelets encapsulated with tumor inhibitors would function as drug carriers for tumor therapy. We propose a therapeutic strategy for HCC using autologous platelets encapsulating multiple tyrosine kinase inhibitors in a rat chemically induced HCC model. Sorafenib or lenvatinib was encapsulated in platelets isolated from tumor-bearing rats in vitro. The rats were divided into groups that received repeated intravenous injections (twice a week for 10 weeks) of the following materials: placebo, sorafenib (SOR), lenvatinib (LEN), autologous platelets, autologous platelets encapsulating sorafenib (SOR-PLT) and autologous platelets encapsulating lenvatinib (LEN-PLT). The therapeutic effect was then analyzed by ultrasonography (US) and histopathological analysis. Histopathological and US analysis demonstrated extensive tumor necrosis in the tumor tissue of SOR-PLT or LEN-PLT, but not in other experimental groups. By liquid chromatography-mass spectrometry, more abundant sorafenib was detected in tumor tissues after SOR-PLT administration than in surrounding normal tissues, but no such difference in sorafenib level was observed with SOR administration. Therefore, the use of autologous platelets encapsulating drugs might be a novel therapeutic strategy for HCC.

Endothelial SIRT1 as a Target for the Prevention of Arterial Aging: Promises and Challenges.

ABSTRACT: SIRT1, a member of the sirtuin family of longevity regulators, possesses potent activities preventing vascular aging. The expression and function of SIRT1 in endothelial cells are downregulated with age, in turn causing early vascular aging and predisposing various vascular abnormalities. Overexpression of SIRT1 in the vascular endothelium prevents aging-associated endothelial dysfunction and senescence, thus the development of hypertension and atherosclerosis. Numerous efforts have been directed to increase SIRT1 signaling as a potential strategy for different aging-associated diseases. However, the complex mechanisms underlying the regulation of SIRT1 have posed a significant challenge toward the design of specific and effective therapeutics. This review aimed to provide a summary on the regulation and function of SIRT1 in the vascular endothelium and to discuss the different approaches targeting this molecule for the prevention and treatment of age-related cardiovascular and cerebrovascular diseases.

A Potential New Role for Zinc in Age-Related Macular Degeneration through Regulation of Endothelial Fenestration.

Age-related macular degeneration (AMD) is a common blinding disease in the western world that is linked to the loss of fenestration in the choriocapillaris that sustains the retinal pigment epithelium and photoreceptors in the back of the eye. Changes in ocular and systemic zinc concentrations have been associated with AMD; therefore, we hypothesized that these changes might be directly involved in fenestrae formation. To test this hypothesis, an endothelial cell (bEND.5) model for fenestrae formation was treated with different concentrations of zinc sulfate (ZnSO4) solution for up to 20 h. Fenestrae were visualized by staining for Plasmalemmal Vesicle Associated Protein-1 (PV-1), the protein that forms the diaphragms of the fenestrated endothelium. Size and distribution were monitored by transmission electron microscopy (TEM). We found that zinc induced the redistribution of PV-1 into areas called sieve plates containing ~70-nm uniform size and typical morphology fenestrae. As AMD is associated with reduced zinc concentrations in the serum and in ocular tissues, and dietary zinc supplementation is recommended to slow disease progression, we propose here that the elevation of zinc concentration may restore choriocapillaris fenestration resulting in improved nutrient flow and clearance of waste material in the retina.

Roles of glomerular endothelial hyaluronan in the development of proteinuria.

Vascular endothelial cells are covered with glycocalyx comprising heparan sulfate, hyaluronan, chondroitin sulfate, and associated proteins. Glomerular endothelial glycocalyx is involved in protecting against induction of proteinuria and structural damage, but the specific components in glycocalyx that represent therapeutic targets remain unclear. Anti-vascular endothelial growth factor (VEGF) therapy is associated with an increased risk of glomerular endothelial injury. This study investigated whether hyaluronan could provide a therapeutic target to protect against proteinuria. We conducted ex vivo and in vivo experiments to explore the effects of degrading glomerular hyaluronan by administering hyaluronidase and of supplementation with hyaluronan. We investigated hyaluronan expression using biotin-labeled hyaluronan-binding protein (HABP) in human kidney specimens or serum hyaluronan in endothelial injuries under inhibition of VEGF signaling. We directly demonstrated hyaluronan in glomerular endothelial layers using HABP staining. Ex vivo and in vivo experiments showed the development of proteinuria after digestion of hyaluronan in glomerular capillaries. Supplementation with hyaluronan after hyaluronidase treatment suppressed proteinuria. Mice in the in vivo study developed albuminuria after intraperitoneal injection of hyaluronidase with decreased glomerular hyaluronan and increased serum hyaluronan. In human kidneys with endothelial cell dysfunction and proteinuria due to inhibition of VEGF, glomerular expression of hyaluronan was reduced even in normal-appearing glomeruli. Serum hyaluronan levels were elevated in patients with pre-eclampsia with VEGF signaling inhibition. Our data suggest that hyaluronan itself plays crucial roles in preventing proteinuria and preserving the integrity of endothelial cells. Hyaluronan could provide a therapeutic target for preventing glomerular endothelial glycocalyx damage, including VEGF signaling inhibition.

Vascular Endothelial Growth Factor, a Key Modulator of the Anti-Tumor Immune Response.

During tumor growth, angiogenesis is required to ensure oxygen and nutrient transport to the tumor. Vascular endothelial growth factor (VEGF) is the major inducer of angiogenesis and appears to be a key modulator of the anti-tumor immune response. Indeed, VEGF modulates innate and adaptive immune responses through direct interactions and indirectly by modulating protein expressions on endothelial cells or vascular permeability. The inhibition of the VEGF signaling pathway is clinically approved for the treatment of several cancers. Therapies targeting VEGF can modulate the tumor vasculature and the immune response. In this review, we discuss the roles of VEGF in the anti-tumor immune response. In addition, we summarize therapeutic strategies based on its inhibition, and their clinical approval.

Propionate and Butyrate Produced by Gut Microbiota after Probiotic Supplementation Attenuate Lung Metastasis of Melanoma Cells in Mice.

SCOPE: The beneficial effects of probiotics in reducing gastrointestinal inflammation and in preventing colorectal cancer have been reported, but the mechanism underlying the immunomodulatory effect of probiotics in inhibiting extra-intestinal tumor progression remains unclear. METHODS AND RESULTS: This study shows that probiotic supplementation attenuate lung metastasis of melanoma cells in mice. Feeding mice with VSL#3 probiotics change the composition and proportion of gut microbiota. The changes in gut bacteria composition, such as in the abundance of Lachnospiraceae, Streptococcus, and Lachnoclostridium, are associated with the production of short-chain fatty acids in the gut. The concentrations of propionate and butyrate are upregulated in gut and blood after feeding VSL#3, and the increase in propionate and butyrate levels promotes the expression of chemokine (C-C motif) ligand 20 (CCL20) in lung endothelial cells and the recruitment of T helper 17 (Th17) cells to the lungs via the CCL20/chemokine receptor 6 axis. The recruitment of Th17 cells decreases the number of tumor foci in lungs and attenuates the lung metastasis of melanoma cells in mice. CONCLUSIONS: The results provide new information on the role and mechanisms of action of probiotics in attenuating extra-intestinal tumor metastasis.

Development and characterization of a monoclonal antibody blocking human TRPM4 channel.

TRPM4 is a calcium-activated non-selective monovalent cation channel implicated in diseases such as stroke. Lack of potent and selective inhibitors remains a major challenge for studying TRPM4. Using a polypeptide from rat TRPM4, we have generated a polyclonal antibody M4P which could alleviate reperfusion injury in a rat model of stroke. Here, we aim to develop a monoclonal antibody that could block human TRPM4 channel. Two mouse monoclonal antibodies M4M and M4M1 were developed to target an extracellular epitope of human TRPM4. Immunohistochemistry and western blot were used to characterize the binding of these antibodies to human TRPM4. Potency of inhibition was compared using electrophysiological methods. We further evaluated the therapeutic potential on a rat model of middle cerebral artery occlusion. Both M4M and M4M1 could bind to human TRPM4 channel on the surface of live cells. Prolonged incubation with TRPM4 blocking antibody internalized surface TRPM4. Comparing to M4M1, M4M is more effective in blocking human TRPM4 channel. In human brain microvascular endothelial cells, M4M successfully inhibited TRPM4 current and ameliorated hypoxia-induced cell swelling. Using wild type rats, neither antibody demonstrated therapeutic potential on stroke. Human TRPM4 channel can be blocked by a monoclonal antibody M4M targeting a key antigenic sequence. For future clinical translation, the antibody needs to be humanized and a transgenic animal carrying human TRPM4 sequence is required for in vivo characterizing its therapeutic potential.

Suppression of apoptosis in vascular endothelial cell, the promising way for natural medicines to treat atherosclerosis.

Atherosclerosis, a chronic multifactorial disease, is closely related to the development of cardiovascular diseases and is one of the predominant causes of death worldwide. Normal vascular endothelial cells play an important role in maintaining vascular homeostasis and inhibiting atherosclerosis by regulating vascular tension, preventing thrombosis and regulating inflammation. Currently, accumulating evidence has revealed that endothelial cell apoptosis is the first step of atherosclerosis. Excess apoptosis of endothelial cells induced by risk factors for atherosclerosis is a preliminary event in atherosclerosis development and might be a target for preventing and treating atherosclerosis. Interestingly, accumulating evidence shows that natural medicines have great potential to treat atherosclerosis by inhibiting endothelial cell apoptosis. Therefore, this paper reviewed current studies on the inhibitory effect of natural medicines on endothelial cell apoptosis and summarized the risk factors that may induce endothelial cell apoptosis, including oxidized low-density lipoprotein (ox-LDL), reactive oxygen species (ROS), angiotensin II (Ang II), tumor necrosis factor-α (TNF-α), homocysteine (Hcy) and lipopolysaccharide (LPS). We expect this review to highlight the importance of natural medicines, including extracts and monomers, in the treatment of atherosclerosis by inhibiting endothelial cell apoptosis and provide a foundation for the development of potential antiatherosclerotic drugs from natural medicines.

Effects of carotid baroreceptor stimulation on aortic remodeling in obese rats.

BACKGROUND AND AIM: Our previous study found carotid baroreceptor stimulation (CBS) reduces body weight and white adipose tissue (WAT) weight, restores abnormal secretion of adipocytokines and inflammation factors, decreases systolic blood pressure (SBP) by inhibiting activation of sympathetic nervous system (SNS) and renin-angiotensin system (RAS) in obese rats. In this study, we explore effects of CBS on aortic remodeling in obese rats. METHODS AND RESULTS: Rats were fed high-fat diet (HFD) for 16 weeks to induce obesity and underwent either CBS device implantation and stimulation or sham operation at 8 weeks. BP and body weight were measured weekly. RAS activity of WAT, histological, biochemical and functional profiles of aortas were detected after 16 weeks. CBS effectively decreased BP in obese rats, downregulated mRNA expression of angiotensinogen (AGT) and renin in WAT, concentrations of AGT, renin, angiotensin II (Ang II), protein levels of Ang II receptor 1 (AT1R) and Ang II receptor 2 (AT2R) in WAT were declined. CBS inhibited reactive oxygen species (ROS) generation, inflammatory response and endoplasmic reticulum (ER) stress in aortas of obese rats, restrained vascular wall thickening and vascular smooth muscle cells (VSMCs) phenotypic switching, increased nitric oxide (NO) synthesis, promoted endothelium-dependent vasodilatation by decreasing protein expression of AT1R and leptin receptor (LepR), increasing protein expression of adiponectin receptor 1 (AdipoR1) in aortic VSMCs. CONCLUSION: CBS reduced BP and reversed aortic remodeling in obese rats, the underlying mechanism might be related to the suppressed SNS activity, restored adipocytokine secretion and restrained RAS activity of WAT.