[Mechanism of astragaloside â £ combined with Panax notoginseng saponins in regulating angiogenesis to treat cerebral ischemia based on network pharmacology and experimental verification].

Network pharmacology and animal and cell experiments were employed to explore the mechanism of astragaloside Ⅳ(AST Ⅳ) combined with Panax notoginseng saponins(PNS) in regulating angiogenesis to treat cerebral ischemia. The method of network pharmacology was used to predict the possible mechanisms of AST Ⅳ and PNS in treating cerebral ischemia by mediating angiogenesis. In vivo experiment: SD rats were randomized into sham, model, and AST Ⅳ(10 mg·kg~(-1)) + PNS(25 mg·kg~(-1)) groups, and the model of cerebral ischemia was established with middle cerebral artery occlusion(MCAO) method. AST Ⅳ and PNS were administered by gavage twice a day. the Longa method was employed to measure the neurological deficits. The brain tissue was stained with hematoxylin-eosin(HE) to reveal the pathological damage. Immunohistochemical assay was employed to measure the expression of von Willebrand factor(vWF), and immunofluorescence assay to measure the expression of vascular endothelial growth factor A(VEGFA). Western blot was employed to determine the protein levels of vascular endothelial growth factor receptor 2(VEGFR2), VEGFA, phosphorylated phosphatidylinositol 3-kinase(p-PI3K), and phosphorylated protein kinase B(p-AKT) in the brain tissue. In vitro experiment: the primary generation of rat brain microvascular endothelial cells(rBEMCs) was cultured and identified. The third-generation rBMECs were assigned into control, model, AST Ⅳ(50 µmol·L~(-1)) + PNS(30 µmol·L~(-1)), LY294002(PI3K/AKT signaling pathway inhibitor), 740Y-P(PI3K/AKT signaling pathway agonist), AST Ⅳ + PNS + LY294002, and AST Ⅳ + PNS + 740Y-P groups. Oxygen glucose deprivation/re-oxygenation(OGD/R) was employed to establish the cell model of cerebral ischemia-reperfusion injury. The cell counting kit-8(CCK-8) and scratch assay were employed to examine the survival and migration of rBEMCs, respectively. Matrigel was used to evaluate the tube formation from rBEMCs. The Transwell assay was employed to examine endothelial cell permeability. Western blot was employed to determine the expression of VEGFR2, VEGFA, p-PI3K, and p-AKT in rBEMCs. The results of network pharmacology analysis showed that AST Ⅳ and PNS regulated 21 targets including VEGFA and AKT1 of angiogenesis in cerebral infarction. Most of these 21 targets were involved in the PI3K/AKT signaling pathway. The in vivo experiments showed that compared with the model group, AST Ⅳ + PNS reduced the neurological deficit score(P<0.05) and the cell damage rate in the brain tissue(P<0.05), promoted the expression of vWF and VEGFA(P<0.01) and angiogenesis, and up-regulated the expression of proteins in the PI3K/AKT pathway(P<0.05, P<0.01). The in vitro experiments showed that compared with the model group, the AST Ⅳ + PNS, 740Y-P, AST Ⅳ + PNS + LY294002, and AST Ⅳ + PNS + 740Y-P improved the survival of rBEMCs after OGD/R, enhanced the migration of rBEMCs, increased the tubes formed by rBEMCs, up-regulated the expression of proteins in the PI3K/AKT pathway, and reduced endothelial cell permeability(P<0.05, P<0.01). Compared with the LY294002 group, the AST Ⅳ + PNS + LY294002 group showed increased survival rate, migration rate, and number of tubes, up-regulated expression of proteins in the PI3K/AKT pathway, and decreased endothelial cell permeability(P<0.05,P<0.01). Compared with the AST Ⅳ + PNS and 740Y-P groups, the AST Ⅳ + PNS + 740Y-P group presented increased survival rate, migration rate, and number of tubes and up-regulated expression of proteins in the PI3K/AKT pathway, and reduced endothelial cell permeability(P<0.01). This study indicates that AST Ⅳ and PNS can promote angiogenesis after cerebral ischemia by activating the PI3K/AKT signaling pathway.

Effects of moxibustion with wheat-grain size cone at "Zusanli" (ST 36) on vascular injury and oxidative stress in high-fat diet rats through mTOR/HIF-1α/VEGF signaling pathway. / 基于mTOR/HIF-1α/VEGF信号通路探讨麦粒灸"足三里"å¯¹é«˜è„‚é¥®é£Ÿå¤§é¼ è¡€ç®¡æŸä¼¤å’Œæ°§åŒ–åº”æ¿€çš„å½±å“.

OBJECTIVES: To explore the effect mechanism of moxibustion with wheat-grain size cone at "Zusanli" (ST 36) on vascular injury and oxidative stress in hyperlipidemia through mammalian target of rapamycin (mTOR)/hypoxia inducible factor-1α (HIF-1α)/vascular endothelial growth factor (VEGF) signaling pathway. METHODS: Forty healthy male SD rats with SPF grade were randomly divided into a normal group, a model group, a moxibustion group, and an inhibitor group, with 10 rats in each one. The hyperlipidemia model was established by feeding a high-fat diet for 8 weeks in rats of the model group, the moxibustion group and the inhibitor group. The moxibustion with wheat-grain size cone was delivered at bilateral "Zusanli" (ST 36) of each rat in the moxibustion group and the inhibitor group, with 3 cones on each acupoint in each intervention, once daily for 4 weeks. In the inhibitor group, before each intervention with moxibustion, rapamycin solution was injected intraperitoneally, 2.0 mg/kg. After modeling and intervention, using ELISA, the levels of total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) in the serum of rats were determined. After intervention, with HE staining and oil red O staining adopted, the abdominal aortic morphology and peripheral lipid deposition were observed. Separately, using WST-1, TBA and micro-plate method, the superoxide dismutase (SOD) activity and the levels of malondialdehyde (MDA) and nitric oxide (NO) in the serum were detected. The protein expression of mTOR, HIF-1α and VEGF in abdominal aorta were measured by Western blot method. RESULTS: Compared with those in the normal group, the levels of TC, TG and LDL-C increased (P<0.01) and HDL-C decreased (P<0.01) in the serum of the rats in the model group, the moxibustion group and the inhibitor group after model establishment. When compared with the normal group after intervention, in the model group, the serum levels of TC, TG, LDL-C and MDA increased (P<0.01), HDL-C level, SOD activity and NO level were reduced (P<0.01); the cell structure of the abdominal arota was abnormal, the peripheral lipids deposited seriously; and the protein expression of mTOR, HIF-1α and VEGF of abdominal aorta was elevated (P<0.01, P<0.05). In comparison with the model group, the levels of TC, TG, LDL-C and MDA were reduced (P<0.01), HDL-C levels, SOD activities and NO levels elevated (P<0.01, P<0.05), as well as the protein expression of mTOR, HIF-1α and VEGF of abdominal aorta (P<0.01, P<0.05) in the moxibustion group and the inhibitor group; besides, the vascular structure was ameliorated and the lipid deposition reduced in the moxibustion group, while, the vascular structure was still abnormal and the lipid deposition declined in the inhibitor group. When compared with the inhibitor group, the serum SOD activity and NO level increased (P<0.05) and MDA decreased (P<0.05); and the protein expression of mTOR, HIF-1α and VEGF of abdominal aorta was elevated (P<0.01, P<0.05) in the moxibustion group. CONCLUSIONS: The vascular injury due to hyperlipidemia is repaired by moxibustion with wheat-grain size cone at "Zusanli" (ST 36) through ameliorating oxidative stress, which is associated potentially with the modulation of mTOR/HIF-1α/VEGF signaling pathway.

Influence of Maternal Nutrition and One-Carbon Metabolites Supplementation during Early Pregnancy on Bovine Fetal Small Intestine Vascularity and Cell Proliferation.

To investigate the effects of nutrient restriction and one-carbon metabolite (OCM) supplementation (folate, vitamin B12, methionine, and choline) on fetal small intestine weight, vascularity, and cell proliferation, 29 (n = 7 ± 1 per treatment) crossbred Angus beef heifers (436 ± 42 kg) were estrous synchronized and conceived by artificial insemination with female sexed semen from a single sire. Then, they were allotted randomly to one of four treatments in a 2 × 2 factorial arrangement with the main factors of nutritional plane [control (CON) vs. restricted feed intake (RES)] and OCM supplementation [without OCM (-OCM) or with OCM (+OCM)]. Heifers receiving the CON level of intake were fed to target an average daily gain of 0.45 kg/day, which would allow them to reach 80% of mature BW by calving. Heifers receiving the RES level of intake were fed to lose 0.23 kg/heifer daily, which mimics observed production responses in heifers that experience a diet and environment change during early gestation. Targeted heifer gain and OCM treatments were administered from d 0 to 63 of gestation, and then all heifers were fed a common diet targeting 0.45 kg/d gain until d 161 of gestation, when heifers were slaughtered, and fetal jejunum was collected. Gain had no effect (p = 0.17) on the fetal small intestinal weight. However, OCM treatments (p = 0.02) displayed less weight compared to the -OCM groups. Capillary area density was increased in fetal jejunal villi of RES - OCM (p = 0.02). Vascular endothelial growth factor receptor 2 (VEGFR2) positivity ratio tended to be greater (p = 0.08) in villi and was less in the crypts (p = 0.02) of the RES + OCM group. Cell proliferation decreased (p = 0.02) in villi and crypts of fetal jejunal tissue from heifers fed the RES + OCM treatment compared with all groups and CON - OCM, respectively. Spatial cell density increased in RES - OCM compared with CON + OCM (p = 0.05). Combined, these data show OCM supplementation can increase expression of VEGFR2 in jejunal villi, which will promote maintenance of the microvascular beds, while at the same time decreasing small intestine weight and crypt cell proliferation.

Gui ShenWan prevent premature ovarian insufficiency by modulating autophagy and angiogenesis via facilitating VDR.

ETHNOPHARMACOLOGICAL RELEVANCE: Gui Shen Wan (GSW) stands out as a promising therapeutic approach for addressing Premature Ovarian Insufficiency (POI). With deep roots in traditional medicine, GSW highlights the ethnopharmacological significance of herbal interventions in addressing nuanced aspects of women's health, with a specific emphasis on ovarian functionality. Recognizing the importance of GSW in gynecological contexts resonates with a rich tradition of using botanical formulations to navigate the intricacies of reproductive health. Delving into GSW's potential for treating POI emphasizes the crucial role of ethnopharmacological insights in guiding modern research endeavors. AIM OF THE STUDY: GSW is extensively utilized in gynecological disorders and has recently emerged as a potential therapeutic approach for POI. The present investigation aimed to assess the efficacy of GSW in treating POI in rats and elucidate its underlying molecular mechanisms. MATERIALS AND METHODS: The study employed GSW for POI treatment in rats. GSW, prepared as pills, underwent HPLC fingerprinting for quality control. Reagents and drugs, including VCD and dehydroepiandrosterone (DHEA), were sourced from reputable providers. Eighty Sprague-Dawley rats were categorized into groups for POI induction and treatment. Ovarian tissue underwent HE staining, immunohistochemical staining, Western Blot, qRT-PCR, and vaginal secretion testing. ELISA was utilized for target molecule detection. This methodology ensures a robust and reliable experimental framework. RESULTS: The results highlight a robust collaborative improvement in POI among rats subjected to combined GSW and DHEA treatment. Particularly noteworthy is the substantial enhancement in the expression of vascular regeneration-related molecules-VDR-Klotho-VEGFR-accompanied by a significant elevation in autophagy levels. Post-GSW administration, rat ovarian morphology demonstrated increased stability, hormone levels exhibited more consistent maintenance, and there was a marked reduction in inflammatory response compared to other groups (p < 0.01). Furthermore, GSW intervention resulted in a more pronounced upregulation of ovarian autophagy (p < 0.05). CONCLUSION: By modulating VDR-Klotho signaling, GSW exerts regulatory control over ovarian autophagy and vascular regeneration, thereby mitigating the occurrence and progression of POI in rats.

Ononin promotes radiosensitivity in lung cancer by inhibiting HIF-1α/VEGF pathway.

BACKGROUND: In our previous study, we provided evidence that Astragalus mongholicus Bunge(AM) and its extracts possess a protective capability against radiation-induced damage, potentially mediated through the reduction of reactive oxygen species (ROS) and nitric oxide (NO). However, we were pleasantly surprised to discover during our experimentation that AM not only offers protection against radiation damage but also exhibits a radiation sensitization effect. This effect may be attributed to a specific small molecule present in AM known as ononin. Currently, radiation sensitizers are predominantly found in nitrazole drugs and nanomaterials, with no existing reports on the radiation sensitization properties of ononin, nor its underlying mechanism. PURPOSE: This study aims to investigate the sensitization effect of the small molecule ononin derived from AM on lung cancer radiotherapy, elucidating its specific molecular mechanism of action. Additionally, the safety profile of combining astragalus small molecule ononin with radiation therapy will be evaluated. METHODS: The effective concentration of ononin was determined through cell survival experiments, and the impact of ononin combined with varying doses of radiation on lung cancer cells was observed using CCK-8 and cell cloning experiments. The apoptotic effect of ononin combined with radiation on lung cancer cells was assessed using Hochester staining, flow cytometry, and WB assay. Additionally, WB and immunofluorescence analysis were conducted to investigate the influence of ononin on HIF-1α/VEGF pathway. Furthermore, Molecular Dynamics Simulation was employed to validate the targeted binding ability of ononin and HIF-1α. A lung cancer cell line was established to investigate the effects of knockdown and overexpression of HIF-1α. Subsequently, the experiment was repeated using tumor bearing nude mice and C57BL/6 mouse models in an in vivo study. Tumor volume was measured using a vernier caliper, while HE, immunohistochemistry, and immunofluorescence techniques were employed to observe the effects of ononin combined with radiation on tumor morphology, proliferation, and apoptosis. Additionally, Immunofluorescence was employed to examine the impact of ononin on HIF-1α/VEGF pathway in vivo, and its effect on liver function in mice was assessed through biochemistry analysis. RESULTS: At a concentration of 25 µM, ononin did not affect the proliferation of lung epithelial cells but inhibited the survival of lung cancer cells. In vitro experiments demonstrated that the combination of ononin and radiation could effectively inhibit the growth of lung cancer cells, induce apoptosis, and suppress the excessive activation of the Hypoxia inducible factor 1 alpha/Vascular endothelial growth factor pathway. In vivo experiments showed that the combination of ononin and radiation reduced the size and proliferation of lung cancer tumors, promoted cancer cell apoptosis, mitigated abnormal activation of the Hypoxia inducible factor 1 alpha pathway, and protected against liver function damage. CONCLUSION: This study provides evidence that the combination of AM and its small molecule ononin can enhance the sensitivity of lung cancer to radiation. Additionally, it has been observed that this combination can specifically target HIF-1α and exert its effects. Notably, ononin exhibits the unique ability to protect liver function from damage while simultaneously enhancing the tumor-killing effects of radiation, thereby demonstrating a synergistic and detoxifying role in tumor radiotherapy. These findings contribute to the establishment of a solid basis for the development of novel radiation sensitizers derived from traditional Chinese medicine.

Zishen Yutai Pills Promote Angiogenesis at the Maternal-Fetal Interface in Recurrent Spontaneous Abortion Mice by Regulating miR-187/VEGF Axis.

Ethnopharmacological Relevance: Zishen Yutai pills (ZYP), a traditional Chinese patent medicine, was listed in China in 1981. It is composed of 15 traditional Chinese medicines and has the effects of regulating menstruation, helping pregnancy, and preventing abortion. In clinical practice, it is effective in preventing habitual and threatened miscarriages, and continuing to explore its mechanism of action is very meaningful research. Aim of the Study: To explore the possible mechanism of ZYP promoting angiogenesis at the maternal-fetal interface in recurrent spontaneous abortion (RSA). Materials and Methods: In vitro experiments, placental trophoblast cells (PTCs) were isolated from the placental tissue of RSA mice and divided into six groups: Control group, Model group, ZYP group, miR-187 inhibitor NC group, miR-18 7 inhibitor group, and miR-187 inhibitor+ZYP group. Cell viability and cell cycle were measured using CCK8 and flow cytometry, respectively. The expression levels of miR-187, VEGF, VEGF-R1, and VEGF-R2 were measured using RT-qPCR, WB, and IF staining. Animal experiments first establish an RSA mice model (CBA/J × DBA/2) and then randomly divide the mice into four groups (n=10): normal pregnancy group, RSA model group, ZYP group, and progesterone capsule group. Observed the changes in embryo absorption rate, pathological morphology of decidual tissue, and ultrastructure of vascular endothelial cells in each group of mice. RT-qPCR, WB, and IF staining methods were used to determine the expression of miR-187, VEGF, VEGF-R1, and VEGF-R2. Results: In vitro, ZYP promoted the viability of PTCs and regulated their cell cycle, and ZYP down-regulated miR-187, up-regulated VEGF, VEGF-R1 and VEGF-R2 levels. miR-187 inhibitor showed the same effects, and further ZYP intervention enhanced the effects. In vivo, ZYP remarkably reduced embryo resorption rates, and improved the pathological morphology of decidual tissues and ultrastructure of vascular endothelial cells. Moreover, ZYP down-regulated miR-187, up-regulated VEGF, VEGF-R1 and VEGF-R2. Conclusion: In summary, ZYP can regulate the expression of VEGF via miR-187, then promote the angiogenesis at the maternal-fetal interface, and playing a therapeutic role in RSA.

Subthreshold micropulse diode laser treatment in diabetic macular edema: biological impact, therapeutic effects, and safety.

PURPOSE: To introduce the treatment of diabetic macular edema (DME) with subthreshold micropulse diode laser (SMPL), to summarize the biological impact, therapeutic effects, and safety of this treatment, and to discuss the response to DME when SMPL is combined with anti-vascular endothelial growth factor (anti-VEGF) or steroid. METHODS: The literature search was performed on the PubMed database, with a selection of English-language articles published from 2000 to 2023 with the following combinations of search terms: diabetes macular (o) edema, micropulse laser or subthreshold micropulse laser, anti-vascular endothelial growth factor, and steroid. RESULTS: SMPL is a popular, invisible retinal laser phototherapy that is inexpensive, safe, and effective in the treatment of DME. It can selectively target the retinal pigment epithelium, reduce the expression of pro-inflammatory factors, promote the absorption of macular edema, and exert a similar and lasting clinical effect to traditional lasers. No significant difference was found in the therapeutic effects of SMPL between different wavelengths. However, HbA1c level and pretreatment central macular thickness (CMT) may affect the therapeutic outcomes of SMPL. CONCLUSION: SMPL has a slow onset and produces lasting clinical effects similar to conventional photocoagulation. It has been reported that SMPL combined with the intravitreal anti-VEGF injection can significantly reduce the number of injections without influencing the therapeutic effect, which is essential for clinical applications and research. Although 577 nm SMPL is widely used clinically, there are no standardized protocols for SMPL. Additionally, some important problems regarding the treatment of SMPL require further discussion and exploration.

Recent Progress in Systemic Therapy for Advanced Hepatocellular Carcinoma.

Patients with advanced hepatocellular carcinoma (HCC) have several systemic treatment options. There are many known risk factors for HCC, and although some, such as hepatitis C, are now treatable, others are not. For example, metabolic dysfunction-related chronic liver disease is increasing in incidence and has no specific treatment. Underlying liver disease, drug resistance, and an increasing number of treatment options without specific biomarkers are all challenges in selecting the best treatment for each patient. Conventional chemotherapy is almost never used for advanced-stage disease, which instead is treated with immunotherapy, tyrosine kinase inhibitors, and VEGF inhibitors. Immune checkpoint inhibitors targeting various receptors have been or are currently undergoing clinical evaluation. Ongoing trials with three-drug regimens may be the future of advanced-stage HCC treatment. Other immune-modulatory approaches of chimeric antigen receptor-modified T cells, bispecific antibodies, cytokine-induced killer cells, natural killer cells, and vaccines are in early-stage clinical trials. Targeted therapies remain limited for HCC but represent an area of potential growth. As we shift away from first-line sorafenib for advanced HCC, clinical trial control arms should comprise a standard treatment other than sorafenib, one that is a better comparator for advancing therapies.

Insights into the mechanisms of diabetic wounds: pathophysiology, molecular targets, and treatment strategies through conventional and alternative therapies.

Diabetes mellitus is a prevalent cause of mortality worldwide and can lead to several secondary issues, including DWs, which are caused by hyperglycemia, diabetic neuropathy, anemia, and ischemia. Roughly 15% of diabetic patient's experience complications related to DWs, with 25% at risk of lower limb amputations. A conventional management protocol is currently used for treating diabetic foot syndrome, which involves therapy using various substances, such as bFGF, pDGF, VEGF, EGF, IGF-I, TGF-ß, skin substitutes, cytokine stimulators, cytokine inhibitors, MMPs inhibitors, gene and stem cell therapies, ECM, and angiogenesis stimulators. The protocol also includes wound cleaning, laser therapy, antibiotics, skin substitutes, HOTC therapy, and removing dead tissue. It has been observed that treatment with numerous plants and their active constituents, including Globularia Arabica, Rhus coriaria L., Neolamarckia cadamba, Olea europaea, Salvia kronenburgii, Moringa oleifera, Syzygium aromaticum, Combretum molle, and Myrtus communis, has been found to promote wound healing, reduce inflammation, stimulate angiogenesis, and cytokines production, increase growth factors production, promote keratinocyte production, and encourage fibroblast proliferation. These therapies may also reduce the need for amputations. However, there is still limited information on how to prevent and manage DWs, and further research is needed to fully understand the role of alternative treatments in managing complications of DWs. The conventional management protocol for treating diabetic foot syndrome can be expensive and may cause adverse side effects. Alternative therapies, such as medicinal plants and green synthesis of nano-formulations, may provide efficient and affordable treatments for DWs.

Bioinformatics and Network Pharmacology Explore the Role of Immune Cells in the Occurrence of Anti-Vascular Endothelial Growth Factor (VEGF) Resistance in Patients with Neovascular Age-Related Macular Degeneration(nAMD) and the Application of Complementary Medicine Treatment.

PURPOSE: This study explores the immune cells' role in anti-VEGF resistance in nAMD patients, and the potential of Zi-Yin-Jiang-Huo-Tang (ZYJHT), a Traditional Chinese Medicine formula, as complementary therapy. METHODS: Aqueous humor proteomics data from 10 nAMD patients with anti-VEGF resistance and 10 nAMD patients without anti-VEGF resistance were analyzed, investigating immune cells's role in anti-VEGF resistance and its underlying mechanism. Network pharmacology methods are employed to analyze the active ingredients in ZYJHT that contribute to therapeutic effects and their mechanisms. Real-time PCR (polymerase chain reaction) was used to detect changes in the expression of SOD1 (superoxide dismutase 1) after treatment with compounds targeting SOD1 in ARPE-19 cells. RESULTS: nAMD patients with anti-VEGF resistance showed enhancement of biological processes linked to the positive regulation of immune function, along with decreased cellular resistance to oxidative stress. Infiltration of B cells memory, plasma cells, CD8+and γδ-T cells were higher in nAMD patients with anti-VEGF resistance. SOD1 was identified as a hub gene in the occurrence of anti-VEGF resistance and a core therapeutic target of ZYJHT, negatively correlated with B and T cell infiltration. Compounds diosgenin, naringenin, and liquiritin in ZYJHT can bind to SOD1 and upregulating SOD1 expression in ARPE-19 cells.

Intravitreal ranibizumab injection is associated with an increased risk of chronic kidney disease: a population-based study in Taiwan.

Systemic vascular endothelial growth factor (VEGF) blockade has been the top adjunctive chemotherapy since 1990. Anti-VEGF therapy has also been associated with worsened renal function in some patients. However, the association between patient outcomes and use of intravitreal VEGF inhibitors remains controversial. Thus, it is necessary to determine the action mechanism and long-term renal effects of ranibizumab. The National Health Insurance Research Database (NHIRD) is one of the largest global databases that are extensively used for epidemiological research. NHIRD contains the medical information of all insureds, such as inpatient, outpatient, emergency, and traditional Chinese medicine records. We selected subjects aged ≥ 20 years who recently administered ranibizumab for the ranibizumab cohort. Non-ranibizumab cohort consisted of subjects who did not receive ranibizumab, and the index date was a random date between 2008 and 2018. We excluded subjects with missing sex and age records and those in which the date of primary outcome was before the index date. The two cohorts were matched via 1:1 propensity score matching based on sex, age, index year, hypertension, diabetes mellitus, hyperlipidemia, stroke, coronary artery disease, alcoholism, chronic obstructive pulmonary disease, and age-related macular degeneration, retinal vein occlusion, and diabetic macular edema. Medical confounders were angiotensin I-converting enzyme inhibitors, statins, corticosteroids, VEGF inhibitors including bevacizumab and aflibercept, lithium, amphotericin B, adefovir, NSAIDS, cisplatin, and calcineurin inhibitors. Among 48,248 participants aged ≥ 20 years, 24,136 (50%) received ranibizumab (13,565 male [56.20%] and 10,571 female [43.80%]). Moreover, 24,136 participants who did not receive ranibizumab were matched by age, sex, comorbidities, and medications. Subjects who received ranibizumab exhibited a significantly higher risk of CKD than those who did not receive ranibizumab (adjusted hazard ratio = 1.88, 95% CI = 1.79-1.96). Our findings revealed that exposure to intravitreal ranibizumab is an independent risk factor for CKD. Therefore, physicians and ophthalmologists should make the patients aware of such a correlation to increase patient safety and decrease the CKD burden.

Monoterpenoids: An upcoming class of therapeutic agents for modulating cancer metastasis.

Monoterpenoids, a sub-class of terpenoids, are secondary metabolites frequently extracted from the essential oils of aromatic plants. Their antitumor properties including antiproliferative, apoptotic, antiangiogenic, and antimetastatic effects along with other biological activities have been the subject of extensive study due to their diverse characteristics. In recent years, numerous investigations have been conducted to understand its potential anticancer impacts, specifically focusing on antiproliferative and apoptotic mechanisms. Metastasis, a malignancy hallmark, can exert either protective or destructive influences on tumor cells. Despite this, the potential antimetastatic and antiangiogenic attributes of monoterpenoids need further exploration. This review focuses on specific monoterpenoids, examining their effects on metastasis and relevant signaling pathways. The monoterpenoids exhibit a high level of complexity as natural products that regulate metastatic proteins through various signaling pathways, including phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin, mitogen-activated protein kinase/extracellular signal-regulated kinase/jun N-terminal kinase, nuclear factor kappa B, vascular endothelial growth factor, and epithelial mesenchymal transition process. Additionally, this review delves into the biosynthesis and classification of monoterpenoids, their potential antitumor impacts on cell lines, the plant sources of monoterpenoids, and the current status of limited clinical trials investigating their efficacy against cancer. Moreover, monoterpenoids depict promising potential in preventing cancer metastasis, however, inadequate clinical trials limit their drug usage. State-of-the-art techniques and technologies are being employed to overcome the challenges of utilizing monoterpenoids as an anticancer agent.

Panax quinquefolium L. and Salvia miltiorrhiza Bunge. Enhances Angiogenesis by Regulating the miR-155-5p/HIF-1α/VEGF Axis in Acute Myocardial Infarction.

Background: Combination of Panax quinquefolium L and Salvia miltiorrhiza Bunge. (PS) has been widely used in the clinical treatment of ischemic heart disease. The purpose of this study was to explore the therapeutic effect and mechanism of PS on angiogenesis in rats after acute myocardial infarction (AMI). Methods: A rat model of AMI was established by ligating the left anterior descending (LAD) artery. The grouping and administration scheme were as follows: sham group, model group, PS low-dose (PS-L) group, PS high-dose (PS-H) group, PX-478 group and angiotensin converting enzyme inhibitor (ACEI) group. After 28 days of treatment, echocardiography, myocardial infarct size, some angiogenesis markers and the miR-155-5p/HIF-1α/VEGF axis were measured. Results: PS improved cardiac structure and function, reduced infarct size, and alleviated myocardial fibrosis and inflammatory cell infiltration in AMI rats. Mechanistically, PS enhanced the expression of HGF and bFGF in serum, increased the levels of MVD and CD31 in myocardial tissues, and inhibited the activation of the miR-155-5p/HIF-1α/VEGF pathway, which ultimately promoted angiogenesis. In addition, the regulatory effect of PS on angiogenesis was partly abolished by PX-478. Conclusion: PS increased the expression of MVD and CD31 in the myocardium and stimulated angiogenesis. The above effects of PS may be associated with the inhibition of the miR-155-5p/HIF-1α/VEGF axis.

Hepatoprotective Effect of Medicine Food Homology Flower Saffron against CCl4-Induced Liver Fibrosis in Mice via the Akt/HIF-1α/VEGF Signaling Pathway.

Liver fibrosis refers to a complex inflammatory response caused by multiple factors, which is a known cause of liver cirrhosis and even liver cancer. As a valuable medicine food homology herb, saffron has been widely used in the world. Saffron is commonly used in liver-related diseases and has rich therapeutic and health benefits. The therapeutic effect is satisfactory, but its mechanism is still unclear. In order to clarify these problems, we planned to determine the pharmacological effects and mechanisms of saffron extract in preventing and treating liver fibrosis through network pharmacology analysis combined with in vivo validation experiments. Through UPLC-Q-Exactive-MS analysis, a total of fifty-six nutrients and active ingredients were identified, and nine of them were screened to predict their therapeutic targets for liver fibrosis. Then, network pharmacology analysis was applied to identify 321 targets for saffron extract to alleviate liver fibrosis. Functional and pathway enrichment analysis showed that the putative targets of saffron for the treatment of hepatic fibrosis are mainly involved in the calcium signaling pathway, the HIF-1 signaling pathway, endocrine resistance, the PI3K/Akt signaling pathway, lipid and atherosclerosis, and the cAMP signaling pathway. Based on the CCl4-induced liver fibrosis mice model, we experimentally confirmed that saffron extract can alleviate the severity and pathological changes during the progression of liver fibrosis. RT-PCR and Western blotting analysis confirmed that saffron treatment can prevent the CCl4-induced upregulation of HIF-1α, VEGFA, AKT, and PI3K, suggesting that saffron may regulate AKT/HIF-1α/VEGF and alleviate liver fibrosis.

Ethanol extract of basil (Ocimum Basilicum L.) leaves inhibits endometriosis growth in a mouse model by modulating vascular endothelial growth factor (VEGF) expression.

The objective of this study was to examine the effect of administering an ethanol extract obtained from basil leaves on the expression of vascular endothelial growth factor (VEGF) and the severity of endometriosis lesions in a mouse model. A total of 28 female mice, aged 2-3 months and weighing 20-30 grams, were randomly divided into four groups: the control group (C), treatment group 1 (T1) receiving a dose of basil leaf ethanol extract (0.21 mg/g-BW), treatment group 2 (T2) receiving a higher dose (0.42 mg/g BW), and treatment group 3 (T3) receiving the highest dose (0.84 mg/g-BW). Each group underwent a 14-day treatment period, and tissue samples were collected on the 29th day. An immunohistochemical examination was conducted to assess the expression of VEGF and evaluate the severity of endometriosis lesions. The statistical analysis of VEGF expression revealed a significant difference (p=0.026; p<0.05), with the most pronounced effects observed when administering basil leaf ethanol extract at doses of 0.21 mg/g-BW and 0.42 mg/g-BW. Although not statistically significant (p=0.271; p<0.05), a reduction in the severity of endometriosis lesions was observed following the administration of basil leaf ethanol extract at doses of 0.21 mg/g-BW and 0.42 mg/g-BW. Administering basil leaf ethanol extract at doses of 0.21 mg/g-BW and 0.42 mg/g-BW effectively decreased VEGF expression and limited the severity of endometriosis lesions.

Complementary Gene Therapy after Revascularization with the Saphenous Vein in Diabetic Foot Syndrome.

Diabetic foot syndrome (DFS) is one of the most serious macroangiopathic complications of diabetes. The primary treatment option is revascularization, but complementary therapies are still being sought. The study group consisted of 18 patients diagnosed with ischemic ulcerative and necrotic lesions in DFS. Patients underwent revascularization procedures and, due to unsatisfactory healing of the lesions, were randomly allocated to two groups: a group in which bicistronic VEGF165/HGF plasmid was administered and a control group in which saline placebo was administered. Before gene therapy administration and after 7, 30, 90, and 180 days, color duplex ultrasonography (CDU) was performed, the ankle-brachial index (ABI) and transcutaneous oxygen pressure (TcPO2) were measured, and DFS changes were described and documented photographically. In the gene therapy group, four out of eight patients (50%) healed their DFS lesions before 12 weeks. During this time, the ABI increased by an average of 0.25 and TcPO2 by 30.4 mmHg. In the control group, healing of the lesions by week 12 occurred in six out of nine patients (66.67%), and the ABI increased by an average of 0.14 and TcPO2 by 27.1 mmHg. One major amputation occurred in each group. Gene therapy may be an attractive option for complementary treatment in DFS.

Therapeutic Management and New Upcoming Approaches for Age Related Macular Degeneration.

Age-related Macular Degeneration (AMD) is a severe eye illness that is going to lead in the race for incurable blindness globally among the elderly population. AMD is the third common reason responsible for affecting the quality of life globally. The macula and the retinal layers are adversely affected during AMD and are responsible for the loss of vision eventually. Numerous genetic variables, lipid metabolism, ageing and oxidative damage are the causative factors in the genesis of AMD. Lack of antioxidants, smoking and excessive alcohol intake contribute to increasing the risk of AMD. Management of dry AMD involves the use of nutritional supplements like zinc and antioxidants, along with conventional treatment, however, the use of nutritional supplements can only give minor benefits on the progression of dry AMD. Later stages of AMD need to be managed by cell-based interventions where the damaged or lost cells are replaced with fresh donor cells. A plethora of treatment methods are used in the management of AMD, such as nutrition, antibody-based treatments, stem cell management and nanotherapeutics. The available expensive treatments come with a number of adverse effects and future developments require the involvement of risk factor modification approaches, personalized therapy, targeting the disease specific pathways, exploring better anti-vascular endothelial growth factor (VEGF) inhibitors and many other regenerative approaches, that will broaden techniques to diagnose, control and treat AMD. This review provides an overview of the progression of AMD and the causative factors, with considerable emphasises on the current and potential prospects.

Kaempferol attenuates carbon tetrachloride (CCl4)-induced hepatic fibrosis by promoting ASIC1a degradation and suppression of the ASIC1a-mediated ERS.

BACKGROUND: Kaempferol is a flavonoid derived from the herb, Kaempferia galanga L., in addition to exhibiting a wide range of pharmacological properties, kaempferol is also an anti-inflammatory, anti-lipid metabolizing, and anti-oxidative stress agent. The underlying molecular mechanisms of its effects on vascular endothelial growth factor (VEGF) secretion and activation of hepatic stellate cells (HSCs) are yet unknown. Activated HSCs induces VEGF release and extracellular matrix (ECM) accumulation which are important factors in hepatic fibrosis. PURPOSE: Our aim is to explore how kaempferol may affect hepatic fibrosis and the mechanisms behind its effects. METHODS: The in vivo model was Sprague-Dawley rats induced with carbon tetrachloride (CCl4). Histological staining was used to observe histological features of the liver. The levels of (alanine aminotransferase) ALT and (aspartate aminotransferase) AST were detected by the corresponding kits. Platelet-derived growth factor (PDGF) was used to stimulate the HSC-T6 rat hepatic stellate cells. The mechanisms underlying this process were investigated using a variety of molecular approaches, including immunofluorescence, RT-qPCR, and western blotting. Moreover, intracellular Ca2+ were observed by laser confocal microscope. RESULTS: It was found that kaempferol significantly reduced the expression of ASIC1a, VEGF, α-SMA and Collagen-I proteins in a model of CCl4-induced hepatic fibrosis in rats. In HSC-T6, kaempferol inhibits activation of HSCs by decreasing expression of ASIC1a, eIF2α, p-eIF2α and ATF-4. Laser confocal fluorescence showed that kaempferol inhibited Ca2+ influx and reduced Ca2+ concentration around the endoplasmic reticulum. Molecular docking and cellular thermal shift assay (CETSA) results further indicated that kaempferol interacted with ASIC1a. We found that kaempferol may promote the degradation of ASIC1a and inhibited ASIC1a- mediated upregulation of ERS. CONCLUSION: The data from our in vivo experiments demonstrate that kaempferol effectively attenuates hepatic fibrosis. In vitro studies we further propose a novel mechanism of kaempferol against hepatic fibrosis which can interact with ASIC1a and promote ASIC1a degradation while inhibiting the activation and VEGF release of HSCs by suppressing the ASIC1a-eIF2α-ATF-4 signaling pathway.

Unraveling the Angiogenic Puzzle: Pre-Treatment sVEGFR1 and sVEGFR2 Levels as Promising Prognostic Indicators in Early-Stage Breast Cancer Patients.

Despite the advancements in breast cancer (BrC) diagnosis and treatment, a considerable proportion of patients with early-stage disease still experience local recurrence or metastasis. This study aimed to assess the levels of specific angiogenic parameters in the EDTA plasma of BrC patients before and after treatment and to explore their clinical and prognostic significance. The levels of vascular endothelial growth factor A (VEGF-A), soluble form of vascular endothelial growth factor receptor type 1 (sVEGFR1), and soluble form of vascular endothelial growth factor receptor type 2 (sVEGFR2) were measured in 84 early BrC patients, both prior to surgery and within a median time of nine months post-treatment. Prognostic significance was evaluated using Kaplan-Meier survival and Cox regression analyses. Linear regression models were employed to examine the independent impact of selected angiogenic factors on DFS in breast cancer patients. The results of uni- and multivariate analyses indicated that a pre-treatment concentration of sVEGFR1 above 30.99 pg/mL was associated with improved disease-free survival (DFS) (p < 0.0001 for both analyses), while a pre-treatment concentration of sVEGFR2 above 9475.67 pg/mL was associated with an increased risk of BrC relapse (p < 0.0001 for both analyses). Additionally, a post-treatment concentration of sVEGFR2 above 7361.71 pg/mL was associated with better overall survival (OS) based on the Kaplan-Meier survival analysis (p = 0.0141). Furthermore, linear regression models revealed a significant inverse association between pre-treatment levels of sVEGFR1 and the risk of relapse (standardized ß -0.2578, p = 0.0499) and a significant positive association of VEGF-A levels with the risk of recurrence (standardized ß 0.2958, p = 0.0308). In conclusion, the findings suggest that both pre- and post-treatment levels of sVEGFR1 and sVEGFR2 may hold promise as potential prognostic markers for BrC patients.

Lagopsis supina ameliorates myocardial ischemia injury by regulating angiogenesis, thrombosis, inflammation, and energy metabolism through VEGF, ROS and HMGB1 signaling pathways in rats.

BACKGROUND: Lagopsis supina (Steph. ex. Willd.) Ikonn.-Gal. is an important traditional Chinese medicine used to treat various ailments. However, its impact on myocardial ischemia (MI) injury remains unknown. PURPOSE: This research aimed to reveal the therapeutic effect, potential mechanism, and metabolomics of L. supina against MI injury in rats. METHODS: The therapeutic effects of the ethanolic extract of L. supina (LS) and its four fractions (LSA∼D) on a left anterior descending (LAD) artery occlusion-induced MI model rat were explored. The pharmacodynamics including myocardial infraction area, myocardial tissue pathology and apoptosis, and serum biochemical parameters (CK, CK-MB, CTn-T, SOD, ET-1, NO, eNOS, VEGF, TXB2, 6-keto-PGF1α, TNF-α, IL-6, and CRP) were evaluated. The 24 related protein expressions were detected using western blotting assay. Simultaneously, the qualitative and quantitative analyses of microporous adsorption resin with 30% (LSC) and 60% (LSD) aqueous ethanol fractions were performed using UHPLC-MS and HPLC. Moreover, the serum metabolomics analysis of rats was profiled using UHPLC-MS. RESULTS: LS exerted remarkable alleviating effect on MI in rats. Importantly, LSC and LSD, two effective fractions of LS, significantly reduced myocardial infraction area, alleviated myocardial tissue pathology and apoptosis, regulated serum biochemical parameters. Furthermore, LSC and LSD markedly up-regulated the levels of VEGF-A, VEGFR-2, PKC, Bcl-2, Nrf2, HO-1, and thrombin, as well as prominently down-regulated the protein expression of Notch 1, p-PI3K, p-PI3K/PI3K, p-Akt, p-Akt/Akt, Bax, cleaved-caspase-3, cleaved-caspase-3/caspase-3, vWF, p-Erk, p-Erk/Erk, HMGB1, p-p38, p-p38/p38, p-p65, and p-p65/p65. A total of 26 candidate biomarkers were significantly regulated by LSC and LSD and they are mainly involved in amino acid metabolism, glycerophospholipid metabolism, and sphingolipid metabolism. Finally, phenylethanols and flavonoids may be major bio-constituents of LSC and LSD against MI. CONCLUSIONS: This work, for the first time, demonstrated that L. supina had a significant therapeutic effect on MI in rats. Additionally, LSC and LSD, two bio-fractions from L. supina, exerted their potential to ameliorate MI injury by promoting angiogenesis, inhibiting thrombosis, blocking inflammation, and facilitating energy metabolism through promotion of VEGF pathway, as well as suppression of ROS and HMGB1 pathways in rats. These findings suggest that LSC and LSD hold promise as potential therapeutic agents for MI injury in clinical application.