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Stem cell therapy and skin substitutes address the stalled healing of chronic wounds in order to promote wound closure; however, the high cost and regulatory hurdles of these treatments limit patient access. A low‐cost method to induce bioactive healing has the potential to substantially improve patient care and prevent wound‐induced limb loss. A previous study reported that bioactive factors derived from apoptotic‐like mesenchymal stem cells (MSCs) demonstrated anti‐inflammatory and proangiogenic effects and improved ischemic muscle regeneration. In this work, these MSC‐derived bioactive factors were loaded into a hydrogel foam to harness immunomodulatory and angiogenic properties from MSC components to facilitate chronic wound healing without the high cost and translational challenges of cell therapies. After incorporation of bioactive factors, the hydrogel foam retained high absorbency, moisture retention, and target water vapor transmission rate. High loading efficiency was confirmed and release studies indicated that over 90% of loaded factors were released within 24 h. Ethylene oxide sterilization and 4‐week storage did not affect the bioactive factor release profile or physical properties of the hydrogel foam dressing. Bioactivity retention of the released factors was also confirmed for as‐sterilized, 4°C‐stored, and −20°C‐stored bioactive hydrogel foams as determined by relevant gene expression levels in treated pro‐inflammatory (M1) macrophages. These results support the use of the bioactive dressings as an off‐the‐shelf product. Overall, this work reports a new method to achieve a first‐line wound dressing with the potential to reduce persistent inflammation and promote angiogenesis in chronic wounds. [ABSTRACT FROM AUTHOR]

Cell implantation offers an appealing avenue for heart repair after myocardial infarction (MI). Nevertheless, the implanted cells are subjected to the aberrant myocardial niche, which inhibits cell survival and maturation, posing significant challenges to the ultimate therapeutic outcome. The functional cardiac patches (CPs) have been proved to construct an elastic conductive, antioxidative, and angiogenic microenvironment for rectifying the aberrant microenvironment of the infarcted myocardium. More importantly, inducing implanted cardiomyocytes (CMs) adapted to the anisotropic arrangement of myocardial tissue by bioengineered structural cues within CPs are more conducive to MI repair. Herein, a functional Cig/(TA-Cu) CP served as biomimetic cardiac niche was fabricated based on structural anisotropic cigarette filter by modifying with tannic acid (TA)-chelated Cu2+ (TA-Cu complex) via a green method. This CP possessed microstructural anisotropy, electrical conductivity and mechanical properties similar to natural myocardium, which could promote elongation, orientation, maturation, and functionalization of CMs. Besides, the Cig/(TA-Cu) CP could efficiently scavenge reactive oxygen species, reduce CM apoptosis, ultimately facilitating myocardial electrical integration, promoting vascular regeneration and improving cardiac function. Together, our study introduces a functional CP that integrates multimodal cues to create a biomimetic cardiac niche and provides an effective strategy for cardiac repair.

Severe burn injuries with massive dermal loss are often underestimated despite their significant impact on morbidity and mortality. Resembling the natural extracellular matrix (ECM), hyaluronic acid (HA)-based dressings have been extensively explored as suitable candidates for burn wound treatment. However, native HA hydrogel's limitations, such as low mechanical strength, rapid degradation, and uncontrollable drug delivery, hinder its efficacy, especially for full-thickness burns requiring injectable hydrogels with robust antibacterial and angiogenic capabilities. Herein, we present a novel multifunctional sequential dual-curing hydrogel system, combining hyperbranched poly(DMA-DMAPMA-PEGDA) (DDP) polymer with thiolated hyaluronic acid (HA-SH). The DDP copolymer, featuring multi-vinyls and catechol functionalities, facilitates two curing reactions taking place sequentially with HA-SH under physiological conditions, balancing convenient injection with the mechanical strength essential for effective wound management. Furthermore, the resulting DDP/HA hydrogels demonstrate enhanced therapeutic attributes, including intrinsic angiogenic and antimicrobial effects, setting them as promising dressing options for deep burn wound therapy. [Display omitted] [ABSTRACT FROM AUTHOR]

Objective: To evaluate the materno‐fetal outcome of high‐risk women using placental growth factor (PlGF). Methods: This prospective cohort study was performed at a tertiary care hospital from September 2019 to April 2022. Women having clinically major or minor high risk factors of pre‐eclampsia were included after consent. The placental growth factor (PlGF) was evaluated among high‐risk women at 20–22, 28–30, and 34–36 weeks of gestation. They were followed throughout pregnancy until delivery. Materno‐fetal outcome was evaluated based on PlGF levels at three different time points. The gestational age specific cutoff was derived. Those with levels below cutoff were taken as cases and those with values above cutoff were considered as controls. The odds of having complications if the PlGF was below cutoff were determined. Results: Out of 287 high‐risk women, 46 (16%) had pre‐eclampsia (PE). The derived cutoff of PlGF was 224, 211, and 176 pg/mL at 20–22, 28–30, and 34–36 weeks, respectively. With PlGF below the cutoff at 20–22 weeks the odds of having HELLP syndrome was 15.8, with low PlGF at 28–30 weeks the odds for developing early onset PE was 11.3. Low PlGF was also significantly associated with preterm delivery (P < 0.001) and early onset FGR (P < 0.001). The sensitivity (91.7%) and specificity (78.5%) of PlGF for PE prediction was highest at 28–30 weeks. Conclusion: Low PlGF at 28–30 weeks was associated with high likelihood of developing early onset PE, and the PlGF cutoff should be gestational age specific. Synopsis: The best time for the estimation of PlGF was 28–0 weeks low levels at this gestation increased the chance of early onset PE up to four‐fold, and could predict its occurrence in nine out of 10 cases. [ABSTRACT FROM AUTHOR]

A pre-hydrated thermosensitive collagenated biomaterial which sets at body temperature and maintains the space of the missing alveolar bone volume, OsteoBiol GTO® (GTO), has been released as a bone substitute. This study was designed to check its angiogenic and osteogenic potentials compared to OsteoBiol Gen-Os® (Gen-Os) and Geistlich Bio-Oss® (Bio-Oss). Samples of materials were incubated in culture media to obtain the extracts. Collagen release was measured in the extracts, which were used to investigate human periodontal ligament (hPDL) cell proliferation (MTT), colonization (Scratch assays) and growth factor release (ELISA). The effects on endothelial cell proliferation (MTT) and organization (Matrigel® assays) were also studied. Finally, endothelial and mesenchymal Stem Cell (hMSC) recruitment (Boyden Chambers) were investigated, and hMSC Alkaline Phosphatase (ALP) activity was measured. A higher collagen concentration was found in GTO extract, which led to significantly higher hPDL cell proliferation/colonization. All materials increased VEGF/FGF-2 growth factor secretion, endothelial cell recruitment, proliferation, and organization, but the increase was highest with GTO. All materials increased hMSC recruitment and ALP activity. However, the increase was highest with collagenated GTO and Gen-Os, which enhanced C5a and BMP-2 secretion. Overall, GTO has higher angiogenic/osteogenic potentials than the collagenated Gen-Os and the anorganic Bio-Oss. It provides a suitable scaffold for endothelial and mesenchymal stem cell recruitment, which represent essential bone regeneration requirements. [ABSTRACT FROM AUTHOR]

Mammals' immune systems react strongly to lipopolysaccharide, an endotoxin present in the outer membrane of gram-negative bacteria. Previous data show that the lipopolysaccharide challenge has a significant impact on reproductive function. This study aimed to explore the toxic effects of lipopolysaccharide on the uterine and ovarian tissues of female Wistar albino rats. Additionally, we investigated the effects of lipopolysaccharide on the expression of angiogenic and insulin growth factor 1 protein as well as oxidative stress markers in the uterus and ovaries. The experimental rats were allocated into two groups: (1) control group (n = 8): received intraperitoneal injection of pyrogen-free 0.9% NaCl and (2) treatment group (n = 12): single intraperitoneal injection of a non-lethal dose of lipopolysaccharide. Rats were sacrificed, and uterus and ovaries were collected at 6- and 72-hour time points after lipopolysaccharide infusion. The exposure of the female rats to lipopolysaccharide induced a significant change in the antioxidant activity in both ovarian and uterine tissues especially after 72 hours of exposure. The exposure of nonpregnant rats to lipopolysaccharide leads to the degeneration of the ovarian follicles and superficial epithelium layer of the uterus. Also, the exposure of female rats to lipopolysaccharide leads to the upregulation of angiogenic proteins in both the ovaries and uterus and decreased expression of insulin growth factor 1 and insulin growth factor R1, especially after 72 hours. In conclusion, lipopolysaccharide is considered as one of the most potent bacterial virulence factors that causes endometrial inflammation and reproductive disorders. [ABSTRACT FROM AUTHOR]

Blood vessels are a key target for cancer therapy. Compared with the healthy vasculature, tumor blood vessels are extremely immature, highly permeable, and deficient in pericytes. The aberrantly vascularized tumor microenvironment is characterized by hypoxia, low pH, high interstitial pressure, and immunosuppression. The efficacy of chemotherapy, radiotherapy, and immunotherapy is affected by abnormal blood vessels. Some anti-angiogenic drugs show vascular normalization effects in addition to targeting angiogenesis. Reversing the abnormal state of blood vessels creates a normal microenvironment, essential for various cancer treatments, specifically immunotherapy. In addition, immune cells and molecules are involved in the regulation of angiogenesis. Therefore, combining vascular normalization with immunotherapy may increase the efficacy of immunotherapy and reduce the risk of adverse reactions. In this review, we discussed the structure, function, and formation of abnormal vessels. In addition, we elaborated on the role of the immunosuppressive microenvironment in the formation of abnormal vessels. Finally, we described the clinical challenges associated with the combination of immunotherapy with vascular normalization, and highlighted future research directions in this therapeutic area. [ABSTRACT FROM AUTHOR]

Natural bone is a composite tissue made of organic and inorganic components, showing piezoelectricity. Whitlockite (WH), which is a natural magnesium-containing calcium phosphate, has attracted great attention in bone formation recently due to its unique piezoelectric property after sintering treatment and sustained release of magnesium ion (Mg2+). Herein, a composite scaffold (denoted as PWH scaffold) composed of piezoelectric WH (PWH) and poly(ε-caprolactone) (PCL) was 3D printed to meet the physiological demands for the regeneration of neuro-vascularized bone tissue, namely, providing endogenous electric field at the defect site. The sustained release of Mg2+ from the PWH scaffold, displaying multiple biological activities, and thus exhibits a strong synergistic effect with the piezoelectricity on inhibiting osteoclast activation, promoting the neurogenic, angiogenic, and osteogenic differentiation of bone marrow mesenchymal stromal cells (BMSCs) in vitro. In a rat calvarial defect model, this PWH scaffold is remarkably conducive to efficient neo-bone formation with rich neurogenic and angiogenic expressions. Overall, this study presents the first example of biomimetic piezoelectric scaffold with sustained Mg2+ release for promoting the regeneration of neuro-vascularized bone tissue in vivo, which offers new insights for regenerative medicine.

Mesenchymal stem/stromal cell (MSC)-based therapies have been evaluated in over 1500 human clinical trials for a diverse array of disease indication, but outcomes remain unpredictable due to knowledge gaps in the quality attributes that confer therapeutic potency onto cells and their mode of action in vivo. Based on accumulated evidence from pre-clinical models, MSCs exert therapeutic effects by repressing inflammatory and immune-mediated response via paracrine action following reprogramming by the host injury microenvironment, and by polarization of tissue resident macrophages following phagocytosis to an alternatively activated (M2) state. An important tenet of this existing paradigm is that well-established stem/progenitor functions of MSCs are independent of paracrine function and dispensable for their anti-inflammatory and immune suppressive functions. Herein, we review evidence that stem/progenitor and paracrine functions of MSCs are mechanistically linked and organized hierarchically and describe how this link may be exploited to develop metrics that predict MSC potency across a spectrum of activities and regenerative medicine applications. [ABSTRACT FROM AUTHOR]

Background: Neuroendocrine neoplasms are a heterogeneous group of tumors that raise challenges in terms of diagnosis, treatment and monitoring. Despite continuous efforts, no biomarker has showed satisfying accuracy in predicting outcome or response to treatment. Methods: We conducted a systematic review to determine relevant circulating biomarkers for angiogenesis in neuroendocrine tumors. We searched three databases (Pubmed, Embase, Web of Science) using the keywords “neuroendocrine” and “biomarkers”, plus specific biomarkers were searched by full and abbreviated name. From a total of 2448 publications, 11 articles met the eligibility criteria. Results: VEGF is the most potent and the most studied angiogenic molecule, but results were highly controversial. Placental growth factor, Angiopoietin 2 and IL-8 were the most consistent markers in predicting poor outcome and aggressive disease behavior. Conclusions: There is no robust evidence so far to sustain the use of angiogenic biomarkers in routine practice, although the results show promising leads.

One of the most formidable challenges in oncology and tumor biology research is to provide an accurate understanding of tumor dormancy mechanisms. Dormancy refers to the ability of tumor cells to go undetected in the body for a prolonged period, followed by "spontaneous" escape. Various models of dormancy have been postulated, including angiogenic, immune-mediated, and cellular dormancy. While the former two propose mechanisms by which tumor growth may remain static at a population level, cellular dormancy refers to molecular processes that restrict proliferation at the cell level. Senescence is a form of growth arrest, during which cells undergo distinct phenotypic, epigenetic, and metabolic changes. Senescence is also associated with the development of a robust secretome, comprised of various chemokines and cytokines that interact with the surrounding microenvironment, including other tumor cells, stromal cells, endothelial cells, and immune cells. Both tumor and non-tumor cells can undergo senescence following various stressors, many of which are present during tumorigenesis and therapy. As such, senescent cells are present within forming tumors and in residual tumors post-treatment and therefore play a major role in tumor biology. However, the contributions of senescence to dormancy are largely understudied. Here, we provide an overview of multiple processes that have been well established as being involved in tumor dormancy, and we speculate on how senescence may contribute to these mechanisms. [ABSTRACT FROM AUTHOR]

A pre-hydrated thermosensitive collagenated biomaterial which sets at body temperature and maintains the space of the missing alveolar bone volume, OsteoBiol GTO® (GTO), has been released as a bone substitute. This study was designed to check its angiogenic and osteogenic potentials compared to OsteoBiol Gen-Os® (Gen-Os) and Geistlich Bio-Oss® (Bio-Oss). Samples of materials were incubated in culture media to obtain the extracts. Collagen release was measured in the extracts, which were used to investigate human periodontal ligament (hPDL) cell proliferation (MTT), colonization (Scratch assays) and growth factor release (ELISA). The effects on endothelial cell proliferation (MTT) and organization (Matrigel® assays) were also studied. Finally, endothelial and mesenchymal Stem Cell (hMSC) recruitment (Boyden Chambers) were investigated, and hMSC Alkaline Phosphatase (ALP) activity was measured. A higher collagen concentration was found in GTO extract, which led to significantly higher hPDL cell proliferation/colonization. All materials increased VEGF/FGF-2 growth factor secretion, endothelial cell recruitment, proliferation, and organization, but the increase was highest with GTO. All materials increased hMSC recruitment and ALP activity. However, the increase was highest with collagenated GTO and Gen-Os, which enhanced C5a and BMP-2 secretion. Overall, GTO has higher angiogenic/osteogenic potentials than the collagenated Gen-Os and the anorganic Bio-Oss. It provides a suitable scaffold for endothelial and mesenchymal stem cell recruitment, which represent essential bone regeneration requirements.

Abstract Background Malaria related mortality is associated with significant deregulation of host inflammatory factors such as interferon-inducible protein 10, a member of the CXC or α-subfamily (CXCL10), and host angiogenic factors such as angiopoietin 1 (Ang-1) and angiopoietin 2 (Ang-2). However, detection of these factors in malaria patients requires the drawing of blood, which is invasive and increases the risk of accidental blood-borne infections. There has been an increased interest in the use of saliva as the body fluid of choice for the diagnosis of many infectious diseases including malaria. Here, saliva levels of CXCL10, Ang-1, and Ang-2 previously shown to be predictive of severe malaria in malaria patients in Ghana were assessed in malaria patients. Methods This study was conducted in the Shai-Osudoku District Hospital in Dodowa, Accra, Ghana and the study population comprised 119 malaria patients and 94 non-malaria subjects. The non-malaria subjects are healthy community participants with no malaria infection. Plasma and saliva levels of CXCL10, Ang-1 and Ang-2 of the study participants were measured using an enzyme-linked immunoassay. Complete blood counts of each participant were measured with a haematology autoanalyzer. Pearson correlation was used to evaluate the correlation between plasma and saliva levels of each biomarker in malaria patients. A p-value of

Hydrogels with novel antimicrobial properties and accelerated wound healing are of great interest in the field of wound dressings because they not only prevent bacterial infections but also fulfill the essential needs of wound healing. In this study, multifunctional hydrogel dressings consisting of black phosphorus nanosheets(BPNS) surface-modified Zinc oxide (BP@ZnO heterojunction) based on gelatin (Gel), sodium alginate (SA), glutamine transferase (mTG), and calcium ions with a three-dimensional crosslinked network were prepared. The BP@ZnO-Gel/SA hydrogel has excellent mechanical properties, hemocompatibility (hemolysis rate: 3.29 %), swelling rate(832.8 ± 19.2 %), cytocompatibility, photothermal and photodynamic antibacterial properties(Sterilization rate: 96.4 ± 3.3 %). In addition, the hydrogel accelerates wound healing by promoting cell migration, immune regulation and angiogenesis. Thus, this hydrogel achieves the triple effect of antimicrobial, immunomodulation and angiogenesis, and is a tissue engineering strategy with great potential. [ABSTRACT FROM AUTHOR]

In this study, we investigated a mathematical model that integrated mechanisms of tumor angiogenesis and tumor-targeted cytotoxicity in immune cells. The model considered the interaction of cancer cells with the immune system and the treatment that combines unlicensed dendritic cells and anti-vascular endothelial growth factor antibodies. We proposed an unconventional treatment protocol; for now, treatment is purely theoretical and has not been practically attempted. The treatment has been described by analytical functions that depend on time and dose. This was a function of t and q, where q is the amount (dose) of the drug. A customized treatment is a significant advantage of explicit analytical functions. We compared the results obtained from the mathematical model with the proposed treatment to the clinical results and observed an almost complete match between the treatments.In addition, we applied the global quasi-linearization GQL method to the mathematical model, which enabled us to expose the hierarchy of the system and, hence, split the system into fast and slow subsystems. This decomposition enabled us to analytically compute the equilibrium points of the model and their stability, which is crucial for the application.

Angiogenesis is the formation of new blood vessels from pre-existing vessels. Adequate oxygen transport and waste removal are necessary for tissue homeostasis. Restrictions in blood supply can lead to ischaemia which can contribute to disease pathology. Vascular endothelial growth factor (VEGF) is essential in angiogenesis and myogenesis, making it an ideal candidate for angiogenic and myogenic stimulation in muscle. We established C2C12 mouse myoblast cell lines which stably express elevated levels of (i) human VEGF-A and (ii) dual human FGF4-VEGF-A. Both stably transfected cells secreted increased amounts of human VEGF-A compared to non-transfected cells, with the latter greater than the former. In vitro, conditioned media from engineered cells resulted in a significant increase in endothelial cell proliferation, migration, and tube formation. In vivo, this conditioned media produced a 1.5-fold increase in angiogenesis in the chick chorioallantoic membrane (CAM) assay. Delivery of the engineered myoblasts on Matrigel demonstrated continued biological activity by eliciting an almost 2-fold increase in angiogenic response when applied directly to the CAM assay. These studies qualify the use of genetically modified myoblasts in therapeutic angiogenesis for the treatment of muscle diseases associated with vascular defects. [ABSTRACT FROM AUTHOR]

Distraction osteogenesis (DO) represents a highly effective method for addressing significant bone defects; however, it necessitates a long treatment period. Exosomes are key mediators of intercellular communication. To investigate their role in the angiogenesis and osteogenesis of DO, we established a canine mandibular DO model with a bone defect (BD) group as the control. Higher levels of angiogenesis were observed in the regenerating tissue from the DO group compared to those from the BD group, accompanied by earlier osteogenesis. Proteomic analysis was performed on circulating exosomes at different phases of the DO using a data-independent acquisition method. Data are available via ProteomeXchange with the identifier PXD050531. The results indicated specific alterations in circulating exosome proteins at different phases of DO, reflecting the regenerative activities in the corresponding tissues. Notably, fibronectin 1 (FN1), thrombospondin 1 (THBS1), and transferrin receptor (TFRC) emerged as potential candidate proteins related to the angiogenic response in DO. Further cellular experiments validated the potential of DO-associated circulating exosomes to promote angiogenesis in endothelial cells. Collectively, these data reveal previously unknown mechanisms that may underlie the efficacy of DO and suggest that exosome-derived proteins may be useful as therapeutic targets for strategies designed to improve DO-related angiogenesis and bone regeneration.

Objective:To compare the effect of comorbidities on the phenotype and outcomes of preeclampsia. Methods: A matched retrospective cohort study of women delivering at a tertiary maternity center following a diagnosis of preeclampsia. We collected data on signs and symptoms, biochemical markers, and maternal and perinatal outcomes. Results:We studied 474 women; 158 women with and 316 without comorbidities. Compared to women without comorbidities, women with comorbidities delivered earlier. They suffered fewer maternal but more neonatal complications. Conclusion: Women with comorbidities receive earlier intervention than women without comorbidities, which may lead to fewer maternal complications but worse neonatal outcomes.

Background: Malaria related mortality is associated with significant deregulation of host inflammatory factors such as interferon-inducible protein 10, a member of the CXC or α-subfamily (CXCL10), and host angiogenic factors such as angiopoietin 1 (Ang-1) and angiopoietin 2 (Ang-2). However, detection of these factors in malaria patients requires the drawing of blood, which is invasive and increases the risk of accidental blood-borne infections. There has been an increased interest in the use of saliva as the body fluid of choice for the diagnosis of many infectious diseases including malaria. Here, saliva levels of CXCL10, Ang-1, and Ang-2 previously shown to be predictive of severe malaria in malaria patients in Ghana were assessed in malaria patients. Methods: This study was conducted in the Shai-Osudoku District Hospital in Dodowa, Accra, Ghana and the study population comprised 119 malaria patients and 94 non-malaria subjects. The non-malaria subjects are healthy community participants with no malaria infection. Plasma and saliva levels of CXCL10, Ang-1 and Ang-2 of the study participants were measured using an enzyme-linked immunoassay. Complete blood counts of each participant were measured with a haematology autoanalyzer. Pearson correlation was used to evaluate the correlation between plasma and saliva levels of each biomarker in malaria patients. A p-value of < 0.05 was considered significant. Box plots of median biomarker concentrations were plotted. SPSS version 14.2 software was used for statistical analysis. Results: The non-malaria subjects had a median age of 29 years compared to 23 years for malaria patients (p = 0.001). Among the malaria patients, there was a strong significant relationship between CXCL10 (R2 = 0.7, p < 0.0001) and Ang-1 (R2 = 0.7, p < 0.0001). Malaria patients had lower saliva levels of Ang-1 (p = 0.009) and higher saliva levels of CXCL10 (p = 0.004) and Ang-2 (p = 0.001) compared to non-malaria subjects. Conclusions: This study provides the first evidence of elevated levels of CXCL10 and Ang-2 in the saliva of malaria patients. Detection of CXCL10, Ang-1 and Ang-2 in saliva may have a potential application for non-invasive malaria diagnosis. [ABSTRACT FROM AUTHOR]

Preeclampsia (PE) is a multisystem disorder of pregnancy characterized by sudden onset of hypertension and proteinuria. The appearance and diagnosis of the disease remain elusive and the only treatment is the termination of pregnancy. The onset of the disease is preceded by a shift in the balance of the angiogenic and antiangiogenic proteins in the maternal circulation. We surmised that the assessment of the levels of these proteins during pregnancy could lead to a proper diagnosis of the disease. In this study, we determined the levels of angiogenic and antiangiogenic proteins and IL-6 in maternal circulation during normotensive and hypertensive pregnancy, including PE. Serum isolated from pregnant women during antenatal visits was used to determine the concentrations of these proteins. The levels of antiangiogenic proteins, sFlt-1 and sEng, were higher in hypertensive disorders [gestational hypertension (GH), mild PE, and PE] of pregnancy and were significantly higher for PE than for GH. The levels of sFlt-1 and sEng were higher in PE samples compared to those in GH and NT samples. These proteins may have contributed to increased blood pressure. The levels of PlGF were decreased in pregnant women having GH, mild PE, and PE. The levels of the inflammatory intermediate, IL-6, were increased in PE samples compared to those in the GH and normotensive samples. The evaluation of the altered levels of antiangiogenic and angiogenic proteins can be useful for diagnosis of PE. [ABSTRACT FROM AUTHOR]

Hypoxia conditions induced by bone defects would prolong the duration of bone regeneration. The effect of osteostatin (OST) on the osteogenic differentiation of mesenchymal stem cells (MSCs) and angiogenesis under hypoxia conditions remain unexplored. SPF mice were obtained, and MSCs were isolated from bone marrow. MSCs were treated with 1% oxygen for hypoxia induction, and 200 nM of OST was used to treat cells under nomorxia or hypoxia conditions. Cell proliferation was evaluated using CCK8 assay, and trypan blue staining was implemented for determining cell death ratio. Alkaline phosphatase activity and alizarin redS staining was conducted to histologically evaluated osteogenic differentiation. Flow cytometry was used for the detection of CD31hiEmcnhi cells (Type H ECs), whose migration was detected by Transwell assay and angiogenesis was measured by tube formation assay. Protein level was measured by western blotting and mRNA level was monitored via RT-qPCR. The MSC proliferation was enhanced by OST under hypoxia conditions. The osteogenic differentiation of MSCs was decreased under hypoxia conditions, and treatment of OST significantly reversed its inhibitory effect. The hypoxia treated culture medium of MSCs promoted the proliferation, migration, and angiogenesis of type H ECs, while the effects were further strengthened by OST addition. HIF-1α was found to be upregulated in hypoxia treated MSCs, whereas silencing of HIF-1α had reversed effects on the angiogenic capacity of Type H ECs. OST improved the proliferation and osteogenic differentiation of MSCs and further promoted angiogenesis of type H ECs through upregulating HIF-1α expression. • OST enhanced MSCs proliferation and osteogenic differentiation. • OST treated MSCs promoted the migration and angiogenesis of type H ECs. • OST promoted angiogenic factor secretion via regulating HIF-1α levels. • HIF-1α-silenced MSCs decreased angiogenic capacity of Type H ECs. [ABSTRACT FROM AUTHOR]

Oral cancer is a dangerous and extensive cancer with a high death ratio. Oral cancer is the most usual cancer in the world, with more than 300,335 deaths every year. The cancerous tumor appears in the neck, oral glands, face, and mouth. To overcome this dangerous cancer, there are many ways to detect like a biopsy, in which small chunks of tissues are taken from the mouth and tested under a secure and hygienic microscope. However, microscope results of tissues to detect oral cancer are not up to the mark, a microscope cannot easily identify the cancerous cells and normal cells. Detection of cancerous cells using microscopic biopsy images helps in allaying and predicting the issues and gives better results if biologically approaches apply accurately for the prediction of cancerous cells, but during the physical examinations microscopic biopsy images for cancer detection there are major chances for human error and mistake. So, with the development of technology deep learning algorithms plays a major role in medical image diagnosing. Deep learning algorithms are efficiently developed to predict breast cancer, oral cancer, lung cancer, or any other type of medical image. In this study, the proposed model of transfer learning model using AlexNet in the convolutional neural network to extract rank features from oral squamous cell carcinoma (OSCC) biopsy images to train the model. Simulation results have shown that the proposed model achieved higher classification accuracy 97.66% and 90.06% of training and testing, respectively. [ABSTRACT FROM AUTHOR]

Infected diabetic wound (DW) healing entails a series of temporally and spatially regulated stages including antibacterial responses, revascularization, and collagen deposition, underscoring the need for the controlled sequential delivery of appropriate compounds when treating these wounds. Here, we designed a multifunctional core–shell CTS@PLCL/DWJM@Cu nanofiber loaded with three bioactive agents, including chitosan (CTS), copper (Cu), and decellularized Wharton’s jelly matrix (DWJM). We used this platform to facilitate regulated antibacterial, angiogenic, and collagen deposition activity in the context of DW healing. These CTS@PLCL/DWJM@Cu nanofibers exhibited satisfactory mechanical properties, excellent absorption, acceptable biodegradability, a high level of biocompatibility, elevated adhesive rates, and the ability to sequentially mediate controlled sequential CTS and Cu release. Further in vitro analyses revealed that the initial release of the CTS shell was sufficient to exert antibacterial activity, after which the sustained release of the Cu core promoted cellular migration, neovascularization, and enhanced angiogenesis-related gene expression. In vivo, DWJM further accelerated the deposition of collagen. Together, the sequential antibacterial, angiogenic, and collagen deposition activities synergistically enhanced DW healing. We thus posit that the core–shell CTS@PLCL/DWJM@Cu nanofiber holds great promise for use as a dressing material capable of promoting the appropriate stages of DW healing in a regulated, sequential manner.

Phospholipases A 2 (PLA 2 s) from snake venom possess antitumor and antiangiogenic properties. In this study, we evaluated the antimetastatic and antiangiogenic effects of MjTX-II, a Lys49 PLA 2 isolated from Bothrops moojeni venom, on lung cancer and endothelial cells. Using in vitro and ex vivo approaches, we demonstrated that MjTX-II reduced cell proliferation and inhibited fundamental processes for lung cancer cells (A549) growth and metastasis, such as adhesion, migration, invasion, and actin cytoskeleton decrease, without significantly interfering with non-tumorigenic lung cells (BEAS-2B). Furthermore, MjTX-II caused cell cycle alterations, increased reactive oxygen species production, modulated the expression of pro- and antiangiogenic genes, and decreased vascular endothelial growth factor (VEGF) expression in HUVECs. Finally, MjTX-II inhibited ex vivo angiogenesis processes in an aortic ring model. Therefore, we conclude that MjTX-II exhibits antimetastatic and antiangiogenic effects in vitro and ex vivo and represents a molecule that hold promise as a pharmacological model for antitumor therapy. [Display omitted] • PLA 2 Lys49 MjTX-II from Bothrops moojeni venom induces antimetastatic and antiangiogenic effects. • The toxin inhibits cell migration and invasion in lung cancer cells by wound healing and transwell assays. • MjTX-II modulates the expression of Angiopoietin-1, Vascular endothelial growth factor A and sFlt-1 gens. • The Toxin decreased cells in the G0-G1 phase and decreased reactive oxygen species formation in endothelial cells. • MjTX-II is a potential prototype for developing new tools and antitumor drugs in cancer therapy. [ABSTRACT FROM AUTHOR]

Tissue engineering of bones often necessitates the addition of exogenous growth factors and supplements to accelerate the differentiation of mesenchymal stem cells to osteogenic lineage, thereby increasing its cost. On the postulation that a scaffold that mimics the micro-/nano-bone architecture per se can provide the essential cues to favor osteogenesis, we developed gelatin nanofibers and loaded them with zinc-doped nano-hydroxyapatite (ZnHp). To further improve its osteogenic potential, the above nano-composite was additionally decorated with rGO platelets (ZnHp@rGO) and incorporated in gelatin nanofibers. On in vitro evaluation, the respective gelatin nanofibers appeared to aid the accelerated differentiation of mesenchymal stem cells toward the osteogenic lineage without the need for any exogenous osteogenic supplement in the milieu. The biomimetic cues provided by ZnHp and ZnHp@rGO also favored angiogenesis, with enhanced CD-31 and iNOS expression. The ability of these nanofibers to induce vascularization was confirmed using an in ovo and in vivo rat model. Apart from its osteoinductive and angiogenic properties, the nanofibers exhibited favorable anti-biofilm activity by preventing the growth of Staphylococcus aureus. Although these results suggest the potential of the scaffold for inducing bone repair in vivo, it also confirms that bones can be engineered at a relatively low cost by designing scaffolds having topographical and biochemical cues that mimic the bone microarchitecture. [ABSTRACT FROM AUTHOR]

The reported incidence of eclampsia is 1.6 to 10 per 10,000 deliveries in developed countries, whereas it is 50 to 151 per 10,000 deliveries in developing countries. In addition, low-resource countries have substantially higher rates of maternal and perinatal mortalities and morbidities. This disparity in incidence and pregnancy outcomes may be related to universal access to prenatal care, early detection of preeclampsia, timely delivery, and availability of healthcare resources in developed countries compared to developing countries. Because of its infrequency in developed countries, many obstetrical providers and maternity units have minimal to no experience in the acute management of eclampsia and its complications. Therefore, clear protocols for prevention of eclampsia in those with severe preeclampsia and acute treatment of eclamptic seizures at all levels of healthcare are required for better maternal and neonatal outcomes. Eclamptic seizure will occur in 2% of women with preeclampsia with severe features who are not receiving magnesium sulfate and in <0.6% in those receiving magnesium sulfate. The pathogenesis of an eclamptic seizure is not well understood; however, the blood-brain barrier disruption with the passage of fluid, ions, and plasma protein into the brain parenchyma remains the leading theory. New data suggest that blood-brain barrier permeability may increase by circulating factors found in preeclamptic women plasma, such as vascular endothelial growth factor and placental growth factor. The management of an eclamptic seizure will include supportive care to prevent serious maternal injury, magnesium sulfate for prevention of recurrent seizures, and promoting delivery. Although routine imagining following an eclamptic seizure is not recommended, the classic finding is referred to as the posterior reversible encephalopathy syndrome. Most patients with posterior reversible encephalopathy syndrome will show complete resolution of the imaging finding within 1 to 2 weeks, but routine imaging follow-up is unnecessary unless there are findings of intracranial hemorrhage, infraction, or ongoing neurologic deficit. Eclampsia is associated with increased risk of maternal mortality and morbidity, such as placental abruption, disseminated intravascular coagulation, pulmonary edema, aspiration pneumonia, cardiopulmonary arrest, and acute renal failure. Furthermore, a history of eclamptic seizures may be related to long-term cardiovascular risk and cognitive difficulties related to memory and concentration years after the index pregnancy. Finally, limited data suggest that placental growth factor levels in women with preeclampsia are superior to clinical markers in prediction of adverse pregnancy outcomes. This data may be extrapolated to the prediction of eclampsia in future studies. This summary of available evidence provides data and expert opinion on possible pathogenesis of eclampsia, imaging findings, differential diagnosis, and stepwise approach regarding the management of eclampsia before delivery and after delivery as well as current recommendations for the prevention of eclamptic seizures in women with preeclampsia. [ABSTRACT FROM AUTHOR]

Objective:To compare the effect of comorbidities on the phenotype and outcomes of preeclampsia. Methods: A matched retrospective cohort study of women delivering at a tertiary maternity center following a diagnosis of preeclampsia. We collected data on signs and symptoms, biochemical markers, and maternal and perinatal outcomes. Results:We studied 474 women; 158 women with and 316 without comorbidities. Compared to women without comorbidities, women with comorbidities delivered earlier. They suffered fewer maternal but more neonatal complications. Conclusion: Women with comorbidities receive earlier intervention than women without comorbidities, which may lead to fewer maternal complications but worse neonatal outcomes. [ABSTRACT FROM AUTHOR]

Shilajit is a natural substance found in the Himalayan region from Nepal to Pakistan. It is a decomposition product of Royle’s spurge , white clover , and different species of molds. The decomposition takes place over a time span of centuries by the action of microorganism. In the present study, shilajit samples from four different origins including siachen khaplu shilajit (SKS), kharmang pari saspolo shilajit (KPSS), kharmang ghandus shilajit (KGS), and kharmang shilajit center (KSC) of district Skardu, Pakistan were investigated. These samples were characterized using scanning electron microscopy (SEM), Energy-dispersive x-ray spectroscopy (EDS), x-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), and UV-visible spectroscopy (UV/vis). SEM revealed a notable difference in the shape and size of collected samples. All samples were found to possess crystalline nature, which is confirmed from XRD. The presence of multi-components and complex silicates confirmed the presence of humic substances (HS) in shilajit. A slight disparity in physiological properties of four samples were revealed due to geographical variations and ecological conditions, which determine the natural synthesis of shilajit. All samples exhibited antibacterial effects against Gram negative bacteria; Escherichia coli (E.coli) . About 76%, 98%, and 100% of bacteria were killed by SKS, both KPSS and KGS, and KSC samples, respectively. The cell viability analysis revealed that the KPSS (66%) and KGS (53%) were cyto-compatible as compared to the SKS (23%) and KSC (25%) samples. The Chick Chorionic Allantoic Membrane (CAM) assay was used to observe the angiogenic potential for SKS, KSC, and KGS samples. Hence, shilajit sample could be a potential candidate for the medicinal applications and offer a new approach to biomedical applications.

The increasing prevalence of bone replacements and complications associated with bone replacement procedures underscores the need for innovative tissue restoration approaches. Existing synthetic grafts cannot fully replicate bone vascularization and mechanical characteristics. This study introduces a novel strategy utilizing pectin, chitosan, and polyvinyl alcohol to create interpenetrating polymeric network (IPN) scaffolds incorporated with extracellular vesicles (EVs) isolated from human mesenchymal stem cells (hMSCs). We assess the osteointegration and osteoconduction abilities of these models in vitro using hMSCs and MG-63 osteosarcoma cells. Additionally, we confirm exosome properties through Transmission Electron Microscopy (TEM), immunoblotting, and Dynamic Light Scattering (DLS). In vivo , chick allantoic membrane assay investigates vascularization characteristics. The study did not include in vivo animal experiments. Our results demonstrate that the IPN scaffold is highly porous and interconnected, potentially suitable for bone implants. EVs, approximately 100 nm in size, enhance cell survival, proliferation, alkaline phosphatase activity, and the expression of osteogenic genes. EVs-mediated IPN scaffolds demonstrate promise as precise drug carriers, enabling customized treatments for bone-related conditions and regeneration efforts. Therefore, the EVs-mediated IPN scaffolds demonstrate promise as precise carriers for the transport of drugs, allowing for customized treatments for conditions connected to bone and efforts in regeneration., (© 2024 IOP Publishing Ltd.)

Research indicates that soluble fms-like tyrosine kinase 1 (sFLT-1) and placental growth factor (PLGF) have diagnostic and prognostic significance for women with preeclampsia. However, sparse research has studied these biomarkers in women with preexisting comorbidities such as chronic hypertension, diabetes mellitus, systemic lupus erythematosus and chronic kidney disease. We undertook a prospective longitudinal cohort study to compare the sFLT-1: PlGF ratio between women with and without comorbidities who did and did not go on to develop preeclampsia. We found that women with comorbidities may develop preeclampsia with a milder elevation in sFLT-1: PlGF than do women without comorbidities. This has clinical and research implications. [ABSTRACT FROM AUTHOR]

Since the process of angiogenesis is controlled by chemical signals, which stimulate both repair of damaged blood vessels and formation of new blood vessels, then other chemical signals known as angiogenesis inhibitors interfere with blood vessels formation. This implies that the stimulating and inhibiting effects of these chemical signals are balanced as blood vessels form only when and where they are needed. Based on this information, an optimal control problem is formulated and the arising model is a system of coupled non-linear equations with adjoint and transversality conditions. Since many of the numerical methods often fail to capture these type of models, therefore, in this paper, we carry out steady state analysis of these models before implementing the numerical computations. In this paper we analyze and present the numerical estimates as a way of providing more insight into the postvascular dormant state where stimulator and inhibitor come into balance in an optimal manner.

Angiogenesis is the formation of new blood vessels from pre-existing vessels. Adequate oxygen transport and waste removal are necessary for tissue homeostasis. Restrictions in blood supply can lead to ischaemia which can contribute to disease pathology. Vascular endothelial growth factor (VEGF) is essential in angiogenesis and myogenesis, making it an ideal candidate for angiogenic and myogenic stimulation in muscle. We established C2C12 mouse myoblast cell lines which stably express elevated levels of (i) human VEGF-A and (ii) dual human FGF4-VEGF-A. Both stably transfected cells secreted increased amounts of human VEGF-A compared to non-transfected cells, with the latter greater than the former. In vitro, conditioned media from engineered cells resulted in a significant increase in endothelial cell proliferation, migration, and tube formation. In vivo, this conditioned media produced a 1.5-fold increase in angiogenesis in the chick chorioallantoic membrane (CAM) assay. Delivery of the engineered myoblasts on Matrigel demonstrated continued biological activity by eliciting an almost 2-fold increase in angiogenic response when applied directly to the CAM assay. These studies qualify the use of genetically modified myoblasts in therapeutic angiogenesis for the treatment of muscle diseases associated with vascular defects.

Due to the limitations of bone autografts, we aimed to develop new composite biomaterials with pro-angiogenic and osteogenic properties to be used as scaffolds in bone tissue engineering applications. We used a porous, cross-linked and slowly biodegradable fibrin/alginate scaffold originally developed in our laboratory for wound healing, throughout which deposits of calcium phosphate (CaP) were evenly incorporated using an established biomimetic method. Material characterisation revealed the porous nature and confirmed the deposition of CaP precursor phases throughout the scaffolds. MC3T3-E1 cells adhered to the scaffolds, proliferated, migrated and differentiated down the osteogenic pathway during the culture period. Chick chorioallantoic membrane (CAM) assay results showed that the scaffolds were pro-angiogenic and biocompatible. The work presented here gave useful insights into the potential of these pro-angiogenic and osteogenic scaffolds for bone tissue engineering and merits further research in a pre-clinical model prior to its clinical translation. [ABSTRACT FROM AUTHOR]

Bone regeneration is a popular research focus around the world. Recent studies have suggested that the formation of a vascular network as well as intrinsic osteogenic ability is important for bone regeneration. Here, we show for the first time that matrix metalloproteinase (MMP) 2 inhibitor 1 (MMP2-I1) has a positive role in the osteogenesis of human bone marrow mesenchymal stem cells (hBMSCs) and angiogenesis of human vascular endothelial cells (HUVECs). MMP2-I1 activated the p38/mitogen-activated protein kinase signaling pathway to promote the osteogenesis of hBMSCs, and promoted the angiogenesis of HUVECs via the hypoxia-inducible factor-1α signaling pathway. We also found that MMP2-I1 enhanced bone formation using a rat tibial defect model and prevented bone loss using an ovariectomy-induced mouse model of osteoporosis. Data from the mouse model demonstrated that MMP2-I1 generated more type H vessels (CD31hiEmcnhi) when preventing bone loss. These results provide important insights into the regulatory effects of MMP2-I1 on bone regeneration.

Cell implantation offers an appealing avenue for heart repair after myocardial infarction (MI). Nevertheless, the implanted cells are subjected to the aberrant myocardial niche, which inhibits cell survival and maturation, posing significant challenges to the ultimate therapeutic outcome. The functional cardiac patches (CPs) have been proved to construct an elastic conductive, antioxidative, and angiogenic microenvironment for rectifying the aberrant microenvironment of the infarcted myocardium. More importantly, inducing implanted cardiomyocytes (CMs) adapted to the anisotropic arrangement of myocardial tissue by bioengineered structural cues within CPs are more conducive to MI repair. Herein, a functional Cig/(TA-Cu) CP served as biomimetic cardiac niche was fabricated based on structural anisotropic cigarette filter by modifying with tannic acid (TA)-chelated Cu 2+ (TA-Cu complex) via a green method. This CP possessed microstructural anisotropy, electrical conductivity and mechanical properties similar to natural myocardium, which could promote elongation, orientation, maturation, and functionalization of CMs. Besides, the Cig/(TA-Cu) CP could efficiently scavenge reactive oxygen species, reduce CM apoptosis, ultimately facilitating myocardial electrical integration, promoting vascular regeneration and improving cardiac function. Together, our study introduces a functional CP that integrates multimodal cues to create a biomimetic cardiac niche and provides an effective strategy for cardiac repair., Competing Interests: The authors declare that they have no competing interests., (© 2024 The Authors.)

The aim of the present study was to analyze the characteristics of angiogenic factors in patients with hypopharyngeal cancer, and to study the effects of these factors on induction chemotherapy, patient prognosis and survival. Data from 60 eligible patients with hypopharyngeal cancer that were treated between January 2012 and December 2016 were collected retrospectively. The differential expression of angiogenic factors in tumor and peritumoral tissues was analyzed retrospectively to assess the association between five differentially expressed genes, including interleukin (IL)-1β, transforming growth factor (TGF)-β, matrix metalloproteinase-9 (MMP-9), angiopoietin-2 and interferon-inducible T-cell α chemoattractant, and clinicopathological characteristics in different types of chemotherapy-associated blood vessels within samples of poorly differentiated hypopharyngeal cancer. The χ² test or t-test was used to compare the frequency data, the Kaplan-Meier method was used for survival analysis and the log-rank test was used to compare the Kaplan-Meier curves. P<0.05 was considered to indicate a statistically significant difference. The results of the present study demonstrated that there was a significant difference in the expression levels of vascular-associated factors between hypopharyngeal carcinoma and peritumoral tissues. Additionally, the results revealed a significant difference in the overall survival and prognosis of patients with a decreased vascular classification compared with patients with an unchanged vascular classification, which was assessed using narrowband imaging (NBI) following induction chemotherapy (P<0.05). The results of single factor analysis indicated that IL-1β, TGF-β and MMP-9 were associated with decreased blood vessel classification (P<0.05). In conclusion, IL-1β, TGF-β and MMP-9 may be used as predictors of the effect of induction chemotherapy on poorly differentiated hypopharyngeal cancer. Therefore, when patients with advanced hypopharyngeal cancer undergo chemotherapy, NBI vascular examination and screening for associated vascular factors should be performed before and after chemotherapy. Alterations in vascular classification, assessed using NBI, and abnormal expression of vascular factors may also be used as reference factors for prognosis. [ABSTRACT FROM AUTHOR]

Copper is an essential trace element required for human life, and is involved in several physiological mechanisms. Today researchers have found and confirmed that Cu has biological properties which are particularly useful for orthopedic biomaterials applications such as implant coatings or biodegradable filler bone substitutes. Indeed, Cu exhibits antibacterial functions, provides angiogenic ability and favors osteogenesis; these represent major key points for ideal biomaterial integration and the healing process that follows. The antibacterial performances of copper-doped biomaterials present an interesting alternative to the massive use of prophylactic antibiotics and help to limit the development of antibiotic resistance. By stimulating blood vessel growth and new bone formation, copper contributes to the improved bio-integration of biomaterials. This review describes the bio-functional advantages offered by Cu and focuses on the antibacterial, angiogenic and osteogenic properties of Cu-doped biomaterials with potential for orthopedic applications. Image, graphical abstract [ABSTRACT FROM AUTHOR]

Immunotherapy by immune checkpoint inhibitors (ICIs) has showed outstanding efficacy in the treatment of advanced non-small cell lung cancer (NSCLC). The combination of immunotherapy with anti-angiogenic therapy exhibited enhanced efficacy in multiline treatment. However, the potential biomarkers for predicting and monitoring the therapeutic response of the combined therapy remain undefined. In this study, we performed a pilot study by prospectively recruiting 22 advanced NSCLC patients who failed to previous lines of chemotherapy, chemoradiotherapy, TKI therapy, surgery, or any combination of the therapies, and investigated the prognostic factors for patients who received anti-PD-1 (Camrelizumab) and anti-angiogenic (Apatinib) combined therapy. The objective response rate (ORR) assessed by an independent radiology review was 22.7%, and the median progression-free survival (PFS) was 5.25 months. We found that high concentration of circulating-free DNA (cfDNA) (HR = 27.75, P = 0.003), MIKI67 mutation (HR = 114.11, P = 0.009) and gene variations related to hyper-progressive disease (HPD) (HR = 36.85, P = 0.004) were independent risk factors and exhibited significant correlation with PFS. Circulating tumor DNA (ctDNA) mutational status was also a predicting indicator for PFS. In contrast, the blood tumor mutational burden (bTMB) could not stratify the clinical benefit in this combined therapy (HR = 0.81, P = 0.137). Furthermore, we found that the variant allele fraction (VAF) of mutations in ctDNA was sensitive indicators of therapeutic response and therefore can be used to monitor the tumor relief or progression. In conclusion, cfDNA concentration, MIKI67 mutations and HPD-related mutations were independent risk factors and PFS predictors for multiline combined anti-angiogenic/ICI combined therapy. ctDNA may be a novel monitoring biomarker for therapeutic response and predicting biomarker for prognosis in future combined therapy involving PD-1 blockade.

Abstract Background: Angiogenesis occurs in physiologic (wound healing) and pathological conditions and plays an important role in tumor growth, progression and metastasis. Therefore, the inhibition of angiogenesis can be an important approach to treat cancer diseases. In recent years, the use of nanoparticles has been developed to control cancer cells and prevent tumor growth. Various studies have shown the role of nanoparticles in reducing angiogenesis and inhibition of cancer cells. So, in this study, the anti-angiogenic effect of silver nanoparticle synthesis by Rubina tinctorum L (Ru-AgNPs) on Chicken Chorioallantoic Membrane (CAM) was investigated. Materials and Methods: In an experimental study, 60 eggs were randomly divided into 6 groups including control, laboratory control and 4 treatment groups (10 eggs/group). On the second day of incubation, a window was created on the eggs. On the 8th day, the chorioallantoic membrane of samples was treated with different concentrations of nanoparticles and on the 12th day, the image was taken from all samples. Finally, the number and length of vessels on the chorioallantoic membrane and following that weight and length of the embryo from crown to squattiest were measured. Quantitative data were analyzed using LSD-test. Results: The results showed that the Ru-AgNPs significantly reduced the length and number of blood vessels in the treated groups compared to the control group. Also, the comparison of length and weight of embryos in treated samples with control group showed that the Ru-AgNPs had an inhibitory effect on the length of the embryos, but the weight did not differ significantly in the treatment with the control group. Conclusion: Considering the inhibitory effect of the Ru-AgNPs on the angiogenesis of the chorioallantoic membrane, with further studies, this compound can be used to control and inhibit pathological angiogenesis in many diseases such as cancers.

Immunotherapy by immune checkpoint inhibitors (ICIs) has showed outstanding efficacy in the treatment of advanced non-small cell lung cancer (NSCLC). The combination of immunotherapy with anti-angiogenic therapy exhibited enhanced efficacy in multiline treatment. However, the potential biomarkers for predicting and monitoring the therapeutic response of the combined therapy remain undefined. In this study, we performed a pilot study by prospectively recruiting 22 advanced NSCLC patients who failed to previous lines of chemotherapy, chemoradiotherapy, TKI therapy, surgery, or any combination of the therapies, and investigated the prognostic factors for patients who received anti-PD-1 (Camrelizumab) and anti-angiogenic (Apatinib) combined therapy. The objective response rate (ORR) assessed by an independent radiology review was 22.7%, and the median progression-free survival (PFS) was 5.25 months. We found that high concentration of circulating-free DNA (cfDNA) (HR = 27.75, P = 0.003), MIKI67 mutation (HR = 114.11, P = 0.009) and gene variations related to hyper-progressive disease (HPD) (HR = 36.85, P = 0.004) were independent risk factors and exhibited significant correlation with PFS. Circulating tumor DNA (ctDNA) mutational status was also a predicting indicator for PFS. In contrast, the blood tumor mutational burden (bTMB) could not stratify the clinical benefit in this combined therapy (HR = 0.81, P = 0.137). Furthermore, we found that the variant allele fraction (VAF) of mutations in ctDNA was sensitive indicators of therapeutic response and therefore can be used to monitor the tumor relief or progression. In conclusion, cfDNA concentration, MIKI67 mutations and HPD-related mutations were independent risk factors and PFS predictors for multiline combined anti-angiogenic/ICI combined therapy. ctDNA may be a novel monitoring biomarker for therapeutic response and predicting biomarker for prognosis in future combined therapy involving PD-1 blockade. [ABSTRACT FROM AUTHOR]

Purpose: Although biomarkers for patients with metastatic colorectal cancer exist, the benefit patients with RAS mutated tumors derive from established regimens is unclear. Methods: Efficacy of therapeutic strategies available for RAS mutated patients (addition of chemotherapeutic agents and/or anti angiogenic agents) were investigated in fourteen randomized controlled phase III trials at trial level by meta-analysing individual study hazard ratios and 95% confidence intervals (95% CI) for overall survival (OS) and progression free survival (PFS). Results: 6810 of 10,748 patients (63.3%) were available (48.5% RAS wildtype, 51.5% RAS mutated). Across all treatment lines, additional treatment efficacy (chemotherapy and/or anti angiogenic agents) was significantly smaller in RAS mutated compared to wildtype tumors for OS and PFS. In detail, patients with RAS mutated metastatic colorectal cancer derived significant benefit in PFS but not in OS by the addition of either chemotherapy or anti angiogenic agents to the respective comparator. In patients with RAS wildtype metastatic colorectal cancer, PFS and OS were improved by the addition of chemotherapy or anti angiogenic agent. Conclusion: The therapeutic benefit of additional substances is less distinct in patients with RAS mutated as compared to RAS wildtype metastatic colorectal cancer, especially with regard to OS. [ABSTRACT FROM AUTHOR]

The placenta, a temporary organ that forms during pregnancy, is the largest fetal organ and the first to develop. It is recognized as an organ that plays a vital role as a metabolic and physical barrier in the fetoplacental unit; throughout fetal development it acts as the lungs, gut, kidneys, and liver of the fetus. When its two components, the fetal and the maternal one, successfully interact, pregnancy proceeds healthily. However, in some cases there may be pregnancy disorders, such as preeclampsia (PE) and gestational diabetes mellitus (GDM), which can lead to a different outcome for the mother and the newborn. In recent years, several studies have been conducted to try to understand how the expression of factors involved in the development of the placenta varies under pathological conditions compared with normal conditions. The purpose of this review is to summarize recent discoveries in this field. [ABSTRACT FROM AUTHOR]

The aims of this study were to study the effects of miR-2 on cerebral ischemia–reperfusion rats and to explore its further mechanism. Rats were assigned into sham, model, miR-22 control and miR-22 groups. Observation of neurological behaviors at 24 h after operation found that neurological functions were severely damaged in the model and miR-22 control groups and these damages were improved by miR-22. RT-PCR indicated that miR-22 mRNA level in the brain tissue was significantly decreased in the model and miR-22 control groups, but increased in the miR-22 group. TTC staining showed increased percentage of cerebral infarction volume in the model and miR-22 control groups and this increase was reduced by miR-22. Immunohistochemistry showed increased densities of CD34+ and VEGF+ microvessels in the cortex in the model and miR-22 control groups, which were further increased in the miR-22 group. ELISA showed increased serum VEGF and Ang-1 levels in the model and miR-22 control groups, which were also further increased in the miR-22 group. Western blot analysis showed increased phosphorylation level of PI3K and Akt in brain tissue in the model and miR-22 control groups, which were further increased in the miR-22 group. Administration of LY294002, a specific PI3K pathway inhibitor, significantly reversed all the effects of miR-22 on rats in the model group. miR-22 exerts its neuroprotective and angiogenic functions via the PI3K/Akt signaling pathway, at least partly, in rats under cerebral ischemia–reperfusion. [ABSTRACT FROM AUTHOR]

Pathological angiogenesis and apoptosis evasion are common hallmarks of cancer. The present work was an endeavor to evaluate the influence of bee venom (BV) or its major constituent melittin (MEL) as antiapoptotic and angiogenic regulator modifier on the tumor growth and the cell sensitivity to ionizing radiation targeting the improvement of cancer therapeutic protocols. BV (0.56 mg/kg/day) and MEL (500 µg/kg body weight/day) were injected intraperitoneally to mice bearing 1 cm3 solid tumor of Ehrlich ascites carcinoma (EAC) for 21 consecutive days. Mice were whole-body exposed to 1 Gray (Gy) of γ-radiation (2 fractionated doses). Treatment with BV or MEL markedly suppresses the proliferation of tumor in EAC mice. The concentrations of m-RNA for angiogenic factors (TNF-α, VEGF) as well as MMPs 2 and 9 activities and NO concentration were significantly decreased, combined with improvements in apoptotic regulators (caspase-3 activity) and normal cells redox tone (catalase and free radicals content) compared with EAC mice. Moreover, the histopathological investigation confirms the improvement exerted by BV or MEL in the EAC mice group or EAC + R group. Exposure to γ-radiation sustained the modulatory effect of BV on tumor when compared with EAC + BV mice. Convincingly, the role of BV or MEL as a natural antiangiogenic in the biological sequelae after radiation exposure is verified. Hence, BV and its major constituent MEL might represent a potential therapeutic strategy for increasing the radiation response of solid tumors. [ABSTRACT FROM AUTHOR]

Introduction: Endothelial cells cover the surface of the capillary wall and literature review has cemented its angiogenic roles in wound healing and tissue regeneration. However, the angiogenic in vitro models available are inadequate to understand the endothelial differentiation process. Methods: A construct was made using human amniotic membrane (HAM) as a matrix to assist the dental stem cells to differentiate into endothelial-like cells. This study aimed to assess the biological interaction between stem cells from human exfoliated deciduous teeth (SHED) and the stromal side (SS) of the glycerol-preserved HAM in angiogenic-induced environment media using VEGF. The changes were evaluated through cell morphology, migration, as well as gene expression level. Results: There were morphological changes observed in SHED in angiogenic-induced media. SHED appeared to be differentiated from fibroblast-like cells to a new structure, mimicking endothelial-like structure through microscopy analysis. Besides, the cross-section of the construct revealed that the cells seeded on the matrix were able to maintain its monolayer structure at day 1, 7 and 14 but infiltrated into the HAM at day 21, suggesting cell migration. The cells were also able to maintain its stemness (Nestin, Nanog and CD29) and at the same time express the angiogenic markers (IL-8, VEGF and MMP-2). Conclusion: HAM promotes SHED proliferation, migration and has the potential as a differentiating matrix for endothelial-like cells. [ABSTRACT FROM AUTHOR]

Objective  To evaluate to what extent indicators of placenta insufficiency are associated with low concentrations of insulin-like growth factor 1 (IGF-1) and IGF-1–binding protein-1 (IGFBP-1) in neonatal blood, and to what extent the concentrations of these growth factors are associated with concentrations of proteins with inflammatory, neurotrophic, or angiogenic properties. Study Design  Using multiplex immunoassays, we measured the concentrations of IGF-1 and IGFBP-1, as well as 25 other proteins in blood spots collected weekly from ≥ 880 infants born before the 28th week of gestation, and sought correlates of concentrations in the top and bottom quartiles for gestational age and day the specimen was collected. Results  Medically indicated delivery and severe fetal growth restriction (sFGR) were associated with low concentrations of IGF-1 on the first postnatal day and with high concentrations of IGFBP-1 on almost all days. Elevated concentrations of IGF-1 and IGFBP-1 were accompanied by elevated concentrations of many other proteins with inflammatory, neurotrophic, or angiogenic properties. Conclusion  Disorders associated with impaired placenta implantation and sFGR appear to account for a relative paucity of IGF-1 on the first postnatal day. Elevated concentrations of IGF-1 and especially IGFBP-1 were associated with same-day elevated concentrations of inflammatory, neurotrophic, and angiogenic proteins. [ABSTRACT FROM AUTHOR]

Dan Huang,1 Kena Ma,1,2 Xinjie Cai,1,2 Xu Yang,3 Yinghui Hu,1 Pin Huang,1 Fushi Wang,1 Tao Jiang,1,2 Yining Wang1,2 1The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei- MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, 2Department of Prosthodontics, Hospital of Stomatology, Wuhan University, Wuhan, China; 3Department of Oral Biology, School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA, USA Abstract: Titanium (Ti) and its alloys have been widely used in clinics for years. However, their bio-inert surface challenges application in patients with compromised surgical conditions. Numerous studies were conducted to modify the surface topography and chemical composition of Ti substrates, for the purpose of obtaining antibacterial, angiogenic, and osteogenic activities. In this study, using green electrophoretic deposition method, we fabricated gap-bridging chitosan-gelatin (CSG) nanocomposite coatings incorporated with different amounts of copper (Cu; 0.01, 0.1, 1, and 10 mM for Cu I, II, III, and IV groups, respectively) on the Ti substrates. Physicochemical characterization of these coatings confirmed that Cu ions were successfully deposited into the coatings in a metallic status. After rehydration, the coatings swelled by 850% in weight. Mechanical tests verified the excellent tensile bond strength between Ti substrates and deposited coatings. All Cu-containing CSG coatings showed antibacterial property against both Gram-negative Escherichia coli and Gram-positive Staphylococcus aureus. The antibacterial property was positively correlated with the Cu concentration. In vitro cytocompatibility evaluation demonstrated that activities of bone marrow stromal cells were not impaired on Cu-doped coatings except for the Cu IV group. Moreover, enhanced angiogenic and osteogenic activities were observed on Cu II and Cu III groups. Overall, our results suggested that Cu-doped CSG nanocomposite coating is a promising candidate to functionalize Ti materials with antibacterial, angiogenic, and osteogenic properties. Keywords: copper, gap-bridging, antibacterial, angiogenic, osteogenic

Blood vessels are a key target for cancer therapy. Compared with the healthy vasculature, tumor blood vessels are extremely immature, highly permeable, and deficient in pericytes. The aberrantly vascularized tumor microenvironment is characterized by hypoxia, low pH, high interstitial pressure, and immunosuppression. The efficacy of chemotherapy, radiotherapy, and immunotherapy is affected by abnormal blood vessels. Some anti-angiogenic drugs show vascular normalization effects in addition to targeting angiogenesis. Reversing the abnormal state of blood vessels creates a normal microenvironment, essential for various cancer treatments, specifically immunotherapy. In addition, immune cells and molecules are involved in the regulation of angiogenesis. Therefore, combining vascular normalization with immunotherapy may increase the efficacy of immunotherapy and reduce the risk of adverse reactions. In this review, we discussed the structure, function, and formation of abnormal vessels. In addition, we elaborated on the role of the immunosuppressive microenvironment in the formation of abnormal vessels. Finally, we described the clinical challenges associated with the combination of immunotherapy with vascular normalization, and highlighted future research directions in this therapeutic area., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Qian, Liu, Liu, Zhou and Zhao.)