Tissue Angiogenesis Research Articles

CD105-microvessel density analysis and its clinical value in urothelial carcinoma of bladder patients

Background Endoglin/CD105-microvessel density (CD105-MVD) is identified as one of the most potential methods for semi-quantification of angiogenesis in human cancer tissues. Present study aimed to examine the diagnosticand prognostic value of CD105-MVD in two clinically distinct subtypes of urothelial carcinoma of bladder (UCB) namely non-muscle invasive bladder cancer (NMIBC) and muscle invasive bladder cancer (MIBC) patients. Methods Message expression of endoglin was analysed by real-time quantitative polymerase chain reaction (RT-qPCR) and MVD measurement was done by immunohistochemical staining in 90 UCB [NMIBC: 60; MIBC: 30] patients. SEM studies were carried out to examine tumor vasculature and extent of neoangiogenesis in NMIBC and MIBC patients. Results Elevated message expression of CD105 showed statistical significance with tumor stage, grade, smoking/tobacco chewing history in NMIBC andage in MIBC cohort. Higher values of CD105-MVD showed statistical relevance with tumor stage, grade, size, smoking/tobacco chewing history in NMIBC cohort. Kaplan Meier test identified high CD105-MVD as strong predictor of poor RFS in NMIBC patients. Conclusions Association of CD105 expression and MVD with the clinicohistopathological features as well as poor survival outcomes potentially identify it as a preferred marker of clinical significance in a given cohort of UCB patients. Clinical significance Strong association of CD105 at message level with the demographics of UCB patients identifies it as a marker of diagnosis in a given cohort of patients. Survival analysis examined CD105-MVD as an independent strong predictor of poor recurrence free survival in NMIBC patients. Present study provides clear evidence of increased vascular density, vascular sprouts proliferation and new blood vessel formation with disease aggressiveness indicating CD105 as a preferred marker of neoangiogenesis in the given cohort of patients. The study describes CD105-MVD as a biomarker of diagnosis and prognosis with the sensitivity of 91.67% and 93.33% in a given cohort of NMIBC and MIBC patients.

Peptidergic G-Protein-Coupled Receptor Signaling Systems in Cancer: Examination of Receptor Structure and Signaling to Foster Innovative Pharmacological Solutions

Background. Peptidergic GPCR systems are broadly distributed in the human body and regulate numerous physiological processes by activating complex networks of intracellular biochemical events responsible for cell regulation and survival. Excessive stimulation, ill-function, or blockade of GPCRs produces cell disturbances that may cause disease should compensatory mechanisms not suffice. Methods and Results. Revision of updated experimental research provided an evident relationship associating peptidergic GPCR malfunction with tumor formation and maintenance resulting from uncontrolled cell proliferation and migration, colonization, inhibition of apoptosis or altered metabolism, and increased angiogenesis in tumoral tissues. Conclusion. Determination of the implication of GPCR peptide signaling in specific neoplasia is crucial to designing tailored pharmacological treatments to counteract or dismantle the origin of the signaling circuitry causing cellular disruption. In some cases, particular ligands for these receptors may serve as concomitant treatments to aid other pharmacological or physical approaches to eradicate neoplasias.

Reactive oxygen species-responsive polydopamine-PtCuTe nanoparticle-loaded microneedle system for promoting the healing of infected skin wounds

Nanozymes, known for their high efficiency in scavenging reactive oxygen species (ROS), have received significant attention in promoting the healing of infected wounds. Herein, we reported a novel multifunctional PDA-PtCuTe nanozyme with excellent ROS scavenging, antibacterial, pro-angiogenic, anti-inflammatory, and immune regulatory properties. It was loaded onto microneedles (PTPP-MN) for treating infected wounds. In vitro experiments demonstrated its ability to scavenge ROS and exhibit antioxidant properties. Compared to PT-MN (11.03 ± 3.37 %) and PTP-MN (42.30 ± 2.60 %), the ROS scavenging rate of PTPP-MN reached 63.63 ± 4.42 %. The microneedle exhibits good biocompatibility, stimulating fibroblast migration, endothelial angiogenesis, and M2 macrophage polarization. Additionally, it effectively eliminates ROS and provides antioxidant effects while inhibiting the viability of S. aureus and E. coli. Animal experiments showed that the PTPP-MN group achieved near-complete re-epithelialization by the third day compared to other groups. Histological observations revealed that the PTPP-MN group exhibited enhanced granulation tissue formation, epithelial regeneration, and angiogenesis. After PTPP-MN treatment, the local immune response shifted from a pro-inflammatory state to a pro-regenerative state. Our results indicate that PTPP-MN holds great promise for infected wound healing with reduced scar formation.

Fabrication of Antibacterial and Flexible Hydrogels Based on Citric Acid Containing Tannic Acid for Wound Dressing

ABSTRACTIn this research, a biomonomer based on hydroxyethyl methacrylate, citric acid, and polyethylene glycol (HEMA‐CA‐PEG) was synthesized. After confirming the reaction through 1H‐NMR and FT‐IR tests and obtaining the intended monomer, a flexible hydrogel was synthesized as a wound dressing, and its mechanical properties were evaluated using tensile strength, DMTA, and rheometry tests. This synthesized hydrogel exhibited sufficient mechanical properties. To enhance the efficiency of this hydrogel wound dressing and its effectiveness in facilitating wound healing, tannic acid (TA), as an antibacterial and antioxidant substance, was incorporated into it. In the second phase, antibacterial activity and animal studies were conducted. The comparison of the CA–based hydrogel with and without TA demonstrated that the TA–containing hydrogel achieved more than 99.9% inhibition and elimination of bacteria. The use of CA–based hydrogel with TA shown in treating burns on the backs of rats caused the wound to close after 17 days, and hair growth was observed by the 21st day. This synthesized flexible hydrogel wound dressing, along with suitable mechanical properties, exceptional antibacterial activity, increased granulation tissue formation, re‐epithelialization, angiogenesis, and collagen deposition, showed good performance in wound healing.

Electricallymodified bacterial cellulose tailored with plant based green materials for infected wound healing applications

Effective treatment of infected wounds remains a challenge due to the rise of antibiotic-resistant microorganisms. The development of advanced materials with strong antimicrobial properties is necessary to address this issue. In this study, a unique composite of electrically modified bacterial cellulose (EBC) with allantoin (ABC) and zein was developed by dipping diffusion method. Morphological structural analysis revealed a uniform distribution of zein and aligned fibers, confirming the synthesis of the ABC-Zein composite. The formation of ABC-Zein was further confirmed by attenuated total reflection-Fourier transform infrared (ATR-FTIR), which displayed additional peaks corresponding to EBC, indicating the incorporation of zein into ABC. X-ray diffraction (XRD) analysis of ABC-Zein demonstrated a similar crystalline structure with EBC. The ABC-Zein showed mechanical integrity (tensile strength: 1.15 ± 0.21 MPa), thermal stability (degradation temperature: 290 °C), porous structure (porosity: 40.23 ± 0.21 %), and hydrophilic (water contact angle: 53.3 ± 5.3°) properties. Furthermore, the antimicrobial agent terpinen-4-ol (T4O), derived from tea tree oil, was incorporated into the ABC-Zein composite. Biological studies confirmed the antimicrobial efficacy (Staphylococcus aureus inhibition: 88.5 ± 7.19 %) and biocompatible (cell viability: 84.95 ± 5.6 %, hemolysis: 4.479 ± 0.39 %) nature of the T4O-ABC-Zein composite. The combined effects of the aligned fiber structure, zein protein, and antimicrobial T4O significantly enhanced infected wound healing by day 7, promoting inflammatory response, granular tissue formation, cell proliferation, and angiogenesis. By day 14, T4O-ABC-Zein facilitated complete wound healing, with reepithelization, collagen I deposition, and downregulation of CD 31, Ki67, and α-SMA. Overall, the innovative T4O-ABC-Zein composite, with an aligned fiber structure, improved biocompatibility, and antimicrobial properties, holds significant potential for the treatment of infected wounds.

Structural analysis and accelerating wound healing function of a novel galactosylated glycosaminoglycan from the snail Helix lucorum

Diabetic foot ulcers (DFUs) as a nonhealing wound remain a clinical challenge, and the development of pro-healing and cost-effective drugs is in urgent need. Herein, we reported a novel galactosylated glycosaminoglycan (GAG) from the snail Helix lucorum, as an effective pro-healing compound. The snail GAG is composed of a heparan sulfate-like main chain and galactose side chains at C-3 of GlcNAc residue. Its main chain has a repeating disaccharide structure of → 4)-α-D-GlcNAc-(1 → 4)-α-L-IdoA2S(1 →. This is the first example of glycosaminoglycan with galactose branches from mollusks. Pharmacological experiments showed that the H. lucorum GAG significantly promoted skin wound healing in both healthy and diabetic mice by accelerating granulation tissue regeneration, angiogenesis, and collagen deposition. The distinctive galactosylated substitution may play an important role on its pro-healing activity. Our discovery enriches the diversity of non-anticoagulant heparan sulfate-like glycosaminoglycans, and provides a potential candidate of pro-healing drug for treating diabetic wound.

Current advances in the development of microRNA-integrated tissue engineering strategies: a cornerstone of regenerative medicine.

Regenerative medicine is an innovative scientific field focused on repairing, replacing, or regenerating damaged tissues and organs to restore their normal functions. A central aspect of this research arena relies on the use of tissue-engineered scaffolds, which serve as structural supports that mimic the extracellular matrix, providing an environment that orchestrates cell growth and tissue formation. Remarkably, the therapeutic efficacy of these scaffolds can be improved by harnessing the properties of other molecules or compounds that have crucial roles in healing and regeneration pathways, such as phytochemicals, enzymes, transcription factors, and non-coding RNAs (ncRNAs). In particular, microRNAs (miRNAs) are a class of tiny (20-24nt), highly conserved ncRNAs that play a critical role in the regulation of gene expression at the post-transcriptional level. Accordingly, miRNAs are involved in a myriad of biological processes, including cell differentiation, proliferation, and apoptosis, as well as tissue regeneration, angiogenesis, and osteogenesis. On this basis, over the past years, a number of research studies have demonstrated that miRNAs can be integrated into tissue-engineered scaffolds to create advanced therapeutic platforms that precisely modulate cellular behavior and offer a controlled and targeted release of miRNAs to optimize tissue repair and regeneration. Therefore, in this current review, we discuss the most recent advances in the development of miRNA-loaded tissue-engineered scaffolds and provide an overview of the future outlooks that should be aborded in this area of study in order to lay the groundwork for the clinical translation of these tissue engineering approaches.

A patch comprising human umbilical cord-derived hydrogel and mesenchymal stem cells promotes pressure ulcer wound healing

Pressure ulcers (PUs) are common skin injuries known for their high morbidity, rapid onset, susceptibility to infection, and challenging healing process. One potential therapy for PUs is cell-based therapy using mesenchymal stem cells (MSCs). However, poor survival and low cell retention of MSCs on skin lesions limit their therapeutic effects and applications. In this study, we prepared an extracellular matrix (dECM) hydrogel decellularized from the human umbilical cord (UC). A patch composed of UC-dECM and UC-MSCs was employed in the treatment of PUs in C57BL/6 mice. Our results indicate that the UC-dECM hydrogel effectively sustains cell viability, enhances the stemness-related gene expression in UC-MSCs, and promotes human umbilical vein endothelial cells (HUVECs) migration and angiogenesis. Compared to the groups treated with the patch containing only UC-dECM, injection of UC-MSCs or gauze dressing, the patch combining UC-dECM hydrogel with UC-MSCs significantly accelerated PU healing. This positive outcome can be attributed to the promotion of tissue re-epithelialization, collagen deposition, angiogenesis, and inflammation inhibition. Our results suggest that the composite patch, comprised of UC-dECM hydrogel and UC-MSCs, may be a promising therapeutic approach for PU treatment.

Secretome from estrogen-responding human placenta-derived mesenchymal stem cells rescues ovarian function and circadian rhythm in mice with cyclophosphamide-induced primary ovarian insufficiency

BackgroundPrimary ovarian insufficiency (POI) is an early decline in ovarian function that leads to ovarian failure. Conventional treatments for POI are inadequate, and treatments based on mesenchymal stem cells (MSCs) have emerged as an option. However, the lack of consideration of the estrogen niche in ovarian tissue significantly reduces the therapeutic efficacy, with an unclear mechanism in the MSCs in POI treatment. Furthermore, the disruption of circadian rhythm associated with POI has not been previously addressed.MethodsConditioned medium (CM) and estradiol-conditioned medium (E2-CM) were generated from estrogen receptor positive MSCs (ER+pcMSCs). Chemotherapy-induced POI models were established using C57BL/6 mice (in vivo) and KGN cells (in vitro) treated with cyclophosphamide (CTX) or 4-hydroperoxycyclophosphamide (4-OOH-CP). Gene/protein expressions were detected using RT-qPCR, Western blotting, and immunohistochemistry assays. Locomotor activity was monitored for behavioral circadian rhythmicity. Cytokine arrays and miRNA analysis were conducted to analyze potential factors within CM/E2-CM.ResultsThe secretome of ER+pcMSCs (CM and E2-CM) significantly reduced the CTX-induced defects in ovarian folliculogenesis and circadian rhythm. CM/E2-CM also reduced granulosa cell apoptosis and rescued angiogenesis in POI ovarian tissues. E2-CM had a more favorable effect than the CM. Notably, ER+pcMSC secretome restored CTX-induced circadian rhythm defects, including the gene expressions associated with the ovarian circadian clock (e.g., Rora, E4bp4, Rev-erbα, Per2 and Dbp) and locomotor activity. Additionally, the cytokine array analysis revealed a significant increase in cytokines and growth factors associated with immunomodulation and angiogenesis, including angiogenin. Neutralizing the angiogenin in CM/E2-CM significantly reduced its ability to promote HUVEC tube formation in vitro. Exosomal miRNA analysis revealed the miRNAs involved in targeting the genes associated with POI rescue (PTEN and PDCD4), apoptosis (caspase-3, BIM), estrogen synthesis (CYP19A1), ovarian clock regulation (E4BP4, REV-ERBα) and fibrosis (COL1A1).ConclusionThis study is the first to demonstrate that, in considering the estrogen niche in ovarian tissue, an estrogen-priming ER+pcMSC secretome achieved ovarian regeneration and restored the circadian rhythm in a CTX-induced POI mouse model. The potential factors involved include angiogenin and exosomal miRNAs in the ER+pcMSC secretome. These findings offer insights into potential stem cell therapies for chemotherapy-induced POI and circadian rhythm disruption.

Phlebotomy-induced anemia reduces oxygen-induced retinopathy severity and dampens retinal developmental transcriptomic pathways in rats.

Phlebotomy-induced-anemia (PIA), which induces tissue hypoxia and angiogenesis, occurs universally among infants at risk for severe retinopathy of prematurity (ROP). We hypothesized that PIA exacerbates pathologic retinal neovascularization in ROP. We induced PIA to a hematocrit of 18% among rats undergoing the established 50/10 oxygen-induced retinopathy (OIR) model. Rats were euthanized at P15 and P20, during the avascular and neovascular phases of OIR, respectively. Retinal vascular morphometry, cytokine/chemokine concentrations, transcriptomes, and mRNA expression of angiogenic and iron-deficiency markers were compared to non-PIA controls. In OIR, PIA decreased percent avascular area at P15 by 35%, percent neovascular area at P20 by 42%, and select pro-inflammatory cytokine/chemokine concentrations at both time points. At P20, PIA increased mRNA expression of angiopoietin 2/ vascular endothelial growth factor-A 2-fold and transferrin and transferrin receptor 5-fold. RNA sequencing showed dampened pathways of angiogenesis, inflammation, and neural development in anemic OIR females. Contrary to our hypothesis, PIA decreased OIR severity and retinal cytokine and chemokine levels and dampened transcriptomic pathways central to retinal vascular and neural development in neonatal rats. These data suggest PIA provides a protective effect from OIR. Further investigation into the functional effect of these molecular changes is warranted. This is the first preclinical study to investigate the impact of neonatal anemia on oxygen-induced retinopathy (OIR) outcomes. This study adds to the literature that anemia decreases neovascularization, decreases cytokine and chemokine levels, and dampens angiogenic and neural transcriptomic pathways in the rat 50/10 OIR model. The study identifies a sex-specific transcriptomic response to anemia in the 50/10 OIR model, with females primarily impacted.

7410 Bevacizumab Induced Hypothyroidism

Abstract Disclosure: A.L. McKenna: None. S. Thota-Kammili: None. K. Grennan: None. S. Rao: None. It is known that thyroid dysfunction is an adverse effect of tyrosine kinase inhibitors (TKIs) via inhibition of the vascular endothelial growth factor receptor (VEGFR). The VEGF signaling pathway is important in regulating angiogenesis in tumors and normal tissue. As a highly vascularized gland, it is expected the thyroid may be compromised because of VEGFR inhibitors. Proposed mechanisms of thyroid dysfunction include capillary regression and constriction leading to reduced vascular perfusion to the gland. Bevacizumab is a monoclonal antibody that targets VEGF and inhibits activation of VEGFR, reducing angiogenesis; interestingly, this is not commonly reported in the literature. Here we present a case where bevacizumab altered thyroid function in a patient with pre-existing primary hypothyroidism. A 60-year-old woman presented with worsening hypothyroidism. She reported a history of nonautoimmune primary hypothyroidism diagnosed in her early 20s; she still had an intact thyroid with no history of head/neck radiation. In the months leading to the presentation, she had been receiving maintenance chemotherapy with 5 fluorouracil and bevacizumab every 2 weeks for metastatic duodenal carcinoma. Prior to starting chemotherapy, she had been on a steady dose of 112 mcg of levothyroxine (LT4) daily. After 6 months on chemotherapy, she reported symptoms of fatigue and hair loss. Workup revealed an elevated TSH of 41 mIU/L (reference 0.3-4.2 mIU/L). She denied any significant changes in weight or malabsorption issues. Aside from the chemotherapy, no other new medications were introduced. Her LT4 dose was increased to 137 mcg daily, and 3 months later, there was improvement in TSH to 6.5 mIU/L as well as her symptoms. At this point, bevacizumab was briefly on hold for 2 months due to an upcoming procedure, hence there was no change to LT4 to avoid over correction. Her TSH normalized and was trending lower while bevacizumab was on hold. Once bevacizumab resumed, LT4 was preemptively increased to 150 mcg daily. Four months after resuming bevacizumab, her TSH remains within the normal reference range on 150 mcg LT4. It is hypothesized that this VEGF blocker led to worsening of her underlying hypothyroidism.Given the shared down regulation in the VEGF signaling pathway, it would be expected that TKIs and monoclonal antibodies against VEGF would share similar adverse reactions to the thyroid. However, to our knowledge, there have been limited reports of bevacizumab induced thyroid dysfunction in the literature. Explanations to this may include the more targeted VEGF inhibition with bevacizumab versus the inhibition of multiple kinase receptors from the TKIs. Further research into this will be needed. This case demonstrates that bevacizumab can impact thyroid function and thyroid labs may need to be monitored at the onset and during VEGF inhibitor therapies. Presentation: 6/3/2024

HIF1α Counteracts TGFβ1-Driven TSP1 Expression in Endothelial Cells to Stimulate Angiogenesis in the Hypoxic Tumor Microenvironment.

Emerging evidence suggests that transforming growth factor β1 (TGFβ1) can inhibit angiogenesis, contradicting the coexistence of active angiogenesis and high abundance of TGFβ1 in the tumor microenvironment. Here, we investigated how tumors overcome the anti-angiogenic effect of TGFβ1. TGFβ1 treatment suppressed physiological angiogenesis in chick chorioallantoic membrane and zebrafish models but did not affect angiogenesis in mouse hepatoma xenografts. The suppressive effect of TGFβ1 on angiogenesis was recovered in mouse xenografts by a hypoxia-inducible factor 1α (HIF1α) inhibitor. In contrast, a HIF1α stabilizer abrogated angiogenesis in zebrafish, indicating that hypoxia may attenuate the anti-angiogenic role of TGFβ1. Under normoxic conditions, TGFβ1 inhibited angiogenesis by upregulating anti-angiogenic factor thrombospondin 1 (TSP1) in endothelial cells (ECs) via TGFβ type I receptor (TGFβR1)-SMAD2/3 signaling. In a hypoxic microenvironment, HIF1α induced microRNA-145 (miR145) expression; miR145 abolished the inhibitory effect of TGFβ1 on angiogenesis by binding and repressing SMAD2/3 expression and subsequently reducing TSP1 levels in ECs. Primary ECs isolated from human hepatocellular carcinoma (HCC) displayed increased miR145 and decreased SMAD3 and TSP1 compared to ECs from adjacent non-tumor livers. The reduced SMAD3 or TSP1 in ECs was associated with increased angiogenesis in HCC tissues. Collectively, this study identified that TGFβ1-TGFβR1-SMAD2/3-TSP1 signaling in ECs inhibits angiogenesis. This inhibition can be circumvented by a hypoxia-HIF1α-miR145 axis, elucidating a mechanism by which hypoxia promotes angiogenesis.

Low-dose estrogen release from silastic capsule enhanced flap wound healing in an animal model.

Deep and extensive wounds usually cannot be closed directly by suturing or skin grafting. Flap transplantation is typically used to reconstruct large wounds clinically. The flap survival is based on a stable blood perfusion. It is established that estrogen promotes wound healing and angiogenesis, and regulates the inflammatory response, leading to enhanced flap survival after transplantation. However, estrogen concentrations administered in previous studies were significantly higher than physiological levels, potentially causing systemic side effects. Estrogen-sustained-release silastic capsules can maintain blood serum estrogen closer to physiological levels. This study aimed to investigate whether administering estrogen at a lower concentration, closer to physiological levels, could still enhance flap survival. This study was performed in a random skin flap model in ovariectomized (OVX) mice. Sustained-release estrogen silastic capsules were implanted into OVX mice to determine the functional role of estrogen in wound healing after flap transplantation. Flap blood perfusion was analysed using a colour laser Doppler scanner. Immunohistochemical staining of CD31, hypoxia-inducible factor 1 alpha (HIF-1α), alpha-smooth muscle actin (α-SMA), cleaved caspase 3 and apoptotic terminal dUTP nick end-labelling stain was used to investigate flap angiogenesis, tissue hypoxia, wound healing and cell death in the flap tissue, respectively. We observed that administering estrogen at a lower concentration enhanced superficial blood perfusion while reducing the flap's ischemic area and tissue necrosis. HIF-1α expression was significantly decreased in the dermis layer but not in the fascia, whereas cleaved caspase 3 levels decreased in the fascia but remained unchanged in the dermis. Additionally, there was no significant difference in CD31and α-SMA expression between the groups. In summary, the study showed that an estrogen silastic capsule maintained physiological estrogen levels and improved superficial perfusion, thereby reducing dermal hypoxia, and cell death in a mouse random pattern skin flap model. Although no significant promotion of angiogenesis was observed, the study suggests that appropriate estrogen supplements could enhance flap wound recovery.

A molecular docking insight: Phyllanthus niruri L. constituents targeting MMP-9 for angiogenesis inhibition and IL-1beta for antiinflammatory action in endometriosis therapy

Endometriosis, characterized by inflammatory lesions resembling endometrium outside the uterine cavity, induces chronic inflammation, anatomical changes and persistent pain. The expression of Interleukin 1beta (IL-1beta) is significantly associated with endometriosis, contributing to inflammatory process and fertility issues. Matrix metalloproteinase 9 (MMP-9) is crucial in the adhesion and angiogenesis of endometrial tissue. This study investigates the potential of Phyllanthus niruri L. in inhibiting MMP-9 and IL-1beta through molecular docking analysis. Molecular docking was performed using Discovery Studio Visualizer, Open Babel, PyRx and AutoDock Vina. The inhibitory activities of bioactive compounds on MMP-9 and IL-1beta were predicted. Biological activity and cytotoxicity were assessed using PASS and CLC-Pred respectively. Kaempferol and quercetin from P. niruri exhibited significant MMP-9 expression inhibitory activity. Search Tool for Interacting Chemicals (STITCH) analysis revealed interactions of quercetin and galangin with specific proteins involved in pathways related to endometriosis. Biological activity analysis indicated that quercetin, kaempferol, herbacetin and galangin show potential as MMP -9 expression inhibitors. CLC-Pred analysis suggested high cytotoxicity of kaempferol against glioma. Molecular docking results showed quercetin's potential as an MMP-9 inhibitor and galangin's potential as an IL-1 beta inhibitor. These findings support the therapeutic potential of P. niruri for endometriosis, providing insights for further research in developing innovative therapies targeting endometriosis-related inflammation and angiogenesis.

Long-term liver deportalisation in stable and time prolonged prehepatic portal hypertension model affects expression of hypoxia, angiogenesis, apoptosis, and autophagy markers in the young rats’ liver

prehepatic portal hypertension in children cause severe and life-threatening complications, that highlights the need in in-depth investigations of pathogenetic mechanisms, which contribute to prehepatic portal hypertension-associated liver pathology. In developed stable experimental prehepatic portal hypertension model in adolescent rat males we aimed to assess the expression levels of the key molecular markers of hypoxia, angiogenesis, autophagy, and apoptosis in the liver tissue after 6-month deportalization. Partial portal vein ligation was performed in 4-week old male rats. After 6-months tissue samples from PHP-model, sham operated and control animals were studied by western blot to identify protein levels of markers related to prehepatic portal hypertension -induced liver injury. Partial portal vein occlusion upregulated hypoxia inducible factor -1α (by 4.67 folds vs. control, p<0.001) and vascular endothelial growth factor protein expression levels (by 2.33 folds vs. control, p<0.001) suggesting chronic hypoxia development. Abnormally high levels of angiostatin isoforms were found (by 9.88 folds vs. control, p<0.001) to signify angiogenesis dysregulation. Significant caspase-3 (23.4-fold increase vs. control, p<0.001) overexpression is executive phase of apoptotic cell death evidence. Dramatic LC3 level expression indicates existence of crosstalk between autophagy and apoptosis that contribute to fibrotic changes. Hypoxia-induced events, impaired angiogenesis regulation, enhanced autophagy and apoptosis are contributing factors of prehepatic portal hypertension -induced liver injury. A better understanding of subtle molecular mechanisms of this pathology may pave the way for innovative treatment options.

Levels of Matrix Metalloproteinase-9 (MMP-9) and its gene polymorphism of Hydatid Cyst Disease in an Infected Patients

Hydatid cystic disease is an economic burden in Iraq since it decreases the productivity of sheep, goats, cows, and camels by making the organs unpalpable for human consumption, hence weight-loss and ill health. This is one of the most common zoonosis diseases shared between human beings and animals and appears in man hosts inlcuded some organes, such as liver and lung as hydatid cyst . it causes many complications that may lead to death in repured parasites. Now there are no safe and effective in the fight against this parasite, and the search for such medications is in research. The Matrix Metalloproteinase-9 is a one of the enzymes that belong to the family of matrix metalloproteinases (MMPs), which play a crucial role in the proteolytic degradation of the extracellular matrix (ECM). These enzymes have a zinc ion in the active site that is important for their proteolytic activity. MMP-9, also known as Gelatinase B, catalyzes gelatin and degrades components of the ECM, including abundant type IV collagen in basement membranes. MMP-9 plays an important role in various biological processes, including tissue remodeling, angiogenesis, and tissue inflammation. The objective of the study is to determine the impact of MMP-9 serum levels and specific single nucleotide polymorphisms (SNPs) rs17576 and rs76070157 on patients with hydatid disease, in comparison to a control group of healthy individuals. A total of (62) patients diagnosed with hydatid disease, consisting of 18 males and 44 females, were compared to a control group of(75) individuals, comprising 29 males and 46 females .The study examined the MMP-9 rs17576 and rs76070157 )SNPs( in patients with hydatid disease, comparing them to a control group of healthy individuals. The study revealed no statistically significant difference in the average age between the two groups at a significance level of 0.05. Additionally, the study found higher concentrations of MMP-9 in the sera of the infected group (20.40 ± 1.52 pg/µl) compared to the control group (19.49 ± 1.62 pg/µl). The rs17576 )SNPs( data indicated that the TT genotype and T allele exhibited a slightly higher frequency percentage in the group of patients with hydatid disease compared to the healthy group, however this difference was not statistically significant. The values are (98.4% and 99.0%) the value of pc is 0.001. The elevated odds ratio (OR) associated with the TT genotype and T allele may serve as a potential risk factor for hydatid disease. The rs17576 SNPs displayed genotypes that were not in accordance with Hardy-Weinberg equilibrium. However, these genotypes were consistent with those observed in a control group. The GG genotype showed a significant increase in frequency compared to the control group (100.0% vs. 100.0%), while the G allele exhibited a non-significant increase in frequency. The odds ratio (OR) for the TG genotype was 3.68, and the p-value (pc) was 0.05.Elevated value could potentially increase the risk of hydatid disease. The presence of the TG genotype was shown to considerably increase the frequency percentage in the group of patients with hydatid disease. The odds ratio (OR) value of 1.6 suggests that it may be a risk factor for hydatid disease, with a frequency of 98.4% compared to 0.99 % in the control group. The p-value of 0.001 indicates a statistically significant association. The GG genotype was present in (0%) of the affected group but absent (100.0%) in the healthy group. The odds ratio (OR) of 3.68, with a p-value of 0.001, suggests that the GG genotype is associated with a significantly lower risk of hydatid disease.

“All-in-one” tea polyphenol-modified injectable hyaluronic acid-based hydrogel for diabetic wound healing

Refractory diabetic wounds are a devastating and rapidly growing clinical problem, which is associated with high incidence rates, mortality, and recurrence rates. Therapeutic angiogenesis in wound tissues is essential to the healing of diabetic wounds. However, the presence of excessive oxidative stress in diabetic wounds hinders angiogenesis, and conventional anti-oxidative approaches are inefficient to compensate for the systematically impaired angiogenesis. Here, a multifunctional supramolecular hyaluronic acid hydrogel dressing for diabetic wounds is successfully designed and constructed (GHPM). The GHPM hydrogel features outstanding properties, including excellent tissue adhesion, antibacterial ability, conductivity, and antioxidant properties. Based on the dynamic crosslinking structure, the GHPM hydrogel also presents adequate injectable and self-healing capabilities, which play a vital role in covering irregular or deep wounds. Additionally, diabetic wounds treated with GHPM hydrogel showed a significant acceleration of wound closure by preventing wound infection, reducing oxidative stress, and accelerating collagen deposition. More interestingly, the combination of electrical stimulation and GHPM hydrogel can effectively promote angiogenesis and neurogenesis, further accelerating diabetic wound healing in an all-around way. This advanced collaborative strategy opens a new avenue in treating diabetic wounds.

Interaction between adipocytes and macrophages participates in chick subcutaneous adipose tissue angiogenesis under cold stress conditions

Previous studies have shown that subcutaneous adipose tissue is an important energy supply organ for chicks before and after birth, except yolk. So far, the significance of large deposits of subcutaneous adipose tissue in chicks is unclear. Therefore, this study takes the information interaction between adipocytes and macrophages as the starting point to explore whether adipocytes and macrophages could participate in adipose tissue fibrosis, angiogenesis, adaptive thermogenesis and other related functions in a specific metabolic environment. Under cold stress, the expression levels of genes related to lipidolysis, lipid transport and fatty acid oxidation in adipose tissue of chicks were significantly increased, but the expression levels of genes related to mitochondrial uncoupling were not significantly changed. Through Masson staining of adipose tissue of chicks under cold stress, it was found that the level of vascularization in adipose tissue of chicks was significantly increased. We found that the interaction between adipocyte and macrophage could participate in the angiogenesis related process of adipocytes in chicks through the HIF1A–VEGFA pathway. The analysis of lipid metabolism in subcutaneous adipose tissue of chicks from the perspective of cell heterogeneity will expand the understanding of lipid metabolism in chicks and provide a theoretical basis for chick rearing.

Synergistic integration of electrical stimulation, reactive oxygen species regulation, and pro-angiogenic for accelerated wound healing

Wound healing involves a complex series of coordinated events throughout the inflammatory, proliferative, and maturation phases of tissue repair. Current treatment modalities lack a device catering to all wound healing stages for tissue recovery, angiogenesis and epithelialization. Herein, we developed an integrated wound healing system with multiple functions of self-electrical stimulation (ES), reactive oxygen species (ROS) regulation, and bioactive metal-releasing patch (ERMP) to address all wound healing stages including hemostasis, inflammation, proliferation, and remodeling. The multiple functions of ERMP are ES, generated by the movement of the mice, for tissue regeneration, magnesium (Mg) ion release via iontophoresis triggered by ES for pro-angiogenic effects, and simultaneous regulation of ROS. This system employs self-generating ES utilizing the movements of the individuals to trigger triboelectric nanogenerators (TENGs), which consequently transfer ES through Mg microneedles while effectively delivering enhanced Mg ions with an iontophoresis via ES to the wound site. Specially, Prussian blue (PB) was utilized to not only enhance output performance on TENG as charge trap, but also regulate excessive ROS via modified PB with carbon–nitrogen vacancies in the wound site. The synergistic effects of ES, ROS regulation, and enhanced Mg ions releases led to a nine-fold recovery rates in wound healing compared to the control group in vivo tests. This approach addresses the inherent limitations of conventional wound healing methods and provides a viable treatment for various severe wound types.

Spreadable thermosensitive nanocomposite hydrogel dressing with ultrasound-responsive bactericidal/repair-promoting regulation and cascade antioxidantion for infected burn wound repair

Treating severe burn wounds poses significant challenges, including considerable cell loss, excessive inflammation, and a high susceptibility to bacterial infections. Ideal burn dressings should exhibit excellent antibacterial properties, anti-inflammatory effects, and promote cell proliferation. Additionally, they need facilitate painless dressing changes and be user-friendly. Herein, we synthesized a thermosensitive hydrogel by crosslinking poly (N-isopropylacrylamide-co-allyloxybenzaldehyde) (PNA) and amino-terminated Pluronic F127 (APF) through a Schiff base reaction. It exhibited reversible gel-sol transition and spreadability. By incorporating piezoelectric gold nanoparticle-modified barium titanate (Au@BaTiO3) and cascade antioxidant MOF-818, a nanocomposite hydrogel dressing with diverse bioactive functionalities was developed. Results demonstrated that the nanocomposite hydrogel possessed gel-sol transition properties, maintained a stable gel state within a broad temperature range, and desirable self-healing property. Au@BaTiO3 exhibited good piezoelectric properties and ROS generation upon ultrasound stimulation, while MOF-818 displayed highly efficient cascade nanozyme activity. The combination of Au@BaTiO3 and MOF-818 promoted fibroblast proliferation and migration, reduced intracellular ROS levels, and induced anti-inflammatory polarization of macrophages under ultrasound stimulation. In vitro and in vivo antibacterial results disclosed that the nanocomposite hydrogel had excellent antibacterial activity under high-intensity ultrasound stimulation. When applied to infected burn wounds, the nanocomposite hydrogel can rapidly sterilize the wound upon initial high-intensity ultrasound, and then reduce inflammation and promote M2 macrophage polarization by the following low-intensity ultrasound stimulation, and thus accelerating the healing by improving granulation tissue formation, angiogenesis, and collagen deposition.