Melastoma dodecandrum lour. Protects against cerebral ischemia-reperfusion injury by ameliorating oxidative stress and endoplasmic reticulum stress.

ETHNOPHARMACOLOGICAL RELEVANCE: Melastoma dodecandrum Lour. (MD), a traditional Chinese medicine used by the She ethnic group, has been used to treat cerebral ischemia-reperfusion (CIR) injury due to its efficacy in promoting blood circulation and removing blood stasiss; however, the therapeutic effects and mechanisms of MD in treating CIR injury remain unclear. AIM: To investigate the protective effects of MD on CIR injury, in addition to its impact on oxidative stress, endoplasmic reticulum (ER) stress, and cell apoptosis. MATERIALS AND METHODS: The research was conducted using both cell experiments and animal experiments. The CCK-8 method, immunofluorescence staining, and flow cytometry were used to analyze the effects of MD-containing serum on oxygen-glucose deprivation/reperfusion (OGD/R)-induced PC12 cell viability, reactive oxygen species (ROS) clearance, anti-inflammatory, neuroprotection and inhibition of apoptosis. Furthermore, 2,3,5-Triphenyl tetrazolium chloride staining, hematoxylin and eosin staining, Nissl staining, and immunohistochemistry were used to detect infarct size, pathological changes, Nissl corpuscula and neuronal protein expression in middle cerebral artery occlusion (MCAO) rats. Polymerase chain reaction and Western Blotting were conducted in cell and animal experiments to detect the expression levels of ER stress-related genes and proteins. RESULTS: The MD extract enhanced the viability of PC12 cells under OGD/R modeling, reduced ROS and IL-6 levels, increased MBP levels, and inhibited cell apoptosis. Furthermore, MD improved the infarct area in MCAO rats, increased the number of Nissl bodies, and regulated neuronal protein levels including Microtubule-Associated Protein 2 (MAP-2), Myelin Basic Protein (MBP), Glial Fibrillary Acidic Protein (GFAP), and Neurofilament 200 (NF200). Additionally, MD could regulate the expression levels of oxidative stress proteins malondialdehyde (MDA), nitric oxide (NO), superoxide dismutase (SOD), and catalase (CAT). Both cell and animal experiments demonstrated that MD could inhibit ER stress-related proteins (GRP78, ATF4, ATF6, CHOP) and reduce cell apoptosis. CONCLUSION: This study confirmed that the therapeutic mechanism of the MD extract on CIR injury was via the inhibition of oxidative stress and the ER stress pathway, in addition to the inhibition of apoptosis.

Local delivery of platelet-derived factors mitigates ischemia and preserves ovarian function through angiogenic modulation: A personalized regenerative strategy for fertility preservation.

As the most prominent and ideal modality in female fertility preservation, ovarian tissue cryopreservation, and transplantation often confront the challenge of ischemic damage and follicular loss from avascular transplantation. To surmount this impediment, we engineered a novel platelet-derived factors-encapsulated fibrin hydrogel (PFH), a paradigmatic biomaterial. PFH encapsulates autologous platelet-derived factors, utilizing the physiological blood coagulation cascade for precise local delivery of bioactive molecules. In our study, PFH markedly bolstered the success of avascular ovarian tissue transplantation. Notably, the quantity and quality of follicles were preserved with improved neovascularization, accompanied by decreased DNA damage, increased ovulation, and superior embryonic development rates under a Low-concentration Platelet-rich plasma-derived factors encapsulated fibrin hydrogel (L-PFH) regimen. At a stabilized point of tissue engraftment, gene expression analysis mirrored normal ovarian tissue profiles, underscoring the effectiveness of L-PFH in mitigating the initial ischemic insult. This autologous blood-derived biomaterial, inspired by nature, capitalizes on the blood coagulation cascade, and combines biodegradability, biocompatibility, safety, and cost-effectiveness. The adjustable properties of this biomaterial, even in injectable form, extend its potential applications into the broader realm of personalized regenerative medicine. PFH emerges as a promising strategy to counter ischemic damage in tissue transplantation, signifying a broader therapeutic prospect. (197 words).

Naoxintong capsule accelerates mitophagy in cerebral ischemia-reperfusion injury via TP53/PINK1/PRKN pathway based on network pharmacology analysis and experimental validation.

ETHNOPHARMACOLOGICAL RELEVANCE: The incidence and mortality of cerebrovascular diseases are increasing year by year. Cerebral ischemia-reperfusion injury (CIRI) is common in patients with ischemic stroke. Naoxintong (NXT) is composed of a variety of Chinese medicines and has the ability to treat CIRI. AIM OF THE STUDY: The aim of this study is to investigate whether NXT regulates mitophagy in CIRI based on network pharmacology analysis and experimental validation. MATERIALS AND METHODS: Oxygen and glucose deprivation/re-oxygenation (OGD/R, 2/22 h) model of PC12 cells and transient middle cerebral artery occlusion (tMCAO, 2/22 h) model of rats were established. Pharmacodynamic indicators include neurological deficit score, 2,3,5-triphenyte-trazoliumchloride (TTC) staining, hematoxylin-eosin (HE) staining and cell viability. Network pharmacology was used to predict pharmacological mechanisms. Pharmacological mechanism indexes include transmission electron microscopy (TEM), drug affinity responsive target stability (DARTS), cellular thermal shift assay (CETSA), immunohistochemistry (IHC), western blot (WB) and immunofluorescence (IF). Kevetrin (an agonists of p53) and pifithrin-α (an inhibitor of p53) used to detect the key role of p53 in mitophagy of NXT. RESULTS: NXT (1% serum containing NXT and 110 mg/kg) improved the damage of OGD/R PC12 cells and tMCAO rats, and this protective effect was related to the anti-oxidation and ability to promote mitophagy of NXT. NXT and pifithrin-α increased the expression of promoting-mitophagy targets (PINK1, PRKN and LC3B) and inhibited the expression of inhibiting-mitophagy targets (p52) via restraining p53, and finally accelerated mitophagy caused by CIRI. CONCLUSION: This study demonstrates that NXT promotes mitophagy in CIRI through restraining p53 and promoting PINK1/PRKN in vivo and in vitro.

[Buyang Huanwu Decoction attenuates cerebral ischemia-reperfusion injury in rats via miR-26a-5p mediated PTEN/PI3K/Akt signaling pathway].

This study aims to investigate the mechanism of Buyang Huanwu Decoction in treatment of cerebral ischemia-reperfusion injury in rats. A total of 180 SD rats were randomly divided into 5 different groups: sham group, model group, Buyang Huanwu Decoction group, Buyang Huanwu Decoction + miR-26a-5p agomir(agomir) group, Buyang Huanwu Decoction + miR-26a-5p agomir negative control(agomir NC) group. There were 36 rats in each group. Each group was then subdivided into three subgroups for the duration of reperfusion(3, 7, 14 d). A ligature-induced middle cerebral artery occlusion(MCAO) model was carried out on all groups other than sham group. Reperfusion was performed following ischemia for 90 min. Buyang Huanwu Decoction group, agomir group, and agomir NC group were given Buyang Huanwu Decoction twice daily by gavage 24 h after the formation of the model. Sham group and model group were given an equal amount of physiological saline by gavage until the day before sacrifice. At 24 h after ischemia induction, miR-26a-5p agomir was injected into the lateral ventricle in agomir group, miR-26a-5p NC in agomir NC group, and equal amounts of physiological saline in the other groups. 24 h after ischemia induction, BrdU was intraperitoneally injected once daily until the day before sacrifice. Modified neurological severity score(mNSS) was used to evaluate neurological deficits, 2,3,5-triphenyltetrazolium chloride(TTC) staining was used to determine the cerebral infarct volume, TUNEL staining was used to assess the apoptosis of parenchymal ischemic brain tissue, and double immunofluorescence staining was used to examine BrdU/NeuN double positive neurons in the parenchymal ischemic brain tissue to evaluate the neuronal regeneration. We employed a luciferase reporter assay to identify and validate that the target gene of miR-26a-5p is PTEN. Real-time quantitative polymerase chain reaction(RT-qPCR) was used to assess gene expression levels of PTEN and miR-26a-5p and Western blot to assess the protein levels of PTEN, PI3K, p-PI3K, Akt, and p-Akt. The results revealed that compared with model group, Buyang Huanwu Decoction treatment promoted neural function recovery, reduced the cerebral infarct volume, increased the number of BrdU~+/NeuN~+ neurons, upregulated the expression of miR-26a-5p, regulated the PTEN/PI3K/Akt signaling pathway, and promoted neuronal regeneration in the cerebral ischemia-reperfusion rats. These effects were significantly enhanced after lateral ventricle injection of miR-26a-5p agomir. The findings prove that Buyang Huanwu Decoction treatment can promote neural function recovery, reduce the cerebral infarct volume, and promote neuronal regeneration in a cerebral ischemia-reperfusion rat model, which is likely to be achieved via miR-26a-5p mediated PTEN/PI3K/Akt signaling pathway.

Comment on, "Differential DNA methylation associated with delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage: a systematic review".

The article "Differential DNA Methylation Associated with Delayed Cerebral Ischemia after Aneurysmal Subarachnoid Hemorrhage: A Systematic Review" by Tomasz Klepinowski et al. offers an in-depth analysis of the relationship between DNA methylation and delayed cerebral ischemia (DCI) following aneurysmal subarachnoid hemorrhage (aSAH). By systematically reviewing databases like PubMed, MEDLINE, Scopus, and Web of Science, the authors identify key genes, including ITPR3, HAMP, INSR, and CDHR5, as potential biomarkers for early DCI diagnosis. Their meticulous adherence to PRISMA guidelines and the STROBE statement for quality assessment enhances the study's credibility. However, the review could be improved by discussing methodological variability, statistical power, and the functional relevance of identified CpG sites. Additional sections on mechanistic pathways, integration with other omics data, clinical translation, and ethical considerations would further strengthen the review, providing a more comprehensive understanding of epigenetic factors in DCI and paving the way for future therapeutic interventions.

Potential of Edaravone Dexborneol in the treatment of cerebral ischemia: focus on cell death-related signaling pathways.

Cerebral ischemia has the highest global rate of morbidity and mortality. It occurs when a sudden occlusion develops in the arterial system, and consequently some parts of the brain are deprived from glucose and oxygen due to the cessation of blood flow. The ensuing reperfusion of the ischemic area results in a cascade of pathological alternations like neuronal apoptosis by producing excessive reactive oxygen species (ROS), oxidative stress and neuroinflammation. Edaravone Dexborneol is a novel agent, comprised of Edaravone and Dexborneol in a 4:1 ratio. It has documented neuroprotective effects against cerebral ischemia injury. Edaravone Dexborneol improves neurobehavioral and sensorimotor function, cognitive function, brain edema, and blood-brain barrier (BBB) integrity in experimental models. It at dosages ranging between 0.375 and 15 mg/kg (from immediately after ischemia until the 28th post-ischemic days) has shown neuroprotective effects in experimental models of cerebral ischemia by inhibiting cell death-signaling pathways. For example, it inhibits apoptosis by increasing Bcl2, and reducing Bax and caspase-3 expression. Edaravone Dexborneol also inhibits pyroptosis by attenuating NF-κB/NLRP3/GSDMD signaling, as well as ferroptosis by activating the Nrf-2/HO-1/GPX4 signaling pathway. It also inhibits autophagy by targeting PI3K/Akt/mTOR signaling pathway. Here, we provide a review on the impacts of Edaravone Dexborneol on cerebral ischemia.

Autophagy in myocardial ischemia and ischemia/reperfusion.

Myocardial infarction (MI) is a life-threatening condition that leads to loss of viable heart tissue. The best way to treat acute MI and limit the infarct size is to re-open the occluded coronary artery and restore the supply of oxygenated and nutrient-rich blood, but reperfusion can cause additional damage. Autophagy is an intracellular process that recycles damaged cytoplasmic components (molecules and organelles) by loading them into autophagosomes and degrading them in autolysosomes. Autophagy is increased in in vivo animal models of permanent ischemia and ischemia/reperfusion but by different molecular mechanisms. While autophagy is protective during permanent ischemia, it is detrimental during ischemia/reperfusion. Its modulation is being investigated as a potential target to reduce reperfusion injury. This review provides a synopsis of the current knowledge about autophagy, summarizes findings specifically in permanent ischemia and ischemia/reperfusion, and briefly discusses the potential implication of experimental findings.

Experimental study of the effectiveness of warm ischemia and cold ischemia during testis-sparing surgery in rats.

INTRODUCTION: The postpubertal effects of testis-sparing surgery on prepubertal testicular tumors are not fully understood. OBJECTIVE: In this study, we aimed to evaluate the effect of different durations of warm and cold ischemia during a rat prepubertal testis-sparing surgery model on the ischemic and contralateral normal testes in the postpubertal period. STUDY DESIGN: The study encompassed a group of 54 male rats in the prepubertal stage who were then arranged to be put into nine groups: sham (Sh), control-cold (Cc), control-biopsy (Cb), 30, 60 or 90min warm ischemia (WIb30,WIb60,WIb90) and cold ischemia (CIb30,CIb60,CIb90). In the ischemia groups, a microvascular clamp was applied to the right spermatic cord, then testicular biopsy was taken. In the cold ischemia groups, the testicles were preserved in sterile ice mud. After the experiment, the rats were observed for 4 weeks to pinpoint any changes during their progression into the post-pubertal period. Bilateral orchiectomy materials were examined histopathologically, and Johnsen scores were used to evaluate postpubertal fertility potential. RESULTS: In our investigation, rats in all groups exhibited similar weight gains. The postpubertal size of the right testis in the testicular biopsy groups was found to be smaller compared to the remaining groups. In the warm ischemia group, testicular atrophy occurred after ischemic duration exceeding 30 min. Conversely, no testicular atrophy was observed in the cold ischemia groups. The dimensions of the rats' left testicles were similar. On histopathology, right testicular Johnsen scores were significantly lower in the warm ischemic groups than in the cold ischemic groups. DISCUSSION: Our study is the first to investigate the postpubertal effects of varying durations of warm and cold ischemia in a prepubertal testis-sparing surgery model. In our study, the Johnsen scores of testes subjected to 30, 60, and 90 min of ischemia were found to be higher in the cold ischemia groups compared to the warm ischemia groups. As the ischemia duration prolonged, a discernible progression of testicular atrophy was observed in the warm ischemia groups, contrasting with the sustained stability of testicular sizes in the cold ischemia groups. CONCLUSIONS: Warm ischemia applied to the testis causes damage to the testicle within the first 30 min and leads to atrophy after 30 min. In the cases of warm ischemia, both the Johnsen scores, which serve as indicators of post-pubertal fertility, and the testicular size decline in parallel with the duration of ischemia.

[Research progress in osthole for prevention and treatment of central nervous system diseases].

Central nervous system(CNS) disorders can significantly impact patients' daily lives, impairing their ability to work and imposing a substantial financial burden on their families. In recent years, the incidence of CNS diseases has shown a significant increase with the continuous improvement of the quality of life and the aging problem. Therefore, the search for new preventive and curative drugs has been a research hotspot for this group of diseases. Osthole(OST), isolated from Umbelliferae such as Cnidium monnieri, Angelica sinensis, and Heracleum hemsleyanum, possesses a variety of pharmacological effects such as neuroprotective, antioxidant, anti-inflammatory, and antithrombotic effects. There is increasing evidence that OST has demonstrated significant preventive and curative effects in various CNS disease models. This paper systematically reviewed the research progress of OST in preventing and treating CNS diseases by reviewing domestic and international literature to provide more in-depth theoretical support for the future clinical application of OST in the prevention and treatment of CNS diseases.

Neuroprotective Effect of Flavonoid Agathisflavone in the Ex Vivo Cerebellar Slice Neonatal Ischemia.

Agathisflavone is a flavonoid that exhibits anti-inflammatory and anti-oxidative properties. Here, we investigated the neuroprotective effects of agathisflavone on central nervous system (CNS) neurons and glia in the cerebellar slice ex vivo model of neonatal ischemia. Cerebellar slices from neonatal mice, in which glial fibrillary acidic protein (GFAP) and SOX10 drive expression of enhanced green fluorescent protein (EGFP), were used to identify astrocytes and oligodendrocytes, respectively. Agathisflavone (10 µM) was administered preventively for 60 min before inducing ischemia by oxygen and glucose deprivation (OGD) for 60 min and compared to controls maintained in normal oxygen and glucose (OGN). The density of SOX-10+ oligodendrocyte lineage cells and NG2 immunopositive oligodendrocyte progenitor cells (OPCs) were not altered in OGD, but it resulted in significant oligodendroglial cell atrophy marked by the retraction of their processes, and this was prevented by agathisflavone. OGD caused marked axonal demyelination, determined by myelin basic protein (MBP) and neurofilament (NF70) immunofluorescence, and this was blocked by agathisflavone preventative treatment. OGD also resulted in astrocyte reactivity, exhibited by increased GFAP-EGFP fluorescence and decreased expression of glutamate synthetase (GS), and this was prevented by agathisflavone pretreatment. In addition, agathisflavone protected Purkinje neurons from ischemic damage, assessed by calbindin (CB) immunofluorescence. The results demonstrate that agathisflavone protects neuronal and myelin integrity in ischemia, which is associated with the modulation of glial responses in the face of ischemic damage.

Ventricular Tachycardia Storm in a Young Adult Post-ALCAPA Repair.

Anomalous left coronary artery to pulmonary artery (ALCAPA) is a leading cause of pediatric myocardial ischemia. This paper presents a case of a young man presenting with ventricular tachycardia storm 18 years after ALCAPA repair. Clinicians should recognize the risk of ventricular tachycardia in this patient population.

Weisheng-tang protects against ischemic brain injury by modulating microglia activation through the P2Y12 receptor.

Background: Stroke, a leading cause of death and disability, lacks effective treatments. Post-stroke secondary damage worsens the brain microenvironment, further exacerbating brain injury. Microglia's role in responding to stroke-induced damage in peri-infarct regions is crucial. In this study, we explored Weisheng-tang's potential to enhance ischemic outcomes by targeting microglia. Methods: We induced middle cerebral artery occlusion and reperfusion in mice, followed by behavioral assessments and infarct volume analyses after 48 h, and examined the changes in microglial morphology through skeleton analysis. Results: Weisheng-tang (300 mg/kg) significantly reduced infarction volume and alleviated neurological and motor deficits. The number of activated microglia was markedly increased within the peri-infarct territory, which was significantly reversed by Weisheng-tang. Microglial morphology analysis revealed that microglial processes were retracted owing to ischemic damage but were restored in Weisheng-tang-treated mice. This restoration was accompanied by the expression of the purinergic P2Y12 receptor (P2Y12R), a key regulator of microglial process extension. Weisheng-tang increased neuronal Kv2.1 clusters while suppressing juxtaneuronal microglial activation. The P2Y12R inhibitor-ticagrelor-eliminated the tissue and functional recovery that had been observed with Weisheng-tang after ischemic damage. Discussion: Weisheng-tang improved experimental stroke outcomes by modulating microglial morphology through P2Y12R, shedding light on its neuroprotective potential in ischemic stroke.

Donor hepatectomy time and liver transplantation outcomes: An opportunity that cannot be dismissed.

The probability of developing primary dysfunction (PD) is a function of the probability of ischemia/reperfusion (I/R) injury. The probability of I/R injury in turn, is a function of several donor and transplantation process variables, among which is ischemia time. Custodio et al studied the duration of a special type of warm ischemia and showed, contrary to what is known, that a longer duration is not statistically different from a shorter one in PD development. This finding opens the door to the unforeseen opportunity of training fellows in performing hepatectomies, since the duration will not jeopardize liver transplant outcomes, albeit with some precautions.

Combined effect of intermittent hemostasis and a modified external hemorrhage control device in a lethal swine model.

Background: Non-compressible torso hemorrhage (NCTH) presents the ultimate challenge in pre-hospital care. While external hemorrhage control devices (EHCDs) such as the Abdominal Aortic and Junctional Tourniquet (AAJT) and SAM Junctional Tourniquet (SJT) have been invented, the current design and application strategy requires further improvement. Therefore, researchers devised a novel apparatus named Modified EHCD (M-EHCD) and implemented intermittent hemostasis (IH) as a preventive measure against ischemia-reperfusion injury. The objective of this study was to ascertain the combined effect of M-EHCD and IH on the hemostatic effect of NCTH. Methods: Eighteen swine were randomized to M-EHCD, AAJT or SJT. The NCTH model was established by inducing Class Ⅲ hemorrhagic shock and performing a hemi-transection of common femoral artery (CFA). EHCDs were rapidly fastened since the onset of free bleeding (T0min). The IH strategy was implemented by fully releasing M-EHCD at T40min, T70min and T100min, respectively, whereas AAJT and SJT maintained continuous hemostasis (CH) until T120min. All groups underwent CFA bridging at T110min, and EHCDs were removed at T120min. Reperfusion lasted for 60 min, after which euthanasia was performed. Hemodynamics, intra-vesical pressure (IVP), and blood samples were collected periodically. Histological examinations were also conducted. Results: M-EHCD demonstrated the fastest application time (M-EHCD: 26.38 ± 6.32s vs. SJT: 30.84 ± 5.62s vs. AAJT: 54.28 ± 5.45s, P < 0.001) and reduced free blood loss (M-EHCD: 17.77 ± 9.85g vs. SJT: 51.80 ± 33.70g vs. AAJT: 115.20 ± 61.36g, P = 0.011) compared to SJT and AAJT. M-EHCD exhibited inhibitory effects on heart rate (M-EHCD: 91.83 ± 31.61bpm vs. AAJT: 129.00 ± 32.32bpm vs. SJT: 135.17 ± 21.24bpm, P = 0.041) and shock index. The device's external pressure was lowest in M-EHCD and highest in SJT (P = 0.001). The resultant increase in IVP were still the lowest in M-EHCD (M-EHCD: -0.07 ± 0.45 mmHg vs. AAJT: 27.04 ± 5.03 mmHg vs. SJT: 5.58 ± 2.55 mmHg, P < 0.001). Furthermore, M-EHCD caused the least colonic injury (M-EHCD: 1.17 ± 0.41 vs. AAJT: 2.17 ± 0.41 vs. SJT: 2.17 ± 0.41, P = 0.001). The removal of M-EHCD showed the slightest impact on pH (P < 0.001), while AAJT group was more susceptible to the lethal triad based on the arterial lactate and thrombelastogram results. Conclusions: M-EHCD + IH protected the organs and reduced the risk of the lethal triad by decreasing disruptions to IVP, hemodynamics, acid-base equilibrium and coagulation. M-EHCD + IH was superior to the hemostatic safety and efficacy of AAJT/SJT + CH.

Proximalization of arterial inflow with adjunctive arterial pressure measurements for management of hemodialysis access-induced distal ischemia.

Hemodialysis access-induced distal ischemia (HAIDI) is an uncommon, yet potentially devastating, complication of hemodialysis access surgery. Management of HAIDI depends on the access' volume flow and may involve banding, proximalization of arterial inflow, revision using distal inflow, distal revascularization interval ligation, or access ligation. Various adjunctive techniques have been used to confirm improved distal arterial flow intraoperatively. Here, we present a case of a patient with grade 3 HAIDI treated with proximalization of arterial inflow technique with the adjunctive use of intra-arterial pressure gradient measurements.

Renal cell carcinoma as a cause of aortic tumor thrombus embolization and acute limb ischemia.

This article presents a unique case of acute limb ischemia resulting from arterial tumor embolism secondary to renal cell carcinoma involving an aortobi-iliac bypass graft. To the best of our knowledge, this instance is the first documented in the literature of such a complication. The patient, a man in his 70s with a complex medical history, underwent bilateral femoral embolectomy and subsequent endovascular intervention for the resolution of the tumor thrombus. The rarity of this phenomenon poses challenges in formulating a standardized management strategy.

Intramyocardial injection of hypoxia-conditioned extracellular vesicles increases myocardial perfusion in a swine model of chronic coronary disease.

Objective: Coronary artery disease remains a leading cause of morbidity and mortality worldwide. Patients with advanced coronary artery disease who are not eligible for endovascular or surgical revascularization have limited options. Extracellular vesicles have shown potential to improve myocardial function in preclinical models. Extracellular vesicles can be conditioned to modify their components. Hypoxia-conditioned extracellular vesicles have demonstrated the ability to reduce infarct size and apoptosis in small animals. Our objective is to assess the potential benefits of hypoxia-conditioned extracellular vesicles in a large animal model of coronary artery disease. Methods: Coronary artery disease was induced in 14 Yorkshire swine by ameroid constriction of the left circumflex coronary artery. Two weeks postsurgery, swine underwent a repeat left thoracotomy for injections of hypoxia-conditioned extracellular vesicles (n = 7) or saline (control, n = 7). Five weeks later, all animals underwent terminal harvest for perfusion measurements and myocardial sectioning. Results: Myocardial perfusion analysis demonstrated a trend toward increase at rest and a significant increase during rapid pacing (P = .09, P < .001). There were significant increases in activated phosphorylated endothelial nitric oxide synthase, endothelial nitric oxide synthase, phosphatidylinositol 3-kinase, phosphorylated protein kinase B, and the phosphorylated protein kinase B/protein kinase B ratio in the hypoxia-conditioned extracellular vesicles group compared with the control group (all P < .05). Additionally, there was a significant decrease in the antiangiogenic proteins collagen 18 and angiostatin (P = .01, P = .01) in the hypoxia-conditioned extracellular vesicles group. Conclusions: Intramyocardial injection of hypoxia-conditioned extracellular vesicles results in increased myocardial perfusion without a corresponding change in vessel density. Therefore, this improvement in perfusion is possibly due to changes in nitric oxide signaling. Hypoxia-conditioned extracellular vesicles represent a potential therapeutic strategy to increase myocardial perfusion in patients with advanced coronary artery disease.

Retinal ischemia-reperfusion injury and pretreatment with Lycium barbarum glycopeptide.

AIM: To investigate the antioxidant protective effect of Lycium barbarum glycopeptide (LbGP) pretreatment on retinal ischemia-reperfusion (I/R) injury (RIRI) in rats. METHODS: RIRI was induced in Sprague Dawley rats through anterior chamber perfusion, and pretreatment involved administering LbGP via gavage for 7d. After 24h of reperfusion, serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), and creatinine (CREA) levels, retinal structure, expression of Caspase-3 and Caspase-8, superoxide dismutase (SOD) activity, and malondialdehyde (MDA) in the retina were measured. RESULTS: The pretreatment with LbGP effectively protected the retina and retinal tissue from edema and inflammation in the ganglion cell layer (GCL) and nerve fiber layer (NFL) of rats subjected to RIRI, as shown by light microscopy and optical coherence tomography (OCT). Serum AST was higher in the model group than in the blank group (P=0.042), but no difference was found in ALT, AST, and CREA across the LbGP groups and model group. Caspase-3 expression was higher in the model group than in the blank group (P=0.006), but no difference was found among LbGP groups and the model group. Caspase-8 expression was higher in the model group than in the blank group (P=0.000), and lower in the 400 mg/kg LbGP group than in the model group (P=0.016). SOD activity was lower in the model group than in the blank group (P=0.001), and the decrease was slower in the 400 mg/kg LbGP group than in the model group (P=0.003). MDA content was higher in the model group than in the blank group (P=0.001), and lower in the 400 mg/kg LbGP group than in the model group (P=0.016). The pretreatment with LbGP did not result in any observed liver or renal toxicity in the model. CONCLUSION: LbGP pretreatment exhibits dose-dependent anti-inflammatory, and antioxidative effects by reducing Caspase-8 expression, preventing declines of SOD activity, and decreasing MDA content in the RIRI rat model.

Induced Blood Flow Oscillations at 0.1 Hz Protects Oxygenation of Severely Ischemic Tissue in Humans.

Generating 10-second (~0.1 Hz) fluctuations or "oscillations" in arterial pressure and blood flow blunts reductions in cerebral tissue oxygenation in response to 15-20% reductions in cerebral blood flow. To examine the effect of 0.1 Hz hemodynamic oscillations on tissue oxygenation during severe ischemia, we developed a partial limb ischemia protocol targeting a 70-80% reduction in blood flow. We hypothesized that 0.1 Hz hemodynamic oscillations would attenuate reductions in tissue oxygenation during severe ischemia. 13 healthy humans (6M, 7F; 27.3±4.2 y) completed two experimental protocols separated by ≥48 h. In both conditions, an upper arm cuff was used to decrease brachial artery (BA) blood velocity by ~70-80% from baseline. In the oscillation condition (0.1 Hz), 0.1 Hz hemodynamic oscillations were induced by intermittently inflating and deflating bilateral thigh cuffs every 5-s during forearm ischemia. In the control condition (0 Hz), the thigh cuffs were inactive. BA blood flow, forearm tissue oxygenation (SmO2), and arterial pressure were measured continuously. The initial reduction in BA blood velocity was tightly matched between protocols (0 Hz: -76.9±7.9% vs. 0.1 Hz: -75.5±7.4%, p=0.49). While 0.1 Hz oscillations during forearm ischemia had no effect on the reduction in BA velocity (0 Hz: -73.0 ± 9.9% vs. 0.1 Hz: -73.3 ± 8.2%, p=0.91), the reduction in SmO2 was attenuated (0 Hz: -35.7±8.6% vs. 0.1 Hz: -27.2±8.9%; p=0.01). These data provide further evidence for the use of 0.1 Hz hemodynamic oscillations as a potential therapeutic intervention for conditions associated with severe tissue ischemia (e.g., hemorrhage and stroke).