Time Window For Treatment Research Articles

The Changing Landscape of Intravenous Thrombolysis for Acute Ischaemic Stroke

Intravenous thrombolysis remains the most accessible and effective reperfusion therapy available to patients with acute ischaemic stroke. Treatment with intravenous thrombolysis improves the odds of favourable functional outcome with the unacceptably low risk of haemorrhagic complications. Even in the current era of endovascular thrombectomy, intravenous thrombolysis remains the backbone of acute stroke treatment due to its accessibility and relative ease of administration. Since intravenous alteplase was first approved for acute ischaemic stroke in the mid 1990s, there have been significant advances in expanding the indication and time window for treatment, in addition to transitioning towards tenecteplase use for stroke thrombolysis. In this review, we will provide a narrative on the use of thrombolysis in acute ischaemic stroke including an up-to-date discussion on recent advances in thrombolytic therapy.

Single–particle rotational microrheology enables pathological staging of macrophage foaming and antiatherosclerotic studies

The formation of macrophage-derived foam cells has been recognized as the pathological hallmark of atherosclerotic diseases. However, the pathological evolution dynamics and underlying regulatory mechanisms remain largely unknown. Herein, we introduce a single-particle rotational microrheology method for pathological staging of macrophage foaming and antiatherosclerotic explorations by probing the dynamic changes of lysosomal viscous feature over the pathological evolution progression. The principle of this method involves continuous monitoring of out-of-plane rotation-caused scattering brightness fluctuations of the gold nanorod (AuNR) probe-based microrheometer and subsequent determination of rotational relaxation time to analyze the viscous feature in macrophage lysosomes. With this method, we demonstrated the lysosomal viscous feature as a robust pathological reporter and uncovered three distinct pathological stages underlying the evolution dynamics, which are highly correlated with a pathological stage-dependent activation of the NLRP3 inflammasome-involved positive feedback loop. We also validated the potential of this positive feedback loop as a promising therapeutic target and revealed the time window-dependent efficacy of NLRP3 inflammasome-targeted drugs against atherosclerotic diseases. To our knowledge, the pathological staging of macrophage foaming and the pathological stage-dependent activation of the NLRP3 inflammasome-involved positive feedback mechanism have not yet been reported. These findings provide insights into in-depth understanding of evolutionary features and regulatory mechanisms of macrophage foaming, which can benefit the analysis of effective therapeutical drugs as well as the time window of drug treatment against atherosclerotic diseases in preclinical studies.

Blood-based protein biomarkers during the acute ischemic stroke treatment window: a systematic review.

Rapid and accurate acute ischemic stroke (AIS) diagnosis is needed to expedite emergent thrombolytic and mechanical thrombectomy treatment. Changes in blood-based protein biomarkers during the first 24 h of AIS, the time window for treatment, could complement imaging techniques and facilitate rapid diagnosis and treatment. We performed a systematic review according to PRISMA guidelines. MEDLINE, EMBASE, Cochrane Library, and Web of Science databases were searched for eligible studies comparing levels of blood-based protein biomarkers in AIS patients with levels in healthy controls and stroke mimics. Protein biomarkers from the following pathophysiological categories were included: neurovascular inflammation (MMP-9, TNF-alpha), endothelial integrity (VCAM-1, ICAM-1), cell migration (E-Selectin, P-Selectin, L-Selectin), markers of glial and neuronal origin (GFAP, S100, S100B, NSE), and cardiac dysfunction (BNP, NT-proBNP). The literature search was limited to English-language publications before November 7th, 2023. A total of 61 studies from 20 different countries were identified, which included in total, 4,644 AIS patients, 2,242 stroke mimics, and 2,777 controls. Studies investigating TNF-alpha, MMP-9, VCAM-1, ICAM-1, E-Selectin, L-Selectin, GFAP, NSE, and S100B showed pronounced methodological heterogeneity, making between-study comparisons difficult. However, in 80% of NT-proBNP and BNP studies, and all P-selectin studies, higher biomarker levels were observed in AIS patients compared to healthy controls and/or patients with stroke mimics. None of the biomarkers included showed sufficient evidence for additional diagnostic benefit for AIS. Comprehensive standardized global multicenter studies are needed to (1) permit comparability, (2) enable valid statements about protein-based biomarkers, and (3) reflect real-world scenarios.

Permselectivity of Silk Fibroin Hydrogels for Advanced Drug Delivery Neurotherapies.

A promising trend in tissue engineering is using biomaterials to improve the control of drug concentration in targeted tissue. These vehicular systems are of specific interest when the required treatment time window is higher than the stability of therapeutic molecules in the body. Herein, the capacity of silk fibroin hydrogels to release different molecules and drugs in a sustained manner was evaluated. We found that a biomaterial format, obtained by an entirely aqueous-based process, could release molecules of variable molecular weight and charge with a preferential delivery of negatively charged molecules. Although the theoretical modeling suggested that drug delivery was more likely to be driven by Fickian diffusion, the external media had a considerable influence on the release, with lipophilic organic solvents such as acetonitrile-methanol (ACN-MeOH) intensifying the release of hydrophobic molecules. Second, we found that silk fibroin could be used as a vehicular system to treat a variety of brain disorders as this biomaterial sustained the release of different factors with neurotrophic (brain-derived neurotrophic factor) (BDNF), chemoattractant (C-X-C motif chemokine 12) (CXCL12), anti-inflammatory (TGF-β-1), and angiogenic (VEGF) capacities. Finally, we demonstrated that this biomaterial hydrogel could release cholesteronitrone ISQ201, a nitrone with antioxidant capacity, showing neuroprotective activity in an in vitro model of ischemia-reoxygenation. Given the slow degradation rate shown by silk fibroin in many biological tissues, including the nervous system, our study expands the restricted list of drug delivery-based biomaterial systems with therapeutic capacity for both short- and especially long-term treatment windows and has merit for use with brain pathologies.

Pathological polarizations from microglia to astrocyte contributes to spatial memory deficit in methamphetamine abstinence mice.

Previously, we found that dCA1 A1-like polarization of astrocytes contributes a lot to the spatial memory deficit in methamphetamine abstinence mice. However, the underlying mechanism remains unclear, resulting in a lack of promising therapeutic targets. Here, we found that methamphetamine abstinence mice exhibited an increased M1-like microglia and A1-like astrocytes, together with elevated levels of interleukin 1α and tumor necrosis factor α in dCA1. In vitro, the M1-like BV2 microglia cell medium, containing high levels of Interleukin 1α and tumor necrosis factor α, elevated A1-like polarization of astrocytes, which weakened their capacity for glutamate clearance. Locally suppressing dCA1 M1-like microglia activation with minocycline administration attenuated A1-like polarization of astrocytes, ameliorated dCA1 neurotoxicity, and, most importantly, rescued spatial memory in methamphetamine abstinence mice. The effective time window of minocycline treatment on spatial memory is the methamphetamine exposure period, rather than the long-term methamphetamine abstinence.

Micro-CT-assisted identification of the optimal time-window for antifibrotic treatment in a bleomycin mouse model of long-lasting pulmonary fibrosis

Idiopathic Pulmonary Fibrosis (IPF) is a debilitating and fatal lung disease characterized by the excessive formation of scar tissue and decline of lung function. Despite extensive research, only two FDA-approved drugs exist for IPF, with limited efficacy and relevant side effects. Thus, there is an urgent need for new effective therapies, whose discovery strongly relies on IPF animal models. Despite some limitations, the Bleomycin (BLM)-induced lung fibrosis mouse model is widely used for antifibrotic drug discovery and for investigating disease pathogenesis. The initial acute inflammation triggered by BLM instillation and the spontaneous fibrosis resolution that occurs after 3 weeks are the major drawbacks of this system. In the present study, we applied micro-CT technology to a longer-lasting, triple BLM administration fibrosis mouse model to define the best time-window for Nintedanib (NINT) treatment. Two different treatment regimens were examined, with a daily NINT administration from day 7 to 28 (NINT 7–28), and from day 14 to 28 (NINT 14–28). For the first time, we automatically derived both morphological and functional readouts from longitudinal micro-CT. NINT 14–28 showed significant effects on morphological parameters after just 1 week of treatment, while no modulations of these biomarkers were observed during the preceding 7–14-days period, likely due to persistent inflammation. Micro-CT morphological data evaluated on day 28 were confirmed by lung histology and bronchoalveolar lavage fluid (BALF) cells; Once again, the NINT 7–21 regimen did not provide substantial benefits over the NINT 14–28. Interestingly, both NINT treatments failed to improve micro-CT-derived functional parameters. Altogether, our findings support the need for optimized protocols in preclinical studies to expedite the drug discovery process for antifibrotic agents. This study represents a significant advancement in pulmonary fibrosis animal modeling and antifibrotic treatment understanding, with the potential for improved translatability through the concurrent structural–functional analysis offered by longitudinal micro-CT.

Extracorporeal membrane oxygenation states basilar artery thrombectomy and left posterior cerebral artery stent thrombectomy: A case report

BACKGROUND Extracorporeal membrane oxygenation (ECMO) is a new type of extracorporeal respiratory and circulatory assistance device. It can drain venous blood out of the body and inject it into veins or arteries after being oxygenated by an oxygenator (membrane lung) to replace lung and heart functions in a short time. ECMO can provide tissue blood perfusion and gas exchange almost equivalent to cardiac output and extend the effective treatment time window for patients with acute circulatory failure to restore cardiopulmonary function. CASE SUMMARY We report a case of an 81-year-old woman who underwent whole cerebral angiography, basilar artery thrombectomy and stent thrombectomy in the posterior artery of the left brain after implantation of ECMO. The patient was admitted to the hospital due to myocardial infarction. Considering that the cause of the patient’s disturbance of consciousness was unknown and cerebrovascular accident could not be ruled out after the implantation of ECMO, the department of Radioactive Intervention performed cerebral angiography. And the result of the angiography indicated vascular occlusion. After the basilar artery thrombectomy and stent thrombectomy in the posterior artery of the left brain, the patency of the occlusive vessel was achieved. CONCLUSION Although the patient eventually died of circulatory failure, the result of this case verifies the feasibility of cerebral angiography and thrombectomy in patients with implanted ECMO in the intubated state.

Amphetamine and methylphenidate potential on the recovery from stroke and traumatic brain injury: a review.

The prevalence of stroke and traumatic brain injury is increasing worldwide. However, current treatments do not fully cure or stop their progression, acting mostly on symptoms. Amphetamine and methylphenidate are stimulants already approved for attention deficit hyperactivity disorder and narcolepsy treatment, with neuroprotective potential and benefits when used in appropriate doses. This review aimed to summarize pre-clinical and clinical trials testing either amphetamine or methylphenidate for the treatment of stroke and traumatic brain injury. We used PubMed as a database and included the following keywords ((methylphenidate) OR (Ritalin) OR (Concerta) OR (Biphentin) OR (amphetamine) OR (Adderall)) AND ((stroke) OR (brain injury) OR (neuroplasticity)). Overall, studies provided inconsistent results regarding cognitive and motor function. Neurite outgrowth, synaptic proteins, dendritic complexity, and synaptic plasticity increases were reported in pre-clinical studies along with function improvement. Clinical trials have demonstrated that, depending on the brain region, there is an increase in motor activity, attention, and memory due to the stimulation of the functionally depressed catecholamine system and the activation of neuronal remodeling proteins. Nevertheless, more clinical trials and pre-clinical studies are needed to understand the drugs' full potential for their use in these brain diseases namely, to ascertain the treatment time window, ideal dosage, long-term effects, and mechanisms, while avoiding their addictive potential.

CX3CL1-CX3CR1 axis protects retinal ganglion cells by inhibiting microglia activation in a distal optic nerve trauma model

BackgroundThe chemokine CX3CL1 has been reported to play an important role in optic nerve protection, but the underlying mechanism is still unclear. CX3CR1, the only receptor of CX3CL1, is specifically expressed on retinal microglia, whose activation plays a role in the pathological process of optic nerve injury. This study aimed to evaluate whether CX3CL1 exerts optic neuroprotection by affecting the activation of microglia by combining with CX3CR1.MethodsA mouse model of distal optic nerve trauma (ONT) was used to evaluate the effects of the CX3CL1-CX3CR1 axis on the activation of microglia and survival or axonal regeneration of retinal ganglion cells (RGCs). The activation of microglia, loss of RGCs, and damage to visual function were detected weekly till 4 weeks after modeling. CX3CL1 was injected intravitreally immediately or delayed after injury and the status of microglia and RGCs were examined.ResultsIncreases in microglia activation and optic nerve damage were accompanied by a reduced production of the CX3CL1-CX3CR1 axis after the distal ONT modeling. Both immediate and delayed intravitreal injection of CX3CL1 inhibited microglia activation, promoted survival of RGCs, and improved axonal regenerative capacity. Injection with CX3CL1 was no longer effective after 48 h post ONT. The CX3CL1-CX3CR1 axis promotes survival and axonal regeneration, as indicated by GAP43 protein and gene expression, of RGCs by inhibiting the microglial activation after ONT.ConclusionsThe CX3CL1-CX3CR1 axis could promote survival and axonal regeneration of RGCs by inhibiting the microglial activation after optic nerve injury. The CX3CL1-CX3CR1 axis may become a potential target for the treatment of optic nerve injury. Forty-eight hours is the longest time window for effective treatment after injury. The study is expected to provide new ideas for the development of targeted drugs for the repair of optic nerve.

The Effect of Different Hyperbaric Oxygen Treatment Time Windows on Neurological Function and Prognosis in Acute Cerebral Infarction

The Effect of Different Hyperbaric Oxygen Treatment Time Windows on Neurological Function and Prognosis in Acute Cerebral Infarction

Effects of instant controlled pressure drop treatment combined with refractance window drying on infusion quality of made green tea.

The study aimed to determine the effects of instant controlled decompression of steam pressure, termed as ICPD (instant controlled pressure drop) on fresh tea leaves, when combined with refractance window drying (RWD) of rolled green teas during green tea manufacturing. The ICPD steam treatment pressure (TP; 0.1-0.3 MPa), treatment time (TT; 10-20 s) and refractance window drying temperature (RWDT; 70-90 °C) were used as the processing parameters for manufacturing of green tea. Response surface methodology was employed to enumerate the effects of ICPD process conditions and temperature of RWD on total phenolic content (TPC), total flavonoid content (TFC) and DPPH (1,1-diphenyl-2-picrylhydrazyl) radical scavenging activity of the green tea infusion. An optimum condition for green tea processing was found at TP 0.2 MPa, TT 20 s with RWDT at 70 °C. In comparison to made green tea manufactured without ICPD treatment, the ICPD treated green tea showed enhanced TPC, TFC and DPPH radical scavenging activity along with better colour and sensory attributes. The microstructural study of ICPD treated green tea samples showed more deformed cell surface integrity, larger stomatal pore size and cracks at the leaf surface in comparison with non-treated green tea sample. Present study reveals that an ICPD treatment at 0.2 MPa for 20 s can be used as an alternative to the traditional enzyme inactivation step of hot water treatment, for green tea leaves to improve the infusion quality in terms of increased levels of TPC and TFC and DPPH radical scavenging activity. © 2024 Society of Chemical Industry.

Salidroside derivative SHPL-49 attenuates glutamate excitotoxicity in acute ischemic stroke via promoting NR2A-CAMKⅡα-Akt /CREB pathway

BackgroundIschemic stroke is a significant cause of death and disability with a limited treatment time window. The reduction of early glutamate excitotoxicity using neuroprotective agents targeting N-methyl-d-aspartic acid (NMDA) receptors have attracted recent research attention. SHPL-49, a structurally modified derivative of salidroside, was synthesized by our team. Previous studies have confirmed the neuroprotective efficacy of SHPL-49 in rats with ischemic stroke. However, the underlying mechanisms need to be clarified. MethodsWe conducted in vivo experiments using the permanent middle cerebral artery occlusion rat model to investigate the role of SHPL-49 in glutamate release at different time points and treatment durations. Glutamate transporters and receptor proteins and neural survival proteins in the brain were also examined at the same time points. In vitro, primary neurons and the coculture system of primary neurons–astrocytes were subjected to oxygen–glucose deprivation and glutamate injury. Proteomics and parallel reaction monitoring analyses were performed to identify potential therapeutic targets of SHPL-49, which were further confirmed through in vitro experiments on the inhibition and mutation of the target. ResultsSHPL-49 significantly reduced glutamate release caused by hypoxia–ischemia. One therapeutic pathway of SHPL-49 was promoting the expression of glutamate transporter-1 to increase glutamate reuptake and further reduce the occurrence of subsequent neurotoxicity. In addition, we explored the therapeutic targets of SHPL-49 and its regulatory effects on glutamate receptors for the first time. SHPL-49 enhanced neuroprotection by activating the NMDA subunit NR2A, which upregulated the cyclic-AMP response binding protein (CREB) neural survival pathway and Akt phosphorylation. Since calcium/calmodulin-dependent kinase IIα (CaMKIIα) is necessary for synaptic transmission of NMDA receptors, we explored the interaction between CaMKIIα and SHPL-49, which protected CaMKIIα from hypoxia–ischemia-induced autophosphorylation damage. ConclusionOverall, SHPL-49 enhanced neuronal survival and attenuated acute ischemic stroke by promoting the NR2A–CAMKⅡα–Akt/CREB pathway. Our study provides the first evidence demonstrating that the neuroprotective effect of SHPL-49 is achieved by promoting the NR2A subunit to extend the treatment time window, making it a promising drug for ischemic stroke.

Effectiveness and safety of edaravone dexborneol in acute ischemic stroke (EXPAND): Study protocol for a prospective, multicenter, real-world cohort study

Background: Edaravone dexborneol has been confirmed as a novel neuroprotective agent by acting on multiple active targets of antioxidation and anti-inflammation. Objectives: This study aims to evaluate the effectiveness and safety of edaravone dexborneol in patients with acute ischemic stroke (AIS) within 14 days of symptom onset in real-world clinical practice. Methods: This prospective, multicenter, 2-arm, parallel, real-world cohort study will involve 72 stroke centers in China and plans to recruit 4750 exposed/unexposed patients with a 2:1 ratio to gather additional safety information on edaravone dexborneol. Patients eligible of the Effectiveness and Safety of Edaravone Dexborneol in Acute Ischemic Stroke (EXPAND) are diagnosed with AIS within 14 days of symptom onset. The eligible patients who receive edaravone dexborneol will be assigned to the exposed group, while those without using edaravone dexborneol will be assigned to the unexposed group. All participants will be followed up for 90 days. The primary outcome is a favorable functional outcome as defined by a modified Rankin Scale (mRS) score 0–1 at 90 days. Primary efficacy in the 2 groups will be compared using multivariable logistic regression. Results: EXPAND is the first real-world study to elucidate the efficacy and safety of edaravone dexbornel in AIS, which has the potential to extend the therapeutic time window of neuroprotective treatment and propose a multiple-target approach for AIS. Conclusions: The protocol was approved by the Ethics Committee at all participating sites [the reference number of central ethic committee: (2022)090] and by the local Institutional Review Board of each participating center. The findings of the study will be published in peer-reviewed scientific journals and presented at national and international conferences. This cohort study only collects real-world patient data during the diagnosis and treatment process. The refusal of a patient to participate or the decision to withdraw from the study will not interfere with the clinical decision-making. Thus, no additional risk will be imposed. Trial registration number: NCT05644223.

Exploring Superselective Intraarterial Thrombolysis for Autologous Fat Injection-Induced Vision Loss.

Intravascular injection represents the most severe complication in fat transplantation procedures. Currently, the prognosis for patients who suffer from blindness due to fat transplantation-induced ocular vascular occlusion is far from optimistic. The aim of this study was to explore and evaluate the efficacy and safety of arterial thrombolysis in the treatment of ocular vascular occlusion caused by fat transplantation. We analyzed the data of 12 patients who underwent intraarterial thrombolysis and conservative treatments for facial autologous fat grafting-associated ocular vascular occlusion. Among the cases, there were 6 instances of ophthalmic artery embolism and 6 cases of central retinal artery occlusion. All patients suffered with sudden blindness, sometimes accompanied by eye pain, ptosis, strabismus, skin necrosis at the injection site, or cerebral microinfarction. They received symptomatic conservative treatments and intraarterial thrombolysis, encompassing mechanical vessel recanalization, vessel dilation, and dissolution of thrombus constituents. Following intraarterial thrombolysis, a noteworthy improvement in the blood flow of both the main trunk and peripheral branches of the ophthalmic artery was observed in the majority of patients when contrasted with their pretreatment status. One patient experienced a headache intraoperatively, while no significant discomfort was reported by the remaining patients. After conservative treatments and intraarterial thrombolysis, all patients experienced improvement in ocular symptoms, skin necrosis, and cerebral infarction. Three patients demonstrated improvement in visual acuity. These patients had surpassed the recommended time window for treatment, yet the occlusion of the ophthalmic artery was not complete. Intraarterial thrombolysis combined with conservative treatments achieves early perfusion and is expected to promote visual recovery. Hospitals that possess the necessary treatment capabilities are encouraged to establish this therapeutic pathway.

Image-free recognition of moderate ROP from mild with machine learning algorithm on plasma Raman spectrum

The retinopathy of prematurity (ROP) can cause serious clinical consequences and, fortunately, it is remediable while the time window for treatment is relatively narrow. Therefore, it is urgent to screen all premature infants and diagnose ROP degree timely, which has become a large workload for pediatric ophthalmologists. We developed a retinal image-free procedure using small amount of blood samples based on the plasma Raman spectrum with the machine learning model to automatically classify ROP cases before medical intervention was performed. Statistical differences in infrared Raman spectra of plasma samples were found among the control, mild (ZIIIS1), moderate (ZIIIS2 & ZIIS1), and advanced (ZIIS2) ROP groups. With the different wave points of Raman spectra as the inputs, the outputs of our support vector machine showed that the area under the curves in the receiver operating characteristic (AUC) were 0.763 for the pair comparisons of the control with the mild groups, 0.821 between moderate and advanced groups (ZIIS2), while more than 90% in comparisons of the other four pairs: control vs. moderate (0.981), control vs. advanced (0.963), mild vs. moderate (0.936), and mild vs. advanced (0.953), respectively. Our study could advance principally the ROP diagnosis in two dimensions: the moderate ROPs have been classified remarkably from the mild ones, which leaves more time for the medical treatments, and the procedure of Raman spectrum with a machine learning model based on blood samples can be conveniently promoted to those hospitals lacking of the pediatric ophthalmologists with experience in reading retinal images.

Mechanisms and Implications of Mitochondrial Autophagy in Stroke

Stroke is an acute cerebrovascular disease that is caused by disruptions in the cerebral blood supply and leads to brain tissue damage. Its pathological mechanisms remain to be fully elucidated. Stroke has high incidence, disability, and mortality rates, thus substantially affecting life and health. Against this backdrop, intracellular mitochondria, which are central to cellular energy metabolism and crucial for cell survival, have major roles in ischemic stroke. Ischemic stroke results in brain cell oxygen and nutrient deprivation, thereby triggering oxidative stress and inflammatory reactions, impairing mitochondrial function, and disrupting energy metabolism. Mitochondrial autophagy is a protective mechanism to improve the quality and quantity of mitrochondria, and exerts neuroprotective effects. In recent years, preserving mitochondrial function after ischemic stroke has emerged as a major research topic. Increasing evidence suggests a close relationship between abnormal mitochondrial autophagy and the occurrence, progression, and pathophysiology of ischemic stroke. However, current research has not adequately explained how ischemic stroke regulates the initiation and execution of mitochondrial autophagy. Elucidating this mechanism in detail will be critical for understanding the development of stroke injury, and identifying novel and effective intervention strategies. Additionally, the optimal treatment time window must be determined to enable effective interventions in mitochondrial autophagy and minimize brain damage. To deepen understanding of mitochondrial autophagy, this review summarizes mitochondrial autophagy’s signaling pathways and its major role in ischemic stroke pathophysiology. Further exploration in this field will provide a crucial theoretical foundation for developing novel therapeutic strategies and clinical applications.

Mechanism of Shenfu injection in suppressing inflammation and preventing sepsis-induced apoptosis in murine cardiomyocytes based on network pharmacology and experimental validation

Ethnopharmacological relevanceShenfu injection(SFI), as a famous classical Chinese patent medicine injection for the treatment of sepsis, has achieved good curative effects in clinical practice. However, its specific ingredients and molecular mechanisms is still unclear. Aim of the studyTo analyze the effective ingredients and molecular mechanisms of SFI in the treatment of sepsis via network pharmacology technology and experimental validation. Materials and methodsA total of 198 mice were used in this experiment. Septic mice model was performed by cecal ligation and puncture (CLP). First, Survival rates were calculted to screen the dosage and the treatment time window of SFI. Cardiac function was evaluated by echocardiography. The potential targets and pathways of SFI in the treatment of sepsis were predicted by network pharmacology. Myocardial tissue samples were harvest from different groups after CLP surgery. Hematoxylin-eosin (H&E) and TUNEL staining were used to examine the injury of heart. Western-blot analysis was performed to determine the protein expression of apoptosis. Meanwhile, the structural changes and mitochondrial membrane potential in the mitochondria of cardiomyocytes were also observed by transmission electron microscopy. ResultsThe Kaplan-Meier survival analysis showed that SFI significantly improved the 7-day survival rate as compared with that of CLP mice (P < 0.05). Echocardiography analysis found that LVEF and FS were significantly reduced in CLP mice compared with Sham mice, while SFI significantly increased LVEF (P < 001). Network pharmacology analysis indicated that the potential targets with higher degrees include IL2, BCL2, BAX, CASP7, BID, CASP8. Pathways with higher degrees include apoptosis, TNF signaling pathway, mitochondrial pathway apoptosis, PI3K-AKT signaling pathway. SFI treatment markedly attenuated the quantity of apoptotic cells as compared with the CLP group (P < 0.01). Western blot analysis indicated that CLP surgery decreased the expression of Bcl-2 (anti-apoptotic) but improved the protein expression of Bid, t-Bid, Cyc (pro-apoptotic) as compared with the Sham group (P < 0.01). While, SFI treatment markedly prevent the expression of Bid, t-Bid, Cyc and Caspase-9. The myocardial mitochondrial membrane potential of CLP group decreased after CLP surgery, while the mitochondrial membrane potential of SFI group increased significantly. Compared with the CLP group, in SFI group, the Z-line of the sarcomere was clear and distinguishable, and swollen mitochondria were significantly improved. ConclusionsThe present study demonstrated that SFI improved survival rate and cardiac function of septic mice mainly by suppressing inflammation and apoptosis.

Drivers of Chronic Pathology Following Ischemic Stroke: A Descriptive Review.

Stroke is the third leading cause of death and long-term disability in the world. Considered largely a disease of aging, its global economic and healthcare burden is expected to rise as more people survive into advanced age. With recent advances in acute stroke management, including the expansion of time windows for treatment with intravenous thrombolysis and mechanical thrombectomy, we are likely to see an increase in survival rates. It is therefore critically important to understand the complete pathophysiology of ischemic stroke, both in the acute and subacute stages and during the chronic phase in the months and years following an ischemic event. One of the most clinically relevant aspects of the chronic sequelae of stroke is its extended negative effect on cognition. Cognitive impairment may be related to the deterioration and dysfunctional reorganization of white matter seen at later timepoints after stroke, as well as ongoing progressive neurodegeneration.The vasculature of the brain also undergoes significant insult and remodeling following stroke, undergoing changes which may further contribute to chronic stroke pathology. While inflammation and the immune response are well established drivers of acute stroke pathology, the chronicity and functional role of innate and adaptive immune responses in the post-ischemic brain and in the peripheral environment remain largely uncharacterized. In this review, we summarize the current literature on post-stroke injury progression, its chronic pathological features, and the putative secondary injury mechanisms underlying the development of cognitive impairment and dementia. We present findings from clinical and experimental studies and discuss the long-term effects of ischemic stroke on both brain anatomy and functional outcome. Identifying mechanisms that occur months to years after injury could lead to treatment strategies in the chronic phase of stroke to help mitigate stroke-associated cognitive decline in patients.

Effect of Bevacizumab on traumatic penumbra brain edema in rats at different time points

ABSTRACT Traumatic penumbra (TP) is a secondary injury area located around the core area of traumatic brain injury after brain trauma, and is an important factor affecting the outcome of traumatic brain injury (TBI). The main pathological change caused by TP is brain edema, including (cellular brain edema and vascular brain edema). The formation and development of brain edema in the TP area are closely related to the blood-brain barrier (BBB) and vascular endothelial growth factor (VEGF). VEGF is a vascular permeability factor that can promote angiogenesis and increase BBB permeability, and there is a debate on the pros and cons of its role in early TBI. Therefore, in the early stage of TBI, when using the VEGF inhibitor bevacizumab to treat TP area brain edema, the timing of bevacizumab administration is particularly important, and there are currently no relevant literature reports. This article explores the treatment time window and optimal treatment time point of bevacizumab in the treatment of cerebral edema in the TP area by administering the same dose of bevacizumab at different time points after brain injury in rats. The results showed that there was traumatic brain edema in TP area, BBB structure and function were damaged, VEGF expression and angiogenesis were increased. Compared with TBI + NS Group, after Bevacizumab treatment, brain edema in TP area was alleviated, BBB structure and function were improved, VEGF expression and angiogenesis were decreased in each treatment group, and the effect of TBI + Bevacizumab 1 h group was the most significant. Bevacizumab can be used as a targeted therapy for traumatic brain edema. The therapeutic time window of bevacizumab for traumatic brain edema is within 12 hours after TBI, and 1 h is the optimal therapeutic time point.

Nanomaterial-Based Drug Delivery Systems for Ischemic Stroke.

Ischemic stroke is a leading cause of death and disability in the world. At present, reperfusion therapy and neuroprotective therapy, as guidelines for identifying effective and adjuvant treatment methods, are limited by treatment time windows, drug bioavailability, and side effects. Nanomaterial-based drug delivery systems have the characteristics of extending half-life, increasing bioavailability, targeting drug delivery, controllable drug release, and low toxicity, thus being used in the treatment of ischemic stroke to increase the therapeutic effects of drugs. Therefore, this review provides a comprehensive overview of nanomaterial-based drug delivery systems from nanocarriers, targeting ligands and stimulus factors of drug release, aiming to find the best combination of nanomaterial-based drug delivery systems for ischemic stroke. Finally, future research areas on nanomaterial-based drug delivery systems in ischemic stroke and the implications of the current knowledge for the development of novel treatment for ischemic stroke were identified.