Nose to brain drug delivery - A promising strategy for active components from herbal medicine for treating cerebral ischemia reperfusion.

Puerarin protects rat brain against ischemia/reperfusion injury by suppressing autophagy via the AMPK-mTOR-ULK1 signaling pathway.

With the rise in the aging global population, stroke comorbidities have become a serious health threat and a tremendous economic burden on human society. Current therapeutic strategies mainly focus on protecting neurons from cytotoxic damage at the acute phase upon stroke onset, which not only is a difficult way to ameliorate stroke symptoms but also presents a challenge for the patients to receive effective treatment in time. The brain-derived neurotrophic factor (BDNF) is the most abundant neurotrophin in the adult brain, which possesses a remarkable capability to repair brain damage. Recent promising preclinical outcomes have made BDNF a popular late-stage target in the development of novel stroke treatments. In this review, we aim to summarize the latest progress in the understanding of the cellular/molecular mechanisms underlying stroke pathogenesis, current strategies and difficulties in drug development, the mechanism of BDNF action in poststroke neurorehabilitation and neuroplasticity, and recent updates in novel therapeutic methods.

/pdf/brain-derived-neurotrophic-factor-and-its-potential-1hxx4z6ngw.pdf

Brain-Derived Neurotrophic Factor and Its Potential Therapeutic Role in Stroke Comorbidities

Necroptosis, a novel type of programmed cell death, is involved in stroke-induced ischemic brain injury. Although studies have sought to explore the mechanisms of necroptosis, its signaling pathway has not yet to be completely elucidated. Thus, we used oxygen-glucose deprivation (OGD) and middle cerebral artery occlusion (MCAO) models mimicking ischemic stroke (IS) conditions to investigate mechanisms of necroptosis. We found that OGD and MCAO induced cell death, local brain ischemia and neurological deficit, while zVAD-fmk (zVAD, an apoptotic inhibitor), GSK’872 (a receptor interacting protein kinase-3 (RIP3) inhibitor), and combined treatment alleviated cell death and ischemic brain injury. Moreover, OGD and MCAO upregulated protein expression of the triggers of necroptosis: receptor interacting protein kinase-1 (RIP1), RIP3 and mixed lineage kinase domain-like protein (MLKL). The upregulation of these proteins was inhibited by GSK’872, combination treatments and RIP3 siRNA but not zVAD treatment. Intriguingly, hypoxia-inducible factor-1 alpha (HIF-1α), an important transcriptional factor under hypoxic conditions, was upregulated by OGD and MCAO. Similar to their inhibitory effects on aforementioned proteins upregulation, GSK’872, combination treatments and RIP3 siRNA decreased HIF-1α protein level. These findings indicate that necroptosis contributes to ischemic brain injury induced by OGD and MCAO and implicate HIF-1α, RIP1, RIP3, and MLKL in necroptosis.

Hypoxia-inducible factor-1 alpha is involved in RIP-induced necroptosis caused by in vitro and in vivo ischemic brain injury

Glaucoma is a progressive neurodegenerative disease that frequently results in irreversible blindness. Glaucoma causes death of retinal ganglion cells (RGCs) and their axons in the optic nerve, resulting in visual field deficits and eventual loss of visual acuity. Glaucoma is a complex optic neuropathy, and a successful strategy for its treatment requires not only better management of known risk factors such as elevated intraocular pressure and the development of improved tools for detecting RGC injury but also treatments that address this injury (i.e., neuroprotection). Experimental models of glaucoma provide insight into the cellular and molecular mechanisms of glaucomatous optic neuropathy and aid the development of neuroprotective therapies.

Neuroprotection in Glaucoma: Animal Models and Clinical Trials

Puerarin protected the brain from cerebral ischemia injury via astrocyte apoptosis inhibition


 Understanding the physiology and functions of the liver and cancer requires knowing transcriptional patterns driving biological activities within the functional structures of the tissue, especially the zonated features of the liver metabolic networks. Using the powerful and unique capabilities of GeoMx® Digital Spatial Profiler (DSP) with the Whole Transcriptome Atlas (WTA) panel to resolve functional units within FFPE tissues in situ, here we report the spatial analysis of whole transcriptomes across three micro-dissected zones (pericentral zone 3, intermediate zone 2 and periportal zone 1) of human normal liver and HCC. We also report the whole transcriptome expression data from Kupffer cells, portal traits and interlobular bile ducts from four normal liver samples and HCC. 500 - 3000 genes were detected from functional groups within each histological structure. In the liver functional units, 1000 - 2500 genes were detected in zone 1, 2 and 3 separately. By comparing the whole transcriptome profiles of zone 1 and zone 3, we have found 32 differentially expressed targets (fold change > 1.5, p value < 0.05) which showed a gradient expression pattern along the porto-central axis. The expression patterns of CYP1A2, CYP2E1, CYP3A4 and ALDOB matched well with their respective patterns of protein expression (Human Protein Atlas), recapitulating the well-studied distribution of functional activities along the porto-central axis. Moreover, by combining with Gene Set Enrichment Analysis (GSEA), we have found important pathways involved in metabolisms in either the pericentral area or the periportal area. Pathways including biological oxidations (CYP1A2, CYP2E1, CYP3A4, ADH1A, and ADH1B) and lipids metabolism (AKR1C1, AKR1C2, and SLCO1B3) showed high enrichment in zone 3 and decreased towards zone 1. In contrast, pathways including platelet degranulation (FGA, FGB, FGG), glucose metabolism (ALDOB and PCK1) and amino acids metabolism (HAL, SDS, NNMT, and GLS2) showed high enrichment in zone 1 and decreased towards zone 3. In conclusion, our WTA data has revealed clear metabolic zonation in the liver along the porto-central axis. GeoMx technology with WTA is a powerful tool to investigate the underlying mechanisms of liver metabolism, regeneration, and tissue structure. It can be further utilized to study the whole transcriptomic differences in normal and diseased tissue.
 FOR RESEARCH USE ONLY. Not for use in diagnostic procedures.
 Citation Format: Yan Liang, Nan Wang, Xia Li, Kathy Ton, Liang Zhang, Megan Vandenberg, Charlie Glaser, Zhiyong Ding, Joseph Beechem, Andy Nam, Yan Liang. Spatial whole transcriptome profiling of human normal liver and HCC uncovers unique insights into metabolic zonation. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4709.

Abstract 4709: Spatial whole transcriptome profiling of human normal liver and HCC uncovers unique insights into metabolic zonation

Purpose Tumor related atelectasis(TRA) is an essential factor affecting survival that can cause chest pain, cough, hemoptysis, chest tightness, dyspnea, and even death. In the current study, we explored the possible impact of TRA on survival in cancer patients and the guiding significance of 18F-positron emission tomography/computed(PET/CT) in radiotherapy for patients with atelectasis tumors. Methods In this retrospective study, we analyzed the treatment model and survival of patients with centrally located non-small cell lung cancer(NSCLC) treated with radiotherapy at two medical centers between May 2005 and August 2019. We identified 152 eligible patients and used propensity score matching (1:1) to process the data to reduce confounding factors, data bias, and mal-distribution. Results We used propensity scores created well-matched groups of 57 patients overall with or without TRA. The one-year survival rate of all patients was 71.9%, and the two-year survival rate was 33.3%. Compared to the atelectasis group, the overall survival (OS) of patients in the non-atelectasis group was significantly prolonged (25 months vs. 17 months, p = 0.004), as well as in the atelectasis recovery group (28 months vs. 14 months, p = 0.008). In multivariate analysis, non-atelectasis was closely correlated with favorable OS (HR, 1.804 (−2.840); 95% CI, 1.145–2.840; p = 0.011). Conclusion PET/CT can accurately stage NSCLC and better guide the treatment of NSCLC complicated with atelectasis. Tumor-associated atelectasis in patients with centrally located NSCLC can lead to is a poor prognostic marker.

/pdf/in-18f-positron-emission-tomography-computed-tomography-250nopkl.pdf

In 18F-positron emission tomography/computed tomography-guided precision radiotherapy for centrally located non-small cell lung cancer, tumor related atelectasis is a prognostic factor of survival

High-Plex Spatial Profiling of RNA and Protein Using Digital Spatial Profiler.

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Puerarin protected the brain from cerebral ischemia injury via astrocyte apoptosis inhibition

Abstract 4709: Spatial whole transcriptome profiling of human normal liver and HCC uncovers unique insights into metabolic zonation

In 18F-positron emission tomography/computed tomography-guided precision radiotherapy for centrally located non-small cell lung cancer, tumor related atelectasis is a prognostic factor of survival

High-Plex Spatial Profiling of RNA and Protein Using Digital Spatial Profiler.