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Endothelin-1 (ET-1), a vasoconstrictor, has recently been used to induce focal ischemia in rodents and marmoset monkeys. The rhesus monkey, however, has numerous advantages to the rodent and marmoset that make it a superior and irreplaceable animal model for studying stroke in the brain. In the present study, after mapping the preferred hand representation in two healthy male monkeys with intracortical micro-stimulation, ET-1 was microinjected into the contralateral motor cortex (M1) to its preferred hand. The monkeys had been trained in three manual dexterity tasks before the microinjection and were tested for these tasks following the ET-1 injection. Brain Magnetic Resonance Imaging scans were performed 1, 7, 14 and 28 days post ischemia. It was found that ET-1 impaired the manual dexterity of the monkeys in the vertical slot and rotating Brinkman board tasks 3–8 days after the injection. Brain imaging found that severe edema was present 7 days after the focal ischemia. This data suggest that ET-1 can induce transient ischemic stroke in rhesus monkey and that ET-1 induced focal ischemia in non-human primates is a potential model to study the mechanism of stroke and brain repair after stroke.

Adult neurogenesis has been extensively studied in rodent animals, with distinct niches found in the hippocampus and subventricular zone (SVZ). In non-human primates and human postmortem samples, there has been heated debate regarding adult neurogenesis, but it is largely agreed that the rate of adult neurogenesis is much reduced comparing to rodents. The limited adult neurogenesis may partly explain why human brains do not have self-repair capability after injury or disease. A new technology called “ in vivo cell conversion” has been invented to convert brain internal glial cells in the injury areas directly into functional new neurons to replenish the lost neurons. Because glial cells are abundant throughout the brain and spinal cord, such engineered glia-to-neuron conversion technology can be applied throughout the central nervous system (CNS) to regenerate new neurons. Thus, compared to cell transplantation or the non-engineered adult neurogenesis, in vivo engineered neuroregeneration technology can provide a large number of functional new neurons in situ to repair damaged brain and spinal cord.

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The term ginseng refers to the dried roots of several plants belonging to the genus Panax of the Araliaceae family. The 3 major commercial ginsengs are Panax notoginseng (Burk.) F.H. Chen (Notoginseng), P. ginseng C.A. Meyer (Ginseng), and P. quinquefolius L. (American ginseng), which have been used as herbal medicines. Over 18,000 papers on ginsengs have been published on the basis of their structural diversity and biological activities. Many reviews have summarized the phytochemistry, pharmacology, and clinical use of ginsengs, but the structure-activity relationship (SAR) of ginsenosides from ginsengs in autophagy is unavailable. Herein, we review the structural diversity of ginsenosides, especially the ones in notoginseng, and the SAR in autophagic activity is discussed in detail.

Stroke is a leading cause of death and disability but most of the clinical trials have failed in the past, despite our increasing understanding of the molecular and pathological mechanisms underlying stroke. While many signaling pathways have been identified in the aftermath of stroke, the majority of current approaches are focusing on neural protection rather than neuroregeneration. In this study, we report an in vivo neural regeneration approach to convert brain internal reactive astrocytes into neurons through ectopic expression of a neural transcription factor NeuroD1 in adult non-human primate (NHP) brains following ischemic stroke. We demonstrate that NeuroD1 AAV-based gene therapy can convert reactive astrocytes into neurons with high efficiency (90%), but astrocytes are never depleted in the NeuroD1-expressed areas, consistent with the proliferative capability of astrocytes. The NeuroD1-mediated in vivo astrocyte-to-neuron (AtN) conversion in monkey cortex following ischemic stroke increased local neuronal density, reduced reactive microglia, and surprisingly protected parvalbumin interneurons in the converted areas. The NeuroD1 gene therapy showed a broad time window, from 10 days to 30 days following ischemic stroke, in terms of exerting its neuroregenerative and neuroprotective effects. The cortical astrocyte-converted neurons also showed Tbr1+ cortical neuron identity, similar to our earlier findings in rodent animal models. Unexpectedly, NeuroD1 expression in converted neurons showed a significant decrease after 6 months of viral infection, suggesting a potential self-regulatory mechanism of NeuroD1 in adult mature neurons of NHPs. These results suggest that in vivo cell conversion through NeuroD1-based gene therapy may be an effective approach to regenerate new neurons in adult primate brains for tissue repair.

The twenty-first century has already recorded more than ten major epidemics or pandemics of viral disease, including the devastating COVID-19. Novel effective antivirals with broad-spectrum coverage are urgently needed. Herein, we reported a novel broad-spectrum antiviral compound PAC5. Oral administration of PAC5 eliminated HBV cccDNA and reduced the large antigen load in distinct mouse models of HBV infection. Strikingly, oral administration of PAC5 in a hamster model of SARS-CoV-2 omicron (BA.1) infection significantly decreases viral loads and attenuates lung inflammation. Mechanistically, PAC5 binds to a pocket near Asp49 in the RNA recognition motif of hnRNPA2B1. PAC5-bound hnRNPA2B1 is extensively activated and translocated to the cytoplasm where it initiates the TBK1-IRF3 pathway, leading to the production of type I IFNs with antiviral activity. Our results indicate that PAC5 is a novel small-molecule agonist of hnRNPA2B1, which may have a role in dealing with emerging infectious diseases now and in the future.