Acute and chronic excitotoxicity in ischemic stroke and late-onset Alzheimer's disease

Stroke and Alzheimer's disease are common neurological disorders and often occur in the same individuals.The comorbidity of the two neurological disorders represents a grave health threat to older populations.This review presents a brief background of the development of novel concepts and their clinical potentials.The activity of glutamatergic N-methyl-D-aspartate receptors and N-methyl-D-aspartate receptor-mediated Ca^(2+)influx is critical for neuronal function.An ischemic insult induces prompt and excessive glutamate release and drastic increases of intracellular Ca^(2+)mainly via N-methyl-D-aspartate receptors,particularly of those at the extrasynaptic site.This Ca^(2+)-evoked neuronal cell death in the ischemic core is dominated by necrosis within a few hours and days known as acute excitotoxicity.Furthermore,mild but sustained Ca^(2+)increases under neurodegenerative conditions such as in the distant penumbra of the ischemic brain and early stages of Alzheimer's disease are not immediately toxic,but gradually set off deteriorating Ca^(2+)-dependent signals and neuronal cell loss mostly because of activation of programmed cell death pathways.Based on the Ca^(2+)hypothesis of Alzheimer's disease and recent advances,this Ca^(2+)-activated“silent”degenerative excitotoxicity evolves from years to decades and is recognized as a unique slow and chronic neuropathogenesis.The N-methyl-D-aspartate receptor subunit GluN3A,primarily at the extrasynaptic site,serves as a gatekeeper for the N-methyl-D-aspartate receptor activity and is neuroprotective against both acute and chronic excitotoxicity.Ischemic stroke and Alzheimer's disease,therefore,share an N-methyl-D-aspartate receptor-and Ca^(2+)-mediated mechanism,although with much different time courses.It is thus proposed that early interventions to control Ca^(2+)homeostasis at the preclinical stage are pivotal for individuals who are susceptible to sporadic late-onset Alzheimer's disease and Alzheimer's disease-related dementia.This early treatment simultaneously serves as a preconditioning therapy against ischemic stroke that often attacks the same individuals during abnormal aging.

Recent advances in orally administered cell-specific nanotherapeutics for inflammatory bowel disease

Inflammatory bowel disease(IBD) is a chronic relapsing disease in gastrointestinal tract. Conventional medications lack the efficacy to offer complete remission in IBD therapy,and usually associate with serious side effects. Recent studies indicated that nanoparticle-based nanotherapeutics may offer precise and safe alternative to conventional medications via enhanced targeting,sustained drug release,and decreased adverse effects. Here,we reviewed orally cell-specific nanotherapeutics developed in recent years. In addition,the various obstacles for oral drug delivery are also reviewed in this manuscript. Orally administrated cell-specific nanotherapeutics is expected to become a novel therapeutic approach for IBD treatment.

Trends in outpatient breast cancer surgery among Medicare fee-for-service patients in the United States from 1993 to 2002

The practice of outpatient breast cancer surgery has been controversial in the United States. This study aimed to update time trends and geographic variation in outpatient breast cancer surgery among elderly Medicare fee-for-service women in the United States. Using the 1993-2002 linked Surveillance, Epidemiology and End Results (SEER)-Medicare claims data and the Area Resource Files, we identified 2 study samples, including the women whose breast cancers were the first-ever-diagnosed cancer at age 65 years or older from 9 regions continuously covered by the SEER registries since 1993. The first sample included the women receiving unilateral mastectomy for stage 0-IV cancer; the second included the women receiving the breast-conserving surgery with lymph node dissection (BCS/LND) for stage 0-II cancer. The proportions of patients receiving outpatient surgery increased from 3.2% to 19.4% for mastectomy and from 48.9% to 77.8% for BCS/LND from 1993 to 2002. We observed substantial geographic variation in the average proportion of the patients receiving outpatient surgery in the studied areas across the 10-year period, ranging from 3.9% in Connecticut to 27.2% in Utah for mastectomy and from 54.7% in Hawaii to 78.1% in Seattle, Washington, for BCS/LND. As the popularity of outpatient breast cancer surgery continues to grow, more evidence-based analyses related to quality and outcomes of outpatient breast cancer surgery among various populations are needed in order to facilitate the public debates about state and federal mandated health benefit legislations.

Distal esophageal spasm:Update on diagnosis and management in the era of high-resolution manometry

Distal esophageal spasm (DES) is a rare major motility disorder in the Chicago dassification of esophageal motility disorders (CC).DES is diagnosed by finding of≥20%premature contractions,with normal lower esophageal sphincter (LES)relaxation on high-resolution manometry (HRM) in the latest version of CCv3.0.This feature differentiates it from achalasia type 3,which has an elevated LES relaxation pressure.Like other spastic esophageal disorders,DES has been linked to conditions such as gastroesophageal reflux disease,psychiatric conditions,and narcotic use.In addition to HRM,ancillary tests such as endoscopy and barium esophagram can provide supplemental information to differentiate DES from other conditions.Functional lumen imaging probe (FLIP),a new cutting-edge diagnostic tool,is able to recognize abnormal LES dysfunction that can be missed by HRM and can further guide LES targeted treatment when esophagogastric junction outflow obstruction is diagnosed on FLIP.Medical treatment in DES mostly targets symptomatic relief and often fails.Botulinum toxin injection during endoscopy may provide a temporary therapy that wears off over time.Myotomy through peroral endoscopic myotomy or via surgical Heller myotomy can provide long term relief in cases with persistent symptoms.

Gas-propelled nanomotors alleviate colitis through the regulation of intestinal immunoenvironment-hematopexis-microbiota circuits

The progression of ulcerative colitis(UC)is associated with immunologic derangement,intestinal hemorrhage,and microbiota imbalance.While traditional medications mainly focus on mitigating inflammation,it remains challenging to address multiple symptoms.Here,a versatile gas-propelled nanomotor was constructed by mild fusion of post-ultrasonic CaO_(2) nanospheres with Cu_(2)O nanoblocks.The resulting CaO_(2)–Cu_(2)O possessed a desirable diameter(291.3 nm)and a uniform size distribution.It could be efficiently internalized by colonic epithelial cells and macrophages,scavenge intracellular reactive oxygen/nitrogen species,and alleviate immune reactions by pro-polarizing macrophages to the anti-inflammatory M2 phenotype.This nanomotor was found to penetrate through the mucus barrier and accumulate in the colitis mucosa due to the driving force of the generated oxygen bubbles.Rectal administration of CaO_(2)–Cu_(2)O could stanch the bleeding,repair the disrupted colonic epithelial layer,and reduce the inflammatory responses through its interaction with the genes relevant to blood coagulation,anti-oxidation,wound healing,and anti-inflammation.Impressively,it restored intestinal microbiota balance by elevating the proportions of beneficial bacteria(e.g.,Odoribacter and Bifidobacterium)and decreasing the abundances of harmful bacteria(e.g.,Prevotellaceae and Helicobacter).Our gas-driven CaO_(2)–Cu_(2)O offers a promising therapeutic platform for robust treatment of UC via the rectal route.

Author correction to“Gas-propelled nanomotors alleviate colitis through the regulation of intestinal immunoenvironmenthematopexis-microbiota circuits”[Acta Pharm Sin B 14(2024)2732-2747]

The authors regret that there are errors in the author information and author contributions.The name of the corresponding author,Zhenghua Zhu,should be corrected to Zhenhua Zhu.The modification does not affect the results of the article.The authors apologize for any inconvenience caused to the journal and readers.

AAV6 as an effective gene delivery vector for prolonged transgene expression in intervertebral disc cells in vivo

Intervertebral disc degeneration is the main contributor to low back pain,now the leading cause of disability worldwide.Gene transfer,either in a therapeutic attempt or in basic research to understand the mechanisms of disc degeneration,is a fascinating and promising tool to manipulate the complex physiology of the disc.Viral vectors based on the adeno-associated virus(AAV)have emerged as powerful transgene delivery vehicles yet a systematic investigation into their respective tropism,transduction efficiency,and relative toxicity have not yet been performed in the disc in vivo.Herein,we used in vivo bioluminescence imaging to systematically compare multiple AAV serotypes,injection volumes,titers,promoters,and luciferase reporters to determine which result in high transduction efficiency of murine nucleus pulposus(NP)cells in vivo.We find that AAV6 using a CAG promoter to drive transgene expression,delivered into the NP of murine caudal discs at a titer of 1011 GC/mL,provides excellent transduction efficiency/kinetics and low toxicity in vivo.We also show,for the first time,that the transduction of NP cells can be significantly boosted in vivo by the use of small cell permeabilization peptides.Finally,to our knowledge,we are the first to demonstrate the use of optical tissue clearing and three-dimensional lightsheet microscopy in the disc,which was used to visualize fine details of tissue and cell architecture in whole intact discs following AAV6 delivery.Taken together,these data will contribute to the success of using AAV-mediated gene delivery for basic and translational studies of the IVD.