Compounding warning letters to 503A facilities between 2017 and 2021.

BACKGROUND: The growing population demand and the epidemic lead of coronavirus disease 2019 have highlighted the critical importance of patient access to compounded formulations, including for special purposes such as pediatrics, geriatrics, and other uses. However, there are many potential risks, including quality issues and 503A facilities have not received valid prescriptions for individually-identified patients for a portion of the drug products they produce. OBJECTIVE: The aim is to analyze the (503A facilities) warning letters and identify the problem of compounding medicines not meeting the United States Pharmacopoeia specifications. METHODS: Content analysis and descriptive statistics methods were used to analyze the violations of compounding warning letters from 2017 to 2021. The content of warning letter violations was analyzed in terms of both the compounding environment and 503A facilities that did not received valid prescriptions for individually-identified patients for a portion of the drug products they produced. RESULTS: A total of 113 compounding warning letters (503A facilities, N = 112) from 2017 to 2021 were analyzed in this study. The percentage of 503A facilities involved in sterile compounding environmental issues was 79.46%, with facility design and environmental controls (73/89, 82.02%), cleaning and disinfecting the compounding area (59/89, 66.29%), and personnel cleansing and garbing (44/89, 49.44%) being the top 3 issues. Seventy-two (72/112, 64.29%) 503A facilities that did not received valid prescriptions for individually-identified patients for a portion of the drug products they produced. Fifty-one (51/72, 70.83%) of these warning letters were related to sterile environment issues, and 28 warning letters identified specific drugs that did not qualify for Section 503A exemptions. CONCLUSION: The warning letter of compounding drugs issued by Food and Drug Administration can be used as a learning tool for compounders. Compounders can learn from the experience and lessons, improve compounding operations and reduce mistakes.

Ethyl pyruvate: A newly discovered compound against ischemia-reperfusion injury in multiple organs.

Ischemia-reperfusion injury (IRI) is a process whereby an initial ischemia injury and subsequent recovery of blood flow, which leads to the propagation of an innate immune response and the changes of structural and functional of multiple organs. Therefore, IRI is considered to be a great challenge in clinical treatment such as organ transplantation or coronary angioplasty. In recent years, ethyl pyruvate (EP), a derivative of pyruvate, has received great attention because of its stability and low toxicity. Previous studies have proved that EP has various pharmacological activities, including anti-inflammation, anti-oxidative stress, anti-apoptosis, and anti-fibrosis. Compelling evidence has indicated EP plays a beneficial role in a variety of acute injury models, such as brain IRI, myocardial IRI, renal IRI, and hepatic IRI. Moreover, EP can not only effectively inhibit multiple IRI-induced pathological processes, but also improve the structural and functional lesion of tissues and organs. In this study, we review the recent progress in the research on EP and discuss their implications for a better understanding of multiple organ IRI, and the prospects of targeting the EP for therapeutic intervention.

CB1R dysfunction of inhibitory synapses in the ACC drives chronic social isolation stress-induced social impairments in male mice.

Social isolation is a risk factor for multiple mood disorders. Specifically, social isolation can remodel the brain, causing behavioral abnormalities, including sociability impairments. Here, we investigated social behavior impairment in mice following chronic social isolation stress (CSIS) and conducted a screening of susceptible brain regions using functional readouts. CSIS enhanced synaptic inhibition in the anterior cingulate cortex (ACC), particularly at inhibitory synapses of cholecystokinin (CCK)-expressing interneurons. This enhanced synaptic inhibition in the ACC was characterized by CSIS-induced loss of presynaptic cannabinoid type-1 receptors (CB1Rs), resulting in excessive axonal calcium influx. Activation of CCK-expressing interneurons or conditional knockdown of CB1R expression in CCK-expressing interneurons specifically reproduced social impairment. In contrast, optogenetic activation of CB1R or administration of CB1R agonists restored sociability in CSIS mice. These results suggest that the CB1R may be an effective therapeutic target for preventing CSIS-induced social impairments by restoring synaptic inhibition in the ACC.

Restoring the Function of Thalamocortical Circuit Through Correcting Thalamic Kv3.2 Channelopathy Normalizes Fear Extinction Impairments in a PTSD Mouse Model.

Impaired extinction of fear memory is one of the most common symptoms in post-traumatic stress disorder (PTSD), with limited therapeutic strategies due to the poor understanding of its underlying neural substrates. In this study, functional screening is performed and identified hyperactivity in the mediodorsal thalamic nucleus (MD) during fear extinction. Furthermore, the encoding patterns of the hyperactivated MD is investigated during persistent fear responses using multiple machine learning algorithms. The anterior cingulate cortex (ACC) is also identified as a functional downstream region of the MD that mediates the extinction of fear memory. The thalamocortical circuit is comprehensively analyzed and found that the MD-ACC parvalbumin interneurons circuit is preferentially enhanced in PTSD mice, disrupting the local excitatory and inhibitory balance. It is found that decreased phosphorylation of the Kv3.2 channel contributed to the hyperactivated MD, primarily to the malfunctioning thalamocortical circuit. Using a lipid nanoparticle-based RNA therapy strategy, channelopathy is corrected via a methoxylated siRNA targeting the protein phosphatase 6 catalytic subunit and restored fear memory extinction in PTSD mice. These findings highlight the function of the thalamocortical circuit in PTSD-related impaired extinction of fear memory and provide therapeutic insights into Kv3.2-targeted RNA therapy for PTSD.

[Research updates of C1q/TNF related proteins (CTRPs) in inflammation-related diseases].

Inflammation underlies a wide variety of physiological and pathological processes, and plays a pivotal role in controlling pathogen infection. C1q/tumor necrosis factor (TNF) related proteins (CTRPs), a newly discovered adipokine family with conservative structure and wide distribution, has attracted increasing attention. The CTRP family consists of more than 15 members which fall into the characteristic C1q domain. Increasing studies have demonstrated that CTRPs are involved in the onset and development of inflammation and metabolism as well as related diseases, including myocardial infarction, sepsis and tumors. Here, we first clarified the characteristic domains of CTRPs, and then elucidated their roles in inflammatory-related diseases. Taken together, the information presented here provides new perspectives for therapeutic strategies to improve inflammatory and metabolic abnormalities.

Targeting Mitochondrial Sirtuins in Age-Related Neurodegenerative Diseases and Fibrosis.

Aging is a natural and complex biological process that is associated with widespread functional declines in numerous physiological processes, terminally affecting multiple organs and tissues. Fibrosis and neurodegenerative diseases (NDs) often occur with aging, imposing large burdens on public health worldwide, and there are currently no effective treatment strategies for these diseases. Mitochondrial sirtuins (SIRT3-5), which are members of the sirtuin family of NAD+-dependent deacylases and ADP-ribosyltransferases, are capable of regulating mitochondrial function by modifying mitochondrial proteins that participate in the regulation of cell survival under various physiological and pathological conditions. A growing body of evidence has revealed that SIRT3-5 exert protective effects against fibrosis in multiple organs and tissues, including the heart, liver, and kidney. SIRT3-5 are also involved in multiple age-related NDs, including Alzheimer's disease, Parkinson's disease, and Huntington's disease. Furthermore, SIRT3-5 have been noted as promising targets for antifibrotic therapies and the treatment of NDs. This review systematically highlights recent advances in knowledge regarding the role of SIRT3-5 in fibrosis and NDs and discusses SIRT3-5 as therapeutic targets for NDs and fibrosis.

Axin2 coupled excessive Wnt-glycolysis signaling mediates social defect in autism spectrum disorders.

Social dysfunction is the core syndrome of autism spectrum disorder (ASD) and lacks effective medicine. Although numerous risk genes and relevant environmental factors have been identified, the convergent molecular mechanism underlying ASD-associated social dysfunction remains largely elusive. Here, we report aberrant activation of canonical Wnt signaling and increased glycolysis in the anterior cingulate cortex (ACC, a key brain region of social function) of two ASD mouse models (Shank3-/- and valproic acid-treated mice) and their corresponding human neurons. Overexpressing ß-catenin in the ACC of wild-type mice induces both glycolysis and social deficits. Suppressing glycolysis in ASD mice partially rescued synaptic and social phenotype. Axin2, a key inhibitory molecule in Wnt signaling, interacts with the glycolytic enzyme enolase 1 (ENO1) in ASD neurons. Surprisingly, an Axin2 stabilizer, XAV939, effectively blocked Axin2/ENO1 interaction, switched glycolysis/oxidative phosphorylation balance, promoted synaptic maturation, and rescued social function. These data revealed excessive neuronal Wnt-glycolysis signaling as an important underlying mechanism for ASD synaptic deficiency, indicating Axin2 as a potential therapeutic target for social dysfunction.

Reversal of hyperactive higher-order thalamus attenuates defensiveness in a mouse model of PTSD.

Posttraumatic stress disorder (PTSD) is a highly prevalent and debilitating psychiatric disease often accompanied by severe defensive behaviors, preventing individuals from integrating into society. However, the neural mechanisms of defensiveness in PTSD remain largely unknown. Here, we identified that the higher-order thalamus, the posteromedial complex of the thalamus (PoM), was overactivated in a mouse model of PTSD, and suppressing PoM activity alleviated excessive defensive behaviors. Moreover, we found that diminished thalamic inhibition derived from the thalamic reticular nucleus was the major cause of thalamic hyperactivity in PTSD mice. Overloaded thalamic innervation to the downstream cortical area, frontal association cortex, drove abnormal defensiveness. Overall, our study revealed that the malfunction of the higher-order thalamus mediates defensive behaviors and highlighted the thalamocortical circuit as a potential target for treating PTSD-related overreactivity symptoms.

Lycorine and organ protection: Review of its potential effects and molecular mechanisms.

BACKGROUND: Multiorgan dysfunction, especially sepsis-related multiorgan damage, remains a major cause of high mortality in the late stages of infection and a great clinical challenge. In recent years, natural drugs have received widespread attention because of their low cost, wide sources, high efficacy, low toxicity, and limited side effects. Lycorine, a natural compound extracted from Amaryllidaceae, exhibits multiple pharmacological activities, including in the regulation of autophagy and the induction of cancer cell apoptosis, and has anti-inflammatory, antifungal, antiviral, antimalarial, and antitumor activities. However, studies on lycorine have mainly focused on its antitumor properties, and research on its use for organ protection, especially in sepsis-related organ injury, is relatively limited. PURPOSE: To review and discuss the effects and mechanisms of lycorine in the treatment of multi-organ dysfunction, especially sepsis. METHODS: Literature searches in electronic databases, such as Web of Science, Science Direct, PubMed, Google Scholar, and Scopus, were performed using 'Lycorine', 'Amaryllidaceae', 'Pharmacology', 'Pharmacokinetics', 'Anti-inflammation', 'Autophagy', 'Apoptosis', 'Anti-microbial and anti-parasitic', 'Antitumor', 'Organ protection', and 'Sepsis' as keywords, the correlated literature was extracted and conducted from the databases mentioned above. RESULTS: By summarizing the progress made in existing research, we found that the general effects of lycorine involve the regulation of autophagy and the induction of cancer cell apoptosis, and anti-inflammatory, antifungal, antiviral, antimalarial, and antitumor effects; through these pathways, the compound can ameliorate organ damage. In addition, lycorine was found to have an important effect on organ damage in sepsis. CONCLUSION: Lycorine is a promising natural organ protective agent. This review will provide a new theoretical basis for the treatment of organ protection, especially in sepsis.

Omentin-1: a newly discovered warrior against metabolic related diseases.

INTRODUCTION: Chronic metabolism-related diseases are challenging clinical problems. Omentin-1 is mainly expressed in stromal vascular cells of adipose tissue and can also be expressed in airway goblet cells, mesothelial cells, and vascular cells. Omentin-1 has been found to exert important anti-inflammatory, antioxidative and anti-apoptotic roles and to regulate endothelial dysfunction. Moreover, omentin-1 also has protective effects against cancer, atherosclerosis, type 2 diabetes mellitus, and bone metabolic diseases. The current review will discuss the therapeutic potential of omentin-1. AREAS COVERED: This review summarizes the biological actions of omentin-1 and provides an overview of omentin-1 in metabolic-related diseases. The relevant literature was derived from a PubMed search spanning 1998-2021 using these search terms: omentin-1, atherosclerosis, diabetes mellitus, bone, cancer, inflammation, and oxidative stress. EXPERT OPINION: As a novel adipocytokine, omentin-1 is a promising therapeutic target in metabolic-related diseases. Preclinical animal studies have shown encouraging results. Moreover, circulating omentin-1 has excellent potential as a noninvasive biomarker. In the future, strategies for regulating omentin-1 need to be investigated further in clinical trials in a large cohort.

NLRP3 sparks the Greek fire in the war against lipid-related diseases.

In recent years, the obesity rate worldwide has reached epidemic proportions and contributed to the growing prevalence of lipid-related diseases. A strong link between inflammation and metabolism is becoming increasingly evident. Compelling evidence has indicated the activation of the nucleotide-binding and oligomerization domain-like receptor, leucine-rich repeat and pyrin domain-containing 3 (NLRP3) inflammasome, a cytoplasmic complex containing multiple proteins, in a variety of lipid-related diseases including obesity, atherosclerosis, liver diseases, and type 2 diabetes. Recent studies have further clarified the regulatory mechanisms and the optional therapeutic agents that target NLRP3 inflammasomes. In this study, we review the recent progress in the research on NLRP3 inflammasomes and discuss their implications for a better understanding of inflammation in lipid-related disease and the prospects of targeting the NLRP3 inflammasome for therapeutic intervention.