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Damage-associated molecular patterns (DAMPs) released in large quantities in trauma are important triggers of post-traumatic immune dysfunction and interest in their potential as therapeutic targets for trauma has increased. Targeting DAMPs such as myoglobin, HMGB1, histones, and nucleic acids have potential for the development of vaccines for trauma. Due to the specific nature of trauma, significant challenges such as the possibility of trauma vaccines causing autoimmune diseases requires further research. The development of trauma vaccines has the potential to establish protection for populations at high risk for trauma and may supplement existing trauma management strategies. Despite advances in medical treatments for severe trauma, it remains a critical condition associated with high mortality. During trauma, the release of endogenous damage-associated molecular patterns (DAMPs) can induce immune dysfunction, leading to sepsis or multiple organ dysfunction syndrome (MODS). Vaccines based on specific pathogen antigens and pathogen-associated molecular patterns (PAMPs) contribute largely to the prevention of communicable diseases through the induction of adaptive immune responses. Vaccines developed based on autologous molecules may also promote recovery from non-communicable diseases (NCDs) by eliciting appropriate immune responses, as recent clinical trials indicate. Developing new vaccines targeting DAMPs may be an effective pre-protective measure for trauma management. We describe the role of DAMPs in post-traumatic immune dysfunction and discuss the potential of harnessing them for trauma vaccine development as well as the risks and challenges. [ABSTRACT FROM AUTHOR]

[Display omitted] • Inhibiting ferroptosis could alleviate acute kidney injury following crush syndrome. • Iron overload produced by myoglobin degradation is a risk factor for ferroptosis. • HMGB1 and souble-stranded DNA trigger ferroptosis via multiple signaling pathways. • Crosstalk between inflammation and ferroptosis. • Inhibition of ferroptosis by alleviating inflammation and anti-lipid peroxidation. Crush syndrome (CS) is a kind of traumatic and ischemic injury that seriously threatens life after prolonged compression. It is characterized by systemic inflammatory reaction, myoglobinuria, hyperkalemia and acute kidney injury (AKI). Especially AKI, it is the leading cause of death from CS. There are various cell death forms in AKI, among which ferroptosis is a typical form of cell death. However, the role of ferroptosis has not been fully revealed in CS-AKI. This review aimed to summarize the evidence of ferroptosis in CS-AKI and its related molecular mechanism, discuss the therapeutic significance of ferroptosis in CS-AKI, and open up new ideas for the treatment of CS-AKI. One of the main pathological manifestations of CS-AKI is renal tubular epithelial cell dysfunction and cell death, which has been attributed to massive deposition of myoglobin. Large amounts of myoglobin released from damaged muscle deposited in the renal tubules, impeding the normal renal tubules function and directly damaging the tubules with oxidative stress and elevated iron levels. Lipid peroxidation damage and iron overload are the distinguishing features of ferroptosis. Moreover, high levels of pro-inflammatory cytokines and damage-associated molecule pattern molecules (HMGB1, double-strand DNA, and macrophage extracellular trap) in renal tissue have been shown to promote ferroptosis. However, how ferroptosis occurs in CS-AKI and whether it can be a therapeutic target remains unclear. In our current work, we systematically reviewed the occurrence and underlying mechanism of ferroptosis in CS-AKI. [ABSTRACT FROM AUTHOR]

Myoglobin (Mb) is the main constituent of vertebrate skeletal muscle and myocardium and plays an essential role in oxygen binding, storage, transport, and earliest disease diagnosis. This study focuses on preparing the novel recombinant rabbit anti-Mb monoclonal antibody and applying it to a diagnosis of Mb deposition in rhabdomyolysis-associated acute kidney injury (RM-AKI). The full-length coding sequence of rat Mb was cloned and expressed, and the high-quality and titer rabbit anti-Mb polyclonal antibodies were produced by the immunogen His-Mb fusion protein. A new hybridoma cell was obtained by hybridoma screening technology. With the help of DNA sequencing and a molecular clonal, anti-Mb monoclonal antibody heavy and light chains expression plasmid was constructed. Finally, the recombinant rabbit anti-Mb monoclonal antibody with extraordinarily high affinity (KD = 1.21 pM) was obtained. Meanwhile, it had broad species reactivity (mouse, rat, human, and horse) and good tissue specificity (skeletal muscle and myocardium). It also had a very good performance in western blotting, immunohistochemistry, and immunofluorescence assay to detect the Mb level in the kidney, myocardium, and skeletal muscle of RM-AKI. This study will be significantly helpful for Mb-associated disease diagnosis, and pathogenesis exploration, and further may act as a neutralizing antibody for disease treatment. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by memory deficits and cognitive decline. Current drugs can only relieve symptoms, but cannot really cure AD. Cerebralcare Granule® (CG) is a Traditional Chinese medicine (TCM) containing a variety of biologically active compounds. In our previous studies, CG has shown a beneficial effect against memory impairment in mice caused by d-galactose. However, whether CG can be used as a complementary medicine for the treatment of AD remains unexplored. Here, we use a combination of CG and memantine hydrochloride (Mm) to treat Alzheimer-like pathology and investigate the effects and mechanisms in vivo. Methods: The histology of brain was examined with Hematoxylin–eosin (HE) staining, Golgi staining and Thioflavin S staining. ELISA was applied to assess the expression levels or activities of CAT, SOD, GSH-Px, MDA, alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), total bilirubin (TBIL) in serum, as well as the levels of IL-6, IL-1β, and TNF-α in the mice brain. Western blotting was used to assess the expression of β-secretase (BACE1), amyloid precursor protein (APP), APPβ, APPα, synaptophysin (SYN), growth-associated protein 43 (GAP43), and postsynaptic density 95 (PSD95). Results: In the present study, the combination group (CG + Mm) significantly attenuated Alzheimer-like behavior without adverse effects in APP/PS1 mice, indicating its high degree of safety and efficacy after long-term treatment. CG + Mm reduced AD pathological biomarker Aβ plaque accumulation by inhibiting BACE1 and APP expression (P < 0.05 or P < 0.001). Besides, the combination group markedly inhibited the levels of IL-1β, IL-6, and TNF-α in hippocampus (P < 0.001), as well as activities of SOD, CAT, and GSH-Px in serum (P < 0.001). By contrast, the combination group improved synaptic plasticity by enhancing SYN, PSD95, and GAP43 expression. Conclusions: Taken together, these data supported the notion that CG combined with Mm might ameliorate the cognitive impairment through multiple pathways, suggesting that CG could play a role as complementary medicine to increase anti-AD effect of chemical drugs by reducing Aβ deposition, neuroinflammation, oxidative damage, and improving synaptic plasticity. [ABSTRACT FROM AUTHOR]

Chronic Cerebral Hypoperfusion(CCH)-induced vascular dementia(VD) is a common neurodegenerative disease which seriously affects the patient's quality of life. Therefore, it is critical to find an effective treatment of VD. Autophagy is a natural regulated mechanism that can remove dysfunctional proteins and organelles, however, over-activation or under-activation can of autophagy can induce the apoptosis of cells. Although autophagy plays a role in the central nervous system is unquestionable, the effects of autophagy in the ischemic brain are still controversial. Some autophagy regulators have been tested, suggesting that both activation and inhibition of autophagy can improve the cognitive function. This article reviews the role of autophagy in CCH-induced VD to discuss whether autophagy has the potential to become a target for drug development and provides several potential compounds for treating vascular dementia. [Display omitted] • Autophagy is activated in chronic hypoperfusion-induced vascular dementia. • Mild to moderate autophagy activation is beneficial for the recovery of vascular dementia. • Excessive activation of autophagy can cause apoptosis. • Targeted autophagy therapy may be a new direction for the treatment of vascular dementia. [ABSTRACT FROM AUTHOR]

One of the biggest challenges in drug development for Alzheimer's disease (AD) is how to effectively remove deposits of amyloid-beta (Aβ). Recently, the relationship between microglia and Aβ has become a research hotspot. Emerging evidence suggests that Aβ-induced microglia-mediated neuroinflammation further aggravates the decline of cognitive function, while microglia are also involved in the process of Aβ clearance. Hence, microglia have become a potential therapeutic target for the treatment or prevention of AD. An in-depth understanding of the role played by microglia in the development of AD will help us to broaden therapeutic strategies for AD. In this review, we provide an overview of the dual roles of microglia in AD progression: the positive effect of phagocytosis of Aβ and its negative effect on neuroinflammation after over-activation. With the advantages of novel structure, high efficiency, and low toxicity, small-molecule compounds as modulators of microglial function have attracted considerable attention in the therapeutic areas of AD. In this review, we also summarize the therapeutic potential of small molecule compounds (SMCs) and their structure–activity relationship for AD treatment through modulating microglial phagocytosis and inhibiting neuroinflammation. For example, the position and number of phenolic hydroxyl groups on the B ring are the key to the activity of flavonoids, and the substitution of hydroxyl groups on the benzene ring enhances the anti-inflammatory activity of phenolic acids. This review is expected to be useful for developing effective modulators of microglial function from SMCs for the amelioration and treatment of AD. [Display omitted] • Dual role of microglia in AD: positive effect of phagocytosis of Aβ and negative effect on inflammation after overactivation. • SMCs are potential function regulators of microglia: enhancing phagocytosis of microglia on Aβ and inhibiting inflammatory. • The structure-activity relationship of small molecule components providing reference for drug research and development. [ABSTRACT FROM AUTHOR]

In elderly people, Alzheimer's disease (AD) is the most common form of dementia. It has been shown that traditional Chinese medicine (TCM) based on phytomedicines enhances the therapeutic effects of modern medicine when taken in conjunction with them. Modern medicine N-methyl-D-aspartate receptor (NMDA) antagonist memantine (Mm) are mainly used in the clinical treatment of AD. TCM Cerebralcare Granule® (CG) has long been an effective treatment for headaches, dizziness, and other symptoms. In this study, we employ a blend of CG and Mm to address Alzheimer's disease-like symptoms and explore their impacts and underlying mechanisms. The objective of our study was to observe the effects of CG combined with Memantine (Mm) on learning and memory impairment of AD mice induced by D-galactose and to explore the mechanism at work. CG and Mm were combined to target multiple pathological processes involved in AD. For a thorough analysis, we performed various experiments such as behavioral detection, pathological detection, proteomic detection, and other experimental methods of detection. It was found that the combination of CG and Mm was significantly effective for improving learning and memory in AD mice as well as brain pathology. The serum and hippocampal tissue of AD mice were significantly enhanced with catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px) activities and malondialdehyde (MDA) levels were decreased with this treatment. In AD mice, a combination of Mm and CG (CG + Mm) significantly increased the levels of the anti-inflammatory factors IL-4 and IL-10, decreased the levels of pro-inflammatory factors (IL-6, IL-1β) and tumor necrosis factor-alpha (TNF-α), improved synaptic plasticity by restoring synaptophysin (SYP) and postsynaptic density protein-95 (PSD-95) expression in the hippocampus, enhanced Aβ phagocytosis of microglia in AD mice, and increased mitochondrial respiratory chain enzyme complexes I, II, III, and IV, lead to an increase in the number of functionally active NMDA receptors in the hippocampus. Proteomic analysis GO analysis showed that the positive regulation gene H3BIV5 of G protein coupled receptor signal pathway and synaptic transmission was up-regulated, while the transsynaptic signal of postsynaptic membrane potential and regulation-related gene Q5NCT9 were down-regulated. Most proteins showed significant enriched signal transduction pathway profiles after CG + Mm treatment, based on the KEGG pathway database. The data supported the idea that CG and Mm could be more effective in treating AD mice induced by D-galactose than Mm alone. We provided a basis for the clinical use of CG with Mm. [Display omitted] [ABSTRACT FROM AUTHOR]

Clinically, Cerebralcare Granule® (CG) has been widely utilized to treat various types of headache, chronic cerebral insufficiency and other diseases, and the effect is significant. Clinical studies have shown that CG can significantly relieve vascular dementia (VaD), however, the molecular mechanisms haven't been established. To clear the therapeutic mechanisms of CG against VaD, a hypothesis was proposed that CG could treat neurovascular injury by inhibiting the production of lipocalin-2 (LCN 2). 90 dementia rats were selected by water maze test and randomly divided into 6 groups, including nimodipine (NM), CG L (low dose) (0.314 g kg−1), CG H (high dose) (0.628 g kg−1), and combined group (CG + NM). And in vitro neuronal cell OGD modeling to evaluate the effect of CG on JAK2/STAT3. CG could significantly shorten the escape latency of two-vessel occlusion (2-VO) rats, increase their exploratory behavior, alleviate the symptoms of VaD and improve the ultrastructural pathological damage of neurovascular unit and accelerate the recovery of cerebral blood perfusion. CG combined with NM is better than NM alone. It was further showed that CG could inhibit the pathogenicity of LCN 2 through JAK2/STAT3 pathway and suppress the production of inflammatory cytokines. It plays a role in the protection of cerebral microvasculature and BBB in 2-VO rats. Taken together, there data has supported notion that CG can protect the integrity of cerebral blood vessels and BBB and improve cognitive impairment through mainly inhibiting LCN 2, which provides scientific evidence for clinical application. • Cerebralcare Granule® improves cognitive impairment and memory impairment. • Cerebralcare Granule® protects the integrity of glial cells and BBB. • Cerebralcare Granule® inhibited lipocalin-2 by effecting JAK2/STAT3 phosphorylation. [ABSTRACT FROM AUTHOR]

Cardiac fibrosis occurs in ischemic and non-ischemic heart failure, hereditary cardiomyopathy, diabetes and aging. Energy metabolism, which serves a crucial function in the course and treatment of cardiovascular diseases, might have therapeutic benefits for myocardial fibrosis. Ginsenoside Rb3 (G-Rb3) is one of the main components of Ginseng and exhibits poor oral bioavailability but still exerts regulate energy metabolism effects in some diseases. Therefore, the study investigated the effect of chitosan (CS) @ sodium tripolyphosphate (TPP) nanoparticles conjugation with ginsenoside Rb3 (NpRb3) on myocardial fibrosis and studied its possible mechanisms. The results showed that NpRb3 directly participates in the remodeling of myocardial energy metabolism and the regulation of perixisome proliferation-activated receptor alpha (PPARα), thereby improving the degree of myocardial fibrosis. The study also verifies the protective effect of NpRb3 on energy metabolism and mitochondrial function by targeting the PPARα pathway. Therefore, the prepared nanodrug carrier may be a potential solution for the delivery of G-Rb3, which is a promising platform for oral treatment of myocardial fibrosis. Schematic depiction of the roles of chitosan @ sodium tripolyphosphate nanoparticles with ginsenoside Rb3 (NpRb3) in myocardial fibrosis. [Display omitted] • Nanoparticle conjugation of ginsenoside Rb3 inhibits the myocardial fibrosis in rat with transverse aortic constriction. • Nanoparticle Conjugation of ginsenoside Rb3 participates in the remodeling of energy metabolism by regulating the PPARα. • Chitosan @ sodium tripolyphosphate nanoparticles conjugation improves the solubility and bioavailability of ginsenoside Rb3. [ABSTRACT FROM AUTHOR]

Cardiac fibrosis is a pathogenic factor of many cardiovascular diseases (CVD), which seriously affects people's life and health, causing huge economic losses.Therefore, it is very significant to find an effective treatment for myocardial fibrosis. Adipokines are mainly derived from adipose tissue and have an prominent regulatory effect on glucose and lipid metabolism, inflammation, immune response and cardiovascular function. Adipose tissue is composed of a variety of cell types, including adipocytes, endothelial cells, macrophages and smooth muscle cells. Adipokines mainly include adiponectin, leptin, resistin, visfatin and omentin, which are synthesized and secreted by adipocytes. More and more evidence shows that adipokines can regulate the progress of cardiac fibrosis. This scientific review provides new ideas for targeting adipokines in the treatment of myocardial fibrosis and provides strategies for the development of new, safe, and effective pharmacological antagonists against myocardial fibrosis based on adipokines activity. [Display omitted] [ABSTRACT FROM AUTHOR]

• The key processing techniques of citrus peels are extraction and drying. • Citrus peels from diverse species have been used as folk medicine and food. • The flavonoids of citrus peels have a range of biological functions. • Citrus peels have a good effect on regulation of metabolic disorder. Citrus is one of the main fruits processed worldwide, producing a lot of industrial by-products. As the main part of citrus "residue", citrus peels have a wide application prospect. They could not only be directly used to produce various food products, but also be used as promising biofuels to produce ethanol and methane. Additionally, functional components (flavonoids, limonoids, alkaloids, essential oils and pectin) extracted from citrus peels have been related to the improvement of human health against active oxygen, inflammatory, cancer and metabolic disorders. Therefore, it is clear that the citrus peels have great potential to be developed into useful functional foods, medicines and biofuels. This review systematically summarizes the recent advances in current uses, processing, bioactive components and biological properties of citrus peels. A better understanding of citrus peels may provide reference for making full use of it. [ABSTRACT FROM AUTHOR]