A peripheral system disease-Pulmonary hypertension.

Pulmonary hypertension (PH) is a cardiovascular disorder characterized by substantial morbidity and mortality rates. It is a chronic condition characterized by intricate pathogenesis and uncontrollable factors. We summarized the pathological effects of estrogen, genetics, neuroinflammation, intestinal microbiota, metabolic reorganization, and histone modification on PH. PH is not only a pulmonary vascular disease, but also a systemic disease. The findings emphasize that the onset of PH is not exclusively confined to the pulmonary vasculature, consequently necessitating treatment approaches that extend beyond targeting pulmonary blood vessels. Hence, the research on the pathological mechanism of PH is not limited to target organs such as pulmonary vessels, but also focuses on exploring other fields (such as estrogen, genetics, neuroinflammation, intestinal microbiota, metabolic reorganization, and histone modification).

CCR5 and inflammatory storm.

Chemokines and their corresponding receptors play crucial roles in orchestrating inflammatory and immune responses, particularly in the context of pathological conditions disrupting the internal environment. Among these receptors, CCR5 has garnered considerable attention due to its significant involvement in the inflammatory cascade, serving as a pivotal mediator of neuroinflammation and other inflammatory pathways associated with various diseases. However, a notable gap persists in comprehending the intricate mechanisms governing the interplay between CCR5 and its ligands across diverse and intricate inflammatory pathologies. Further exploration is warranted, especially concerning the inflammatory cascade instigated by immune cell infiltration and the precise binding sites within signaling pathways. This study aims to illuminate the regulatory axes modulating signaling pathways in inflammatory cells by providing a comprehensive overview of the pathogenic processes associated with CCR5 and its ligands across various disorders. The primary focus lies on investigating the pathomechanisms associated with CCR5 in disorders related to neuroinflammation, alongside the potential impact of aging on these processes and therapeutic interventions. The discourse culminates in addressing current challenges and envisaging potential future applications, advocating for innovative research endeavors to advance our comprehension of this realm.

Ginsenoside Rg1 treats ischemic stroke by regulating CKLF1/CCR5 axis-induced neuronal cell pyroptosis.

BACKGROUND: Ischemic stroke, a severe and life-threatening neurodegenerative condition, currently relies on thrombolytic therapy with limited therapeutic window and potential risks of hemorrhagic transformation. Thus, there is a crucial need to explore novel therapeutic agents for ischemic stroke. Ginsenoside Rg1 (Rg1), a potential neuroprotective agent, exhibits anti-ischemic effects attributed to its anti-inflammatory, anti-oxidant, and anti-apoptotic properties. Nevertheless, the precise underlying mechanism of action remains to be fully elucidated. PURPOSE: This study aimed to explore whether Rg1 exerts anti-ischemic stroke effects by inhibiting pyroptotic neuronal cell death through modulation of the chemokine like factor 1 (CKLF1)/ C-C chemokine receptor type 5 (CCR5) axis. METHODS: In this study, the MCAO model was used as an ischemic stroke model, and experimental tests were performed after 6 hours of ischemia. The anti-ischemic effect of Rg1 was examined by TTC staining, nissl-staining and neurobehavioral tests. In the in vitro experiments, PC12 cells were subjected to stimulation with CKLF1's mimetic peptide C27 to assess the potential of CKLF1 to induce focal neuronal cell death. Additionally, the impact of CKLF1 mimetic peptide C27, antagonistic peptide C19, and CCR5 inhibitor MVC on PC12 cells subjected to oxygen-glucose deprivation (OGD) and subsequently treated with Rg1 was investigated. In vivo, Rg1 treatment was examined by quantitative real-time PCR (qPCR), ELISA, immunohistochemistry (IHC), immunofluorescence (IF), western blot (WB), and co-immunoprecipitate (Co-IP) assays to perspective whether Rg1 treatment reduces CKLF1/CCR5 axis-induced pyroptotic neuronal cell death. In addition, to further explore the biological significance of CKLF1 in ischemic stroke, CKLF1-/- rats were used as the observation subjects in this study. RESULTS: The in vitro results suggested that CKLF1 was able to induce neuronal cells to undergo pyroptosis. In vivo pharmacodynamic results showed that Rg1 treatment was able to significantly improve symptoms in ischemic stroke rats. In addition, Rg1 treatment was able to inhibit the interaction between CKLF1 and CCR5 after ischemic stroke and inhibited CKLF1/CCR5 axis-induced pyroptosis. The results of related experiments in CKLF1-/- rats showed that Rg1 lost its therapeutic effect after CKLF1 knockdown. CONCLUSION: Our findings indicate that the activation of the NLRP3 inflammasome is initiated by the CKLF1/CCR5 axis, facilitated through the activation of the NF-κB pathway, ultimately resulting in the pyroptosis of neuronal cells. Conversely, Rg1 demonstrates the capability to mitigate neuronal cell damage following CKLF1-induced effects by suppressing the expression of CKLF1. Thus, CKLF1 represents a crucial target for Rg1 in the context of cerebral ischemia treatment, and it also holds promise as a potential target for drug screening in the management of ischemic stroke.

Higenamine exerts antidepressant effect by improving the astrocytic gap junctions and inflammatory response.

BACKGROUND: Depression is a refractory psychiatric disorder closely associated with dysfunction of the gap junctions (GJs) between astrocytes as well as neuroinflammation. Higenamine (Hig) is a potent cardiotonic ingredient in Fuzi (i.e., Aconitum carmichaeli Debx.) with anti-inflammatory and antioxidant effects, which has a significant protective effect on damaged nerve cells and has great potential for the treatment of neuropsychiatric diseases. METHODS: Rats were stimulated by chronic unpredictable stress (CUS) for 28 days while given Hig (5, 10, 20 mg/kg) and then analyzed behaviorally by the open field test, sucrose preference test, and forced swimming test. Changes in astrocyte GJs function and morphology were observed by dye transfer and transmission electron microscopy, respectively. Expression and phosphorylation of connexin 43 (Cx43) were analyzed by Western blot. Also, considering the close relationship between depression and neuroinflammation, we determined the inflammatory response in serum with ELISA kits and analyzed the expression of inflammation-related proteins with Western blot. RESULTS: Hig ameliorated CUS-induced depression-like behavior in rats. Hig administration improved gap junctional dysfunction in astrocytes, reduced gap junctional gaps and elevated the expression of Cx43 and decreased the phosphorylation of Cx43. Meanwhile, Hig administration was also able to attenuate the inflammatory response that occurs after CUS in rats. LIMITATIONS: For the role of Cx43 in depression, we did not validate it more deeply in animal models with knockout Cx43. In addition, GJs dysfunction might be associated with the inflammatory response seen in depression, but this needs to be further investigated. CONCLUSIONS: Hig ameliorates depression and exerts its antidepressant effect possibly by improving the dysfunctional GJs between astrocytes and the inflammatory response.

CC chemokines Modulate Immune responses in Pulmonary Hypertension.

BACKGROUND: Pulmonary hypertension (PH) represents a progressive condition characterized by the remodeling of pulmonary arteries, ultimately culminating in right heart failure and increased mortality rates. Substantial evidence has elucidated the pivotal role of perivascular inflammatory factors and immune dysregulation in the pathogenesis of PH. Chemokines, a class of small secreted proteins, exert precise control over immune cell recruitment and functionality, particularly with respect to their migration to sites of inflammation. Consequently, chemokines emerge as critical drivers facilitating immune cell infiltration into the pulmonary tissue during inflammatory responses. This review comprehensively examines the significant contributions of CC chemokines in the maintenance of immune cell homeostasis and their pivotal role in regulating inflammatory responses. The central focus of this discussion is directed towards elucidating the precise immunoregulatory actions of CC chemokines concerning various immune cell types, including neutrophils, monocytes, macrophages, lymphocytes, dendritic cells, mast cells, eosinophils, and basophils, particularly in the context of pH processes. Furthermore, this paper delves into an exploration of the underlying pathogenic mechanisms that underpin the development of PH. Specifically, it investigates processes such as cellular pyroptosis, examines the intricate crosstalk between bone morphogenetic protein receptor type 2 (BMPR2) mutations and the immune response, and sheds light on key signaling pathways involved in the inflammatory response. These aspects are deemed critical in enhancing our understanding of the complex pathophysiology of PH. Moreover, this review provides a comprehensive synthesis of findings from experimental investigations targeting immune cells and CC chemokines. AIM OF REVIEW: In summary, the inquiry into the inflammatory responses mediated by CC chemokines and their corresponding receptors, and their potential in modulating immune reactions, holds promise as a prospective avenue for addressing PH. The potential inhibition of CC chemokines and their receptors stands as a viable strategy to attenuate the inflammatory cascade and ameliorate the pathological manifestations of PH. Nonetheless, it is essential to acknowledge the current state of clinical trials and the ensuing progress, which regrettably appears to be less than encouraging. Substantial hurdles exist in the successful translation of research findings into clinical applications. The intention is that such emphasis could potentially foster the advancement of potent therapeutic agents presently in the process of clinical evaluation. This, in turn, may further bolster the potential for effective management of PH.

Targeting oxidative stress as a preventive and therapeutic approach for cardiovascular disease.

Cardiovascular diseases (CVDs) continue to exert a significant impact on global mortality rates, encompassing conditions like pulmonary arterial hypertension (PAH), atherosclerosis (AS), and myocardial infarction (MI). Oxidative stress (OS) plays a crucial role in the pathogenesis and advancement of CVDs, highlighting its significance as a contributing factor. Maintaining an equilibrium between reactive oxygen species (ROS) and antioxidant systems not only aids in mitigating oxidative stress but also confers protective benefits on cardiac health. Herbal monomers can inhibit OS in CVDs by activating multiple signaling pathways, such as increasing the activity of endogenous antioxidant systems and decreasing the level of ROS expression. Given the actions of herbal monomers to significantly protect the normal function of the heart and reduce the damage caused by OS to the organism. Hence, it is imperative to recognize the significance of herbal monomers as prospective therapeutic interventions for mitigating oxidative damage in CVDs. This paper aims to comprehensively review the origins and mechanisms underlying OS, elucidate the intricate association between CVDs and OS, and explore the therapeutic potential of antioxidant treatment utilizing herbal monomers. Furthermore, particular emphasis will be placed on examining the cardioprotective effects of herbal monomers by evaluating their impact on cardiac signaling pathways subsequent to treatment.

Targeting pyroptosis as a preventive and therapeutic approach for stroke.

Stroke has caused tremendous social stress worldwide, yet despite decades of research and development of new stroke drugs, most have failed and rt-PA (Recombinant tissue plasminogen activator) is still the accepted treatment for ischemic stroke. the complexity of the stroke mechanism has led to unsatisfactory efficacy of most drugs in clinical trials, indicating that there are still many gaps in our understanding of stroke. Pyroptosis is a programmed cell death (PCD) with inflammatory properties and are thought to be closely associated with stroke. Pyroptosis is regulated by the GSDMD of the gasdermin family, which when cleaved by Caspase-1/Caspase-11 into N-GSDMD with pore-forming activity can bind to the plasma membrane to form small 10-20 nm pores, which would allow the release of inflammatory factors IL-18 and IL-1ß before cell rupture, greatly exacerbating the inflammatory response. The pyroptosis occurs mainly in the border zone of cerebral infarction, and glial cells, neuronal cells and brain microvascular endothelial cells (BMECs) all undergo pyroptosis after stroke, which largely exacerbates the breakdown of the blood-brain barrier (BBB) and thus aggravates brain injury. Therefore, pyroptosis may be a good direction for the treatment of stroke. In this review, we focus on the latest mechanisms of action of pyroptosis and the process by which pyroptosis regulates stroke development. We also suggest potential therapeutic stroke drugs that target the pyroptosis pathway, providing additional therapeutic strategies for the clinical management of stroke. The role of pyroptosis after stroke. After stroke, microglia first rush to the damaged area and polarize into M1 and M2 types. Under the influence of various stimuli, microglia undergo pyroptosis, release pro-inflammatory factors, and are converted to the M1 type; astrocytes and neuronal cells also undergo pyroptosis under the stimulation of various pro-inflammatory factors, leading to astrocyte death due to increased osmotic pressure in the membrane, resulting in water absorption and swelling until rupture. BMECs, the main structural component of the BBB, also undergo pyroptosis when stimulated by pro-inflammatory factors released from microglia and astrocytes, leading to the destruction of the structural integrity of the BBB, ultimately causing more severe brain damage. In addition, GSDMD in neutrophils mainly mediate the release of NETs rather than pyroptosis, which also aggravates brain injury. IL-10=interleukin-10; TGF-ß = transforming growth factor-ß; IL-18=interleukin-18; IL-1ß = interleukin-1ß; TNF-α = tumor necrosis factor-α; iNOS=induced nitrogen monoxide synthase; MMPs=Matrix metalloproteinases; GSDMD = gasdermin D; BMECs=brain microvascular endothelial cells; BBB = blood-brain barrier.

The mechanism of programmed death and endoplasmic reticulum stress in pulmonary hypertension.

Pulmonary hypertension (PH) was a cardiovascular disease with high morbidity and mortality. PH was a chronic disease with complicated pathogenesis and uncontrollable factors. PH was divided into five groups according to its pathogenesis and clinical manifestations. Although the treatment and diagnosis of PH has made great progress in the past ten years. However, the diagnosis and prognosis of the PAH had a great contrast, which was not conducive to the diagnosis and treatment of PH. If not treated properly, it will lead to right ventricular failure or even death. Therefore, it was necessary to explore the pathogenesis of PH. The problem we urgently need to solve was to find and develop drugs for the treatment of PH. We reviewed the PH articles in the past 10 years or so as well as systematically summarized the recent advance. We summarized the latest research on the key regulatory factors (pyroptosis, apoptosis, necroptosis, ferroptosis, and endoplasmic reticulum stress) involved in PH. To provide theoretical basis and basis for finding new therapeutic targets and research directions of PH.

New Therapeutic Approaches to and Mechanisms of Ginsenoside Rg1 against Neurological Diseases.

Neurological diseases, including Parkinson's disease (PD), Alzheimer's disease (AD), Huntington's disease (HD), stroke, cerebral infarction, ischemia-reperfusion injury, depression and, stress, have high incidence and morbidity and often lead to disability. However, there is no particularly effective medication against them. Therefore, finding drugs with a suitable efficacy, low toxicity and manageable effects to improve the quality of life of patients is an urgent problem. Ginsenoside Rg1 (Rg1) is the main active component of ginseng and has a variety of pharmacological effects. In this review, we focused on the therapeutic potential of Rg1 for improving neurological diseases. We introduce the mechanisms of Ginsenoside Rg1 in neurological diseases, including apoptosis, neuroinflammation, the microRNA (miRNA) family, the mitogen-activated protein kinase (MAPK) family, oxidative stress, nuclear factor-κB (NF-κB), and learning and memory of Rg1 in neurological diseases. In addition, Rg1 can also improve neurological diseases through the interaction of different signal pathways. The purpose of this review is to explore more in-depth ideas for the clinical treatment of neurological diseases (including PD, AD, HD, stroke, cerebral infarction, ischemia-reperfusion injury, depression, and stress). Therefore, Rg1 is expected to become a new therapeutic method for the clinical treatment of neurological diseases.

MicroRNA­195­5p inhibitor prevents the development of osteoarthritis by targeting REGγ.

Osteoarthritis (OA) is a common inflammatory joint disease. MicroRNAs (miRNAs/miRs) have been reported to be involved in the pathogenesis of OA; however, the role of miRNAs in OA remains largely unexplained. The purpose of the present study was to investigate the expression and role of miR­195­5p in OA, and to further explore the mechanism. The expression level of miR­195­5p was measured using reverse transcription­quantitative polymerase chain reaction (RT­qPCR). TargetScan and a luciferase reporter assay were used to reveal the associations between miR­195­5p and REGγ (also known as PSME3). To investigate the role of miR­195­5p in OA, a cell model of OA was established by treating ATDC5 cells with lipopolysaccharide (LPS). Then an MTT assay was conducted to detect cell proliferation ability, and an Annexin V­fluorescein isothiocyanate/propidium iodide apoptosis detection kit was used to measure cell apoptosis. In addition, the levels of interleukin (IL)­1ß, IL­6 and tumor necrosis factor (TNF)­α were determined using ELISA. Furthermore, gene and protein expression was measured via RT­qPCR and western blot assay, respectively. The results revealed that miR­195­5p was significantly upregulated in the articular cartilage tissues of patients with OA and in LPS stimulated ATDC5 cells. REGγ was a direct target of miR­195­5p. The repressed cell proliferation ability and enhanced cell apoptosis of ATDC5 cells induced by LPS were reversed by miR­195­5p downregulation. Furthermore, LPS stimulation significantly upregulated the levels of IL­1ß, IL­6 and TNF­α, while miR­195­5p downregulation markedly reduced the expression of inflammatory factors induced by LPS. The results also revealed that a miR­195­5p inhibitor inhibited the LPS induced repression of the Wnt/ß­catenin signaling pathway and activation of nuclear factor (NF)­κB signaling pathway in ATDC5 cells. Notably, the results of the present study also indicated that all of the effects of the miR­195­5p inhibitor on ATDC5 cells were reversed by REGγ silencing. In conclusion, the results indicated that the miR­195­5p inhibitor served a protective role in OA by inhibiting chondrocyte apoptosis and inflammatory responses by regulating the Wnt/ß­catenin and NF­κB signaling pathways.