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.

A Review of Research on the Association between Neuron-Astrocyte Signaling Processes and Depressive Symptoms.

Depression is a mental illness that has a serious negative impact on physical and mental health. The pathophysiology of depression is still unknown, and therapeutic medications have drawbacks, such as poor effectiveness, strong dependence, adverse drug withdrawal symptoms, and harmful side effects. Therefore, the primary purpose of contemporary research is to understand the exact pathophysiology of depression. The connection between astrocytes, neurons, and their interactions with depression has recently become the focus of great research interest. This review summarizes the pathological changes of neurons and astrocytes, and their interactions in depression, including the alterations of mid-spiny neurons and pyramidal neurons, the alterations of astrocyte-related biomarkers, and the alterations of gliotransmitters between astrocytes and neurons. In addition to providing the subjects of this research and suggestions for the pathogenesis and treatment techniques of depression, the intention of this article is to more clearly identify links between neuronal-astrocyte signaling processes and depressive symptoms.

Koumiss promotes Mycobacterium bovis infection by disturbing intestinal flora and inhibiting endoplasmic reticulum stress.

Mycobacterium bovis is the causative agent of bovine tuberculosis and also responsible for serious threat to public health. Koumiss is a fermented mare's milk product, used as traditional drink. Here, we explored the effect of koumiss on gut microbiota and the host immune response against M bovis infection. Therefore, mice were treated with koumiss and fresh mare milk for 14 days before M bovis infection and continue for 5 weeks after infection. The results showed a clear change in the intestinal flora of mice treated with koumiss, and the lungs of mice treated with koumiss showed severe edema, inflammatory infiltration, and pulmonary nodules in M bovis-infected mice. Notably, we found that the content of short-chain fatty acids was significantly lower in the koumiss-treated group compared with the control group. However, the expression of endoplasmic reticulum stress and apoptosis-related proteins in the lungs of koumiss-treated mice were significantly decreased. Collectively, these findings suggest that koumiss treatment disturb the intestinal flora of, which is associated with disease severity and the possible mechanism that induces lungs pathology. Our current findings can be exploited further to establish the "gut-lung" axis which might be a novel strategy for the control of tuberculosis.

Inhibition of type I interferon signaling abrogates early Mycobacterium bovis infection.

BACKGROUND: Mycobacterium bovis (M. bovis) is the principal causative agent of bovine tuberculosis; however, it may also cause serious infection in human being. Type I IFN is a key factor in reducing viral multiplication and modulating host immune response against viral infection. However, the regulatory pathways of Type I IFN signaling during M. bovis infection are not yet fully explored. Here, we investigate the role of Type I IFN signaling in the pathogenesis of M. bovis infection in mice. METHODS: C57BL/6 mice were treated with IFNAR1-blocking antibody or Isotype control 24 h before M. bovis infection. After 21 and 84 days of infection, mice were sacrificed and the role of Type I IFN signaling in the pathogenesis of M. bovis was investigated. ELISA and qRT-PCR were performed to detect the expression of Type I IFNs and related genes. Lung lesions induced by M. bovis were assessed by histopathological examination. Viable bacterial count was determined by CFU assay. RESULTS: We observed an abundant expression of Type I IFNs in the serum and lung tissues of M. bovis infected mice. In vivo blockade of Type I IFN signaling reduced the recruitment of neutrophils to the lung tissue, mediated the activation of macrophages leading to an increased pro-inflammatory profile and regulated the inflammatory cytokine production. However, no impact was observed on T cell activation and recruitment in the early acute phase of infection. Additionally, blocking of type I IFN signaling reduced bacterial burden in the infected mice as compared to untreated infected mice. CONCLUSIONS: Altogether, our results reveal that Type I IFN mediates a balance between M. bovis-mediated inflammatory reaction and host defense mechanism. Thus, modulating Type I IFN signaling could be exploited as a therapeutic strategy against a large repertoire of inflammatory disorders including tuberculosis.

PP2Ac Modulates AMPK-Mediated Induction of Autophagy in Mycobacterium bovis-Infected Macrophages.

Mycobacterium bovis (M. bovis) is the causative agent of bovine tuberculosis in cattle population across the world. Human beings are at equal risk of developing tuberculosis beside a wide range of M. bovis infections in animal species. Autophagic sequestration and degradation of intracellular pathogens is a major innate immune defense mechanism adopted by host cells for the control of intracellular infections. It has been reported previously that the catalytic subunit of protein phosphatase 2A (PP2Ac) is crucial for regulating AMP-activated protein kinase (AMPK)-mediated autophagic signaling pathways, yet its role in tuberculosis is still unclear. Here, we demonstrated that M. bovis infection increased PP2Ac expression in murine macrophages, while nilotinib a tyrosine kinase inhibitor (TKI) significantly suppressed PP2Ac expression. In addition, we observed that TKI-induced AMPK activation was dependent on PP2Ac regulation, indicating the contributory role of PP2Ac towards autophagy induction. Furthermore, we found that the activation of AMPK signaling is vital for the regulating autophagy during M. bovis infection. Finally, the transient inhibition of PP2Ac expression enhanced the inhibitory effect of TKI-nilotinib on intracellular survival and multiplication of M. bovis in macrophages by regulating the host's immune responses. Based on these observations, we suggest that PP2Ac should be exploited as a promising molecular target to intervene in host-pathogen interactions for the development of new therapeutic strategies towards the control of M. bovis infections in humans and animals.

[Safety evaluation of heavy metals contaminated Astragalus membranaceus using health risk assessment model].

To evaluate the safety of heavy metals contaminated Astragalus membranaceus,an appropriate protocol was established to study the heavy metals pollution level by health risk assessment. This study provided a detailed procedure to assess the medicinal herbs in quality control and safety evaluation,and expected to create awareness among the public on the safety of consuming of A. membranaceus or any other kinds of medicinal herbs. The heavy metals content of Cu,As,Cd,Pb and Hg in a total of 45 batches of A. membranaceus were carefully analyzed with a developed inductively coupled plasma mass spectrometry( ICP-MS). Besides,the heavy metal contamination level was further evaluated through 4 main assessment parameters,including maximum residue limit( MRL) set by International Standard Organization,estimated daily intake( EDI) set by IUPAC,target hazard quotients( THQ) and Total THQ set by USEPA and total THQs in raw herbs of A. membranaceus. In addition,the recommended MRLs of 5 main heavy metals aimed to A. membranaceus were calculated based on the regulated consumption quantity. The result showed that,under the ISO international standard of Chinese medicine-Chinese herbal medicine heavy metals,the unqualified rate was 8. 89% for A. membranaceus,which including 4 batches of A. membranaceus exceeded the MRL of As. Here,the standard THQ value of A. membranaceus was firstly proposed as 0. 02 and 0. 011 25 for adults and children,respectively,which were calculated with the recommended consumption quantity of 30 g and 9 g for adults and children. Furthermore,the values of THQ for As and total THQs in adults and children were exceeded the standard THQ in A. membranaceus,and the recommended MRLs of Pb,Cd,Hg and Cu in above medicinal materials that calculated based on health risk assessment model were higher than the regulated MRLs that set by ISO and Chinese Pharmacopeia. The research showed that the contents of heavy metals in A. membranaceus were not in the safe range and the certain non-carcinogenic risks to human body cannot be neglected. Based on above investigation result,it is easily known that the common evaluation method for raw herbs based on the comparison of MRL of heavy metals was not precise enough,and the international model of health risk assessment should be built for each medicinal herb. Above all,this study provided a more realistic research approach for safety evaluation of any other kinds of heavy metals contaminated medicinal herbs,including the establishment of heavy metals standard limit in a specified medicinal herb under recommended consumption quantity,and it is expected to create awareness among the public on the safety of consuming any other medicinal herbs.

A Clinical-radiomic Nomogram for the Non-invasive Evaluation of Glomerular Status in Diabetic Kidney Disease.

OBJECTIVE: Utilizing ultrasound radiomics, we developed a machine learning (ML) model to construct a nomogram for the non-invasive evaluation of glomerular status in diabetic kidney disease (DKD). MATERIALS AND METHODS: Patients with DKD who underwent renal biopsy were retrospectively enrolled between February 2017 and February 2023. The patients were classified into mild or moderate-severe glomerular severity based on pathological findings. All patients were randomly divided into a training (n =79) or testing cohort (n = 35). Radiomic features were extracted from ultrasound images, and a logistic regression ML algorithm was applied to construct an ultrasound radiomic model after selecting the most significant features using univariate analysis and the least absolute shrinkage and selection operator algorithm (LASSO). A clinical model was created following univariate and multivariate logistic regression analyses of the patient's clinical characteristics. Then, the clinical-radiomic model was constructed by combining rad scores and independent clinical characteristics and plotting the nomogram. The receiver operating characteristic curve (ROC) and decision curve analysis (DCA), respectively, were used to evaluate the prediction abilities of the clinical model, ultrasound-radiomics model, and clinical-radiomics model. RESULTS: A total of 114 DKD patients were included in the study, including 43 with mild glomerulopathy and 71 with moderate-severe glomerulopathy. The area under the curve (AUC) for the clinical model based on clinical features and the radiomic model based on 2D ultrasound images in the testing cohort was 0.729 and 0.761, respectively. Further, the AUC for the clinical-radiomic nomogram was constructed by combining clinical features, and the rad score was 0.850 in the testing cohort. The outcomes were better than those of both the radiomic and clinical single-model approaches. CONCLUSION: The nomogram constructed by combining ultrasound radiomics and clinical features has good performance in assessing the glomerular status of patients with DKD and will help clinicians monitor the progression of DKD.

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.

Dihydromyricetin treats pulmonary hypertension by modulating CKLF1/CCR5 axis-induced pulmonary vascular cell pyroptosis.

Pulmonary hypertension (PH) is a progressive cardiopulmonary disease characterized by elevated pulmonary artery pressure and vascular remodeling, resulting in poor prognosis and increased mortality rates. Chemokine-like factor 1 (CKLF1) plays a significant role in inducing inflammation and cell proliferation, both of which are critical processes in the pathogenesis of various diseases. Dihydromyricetin (DMY) has garnered attention for its potent anti-inflammatory properties. This study evaluated the protective effects of DMY against PH, demonstrating that DMY treatment can mitigate pyroptosis in pulmonary artery endothelial cells (PAECs) and pulmonary artery smooth muscle cells (PASMCs) in vivo via the CKLF1/CCR5 axis. Results indicated significant improvements in hemodynamics, inflammatory responses, fibrosis, vascular remodeling, and right ventricular hypertrophy in PH rats following DMY treatment. Furthermore, the interaction between CKLF1 and CCR5 was investigated in CKLF1-/- rats after PH induction. DMY was found to downregulate CKLF1 expression and the inflammatory response in the lungs, with its therapeutic efficacy diminished following CKLF1 knockdown. This study underscores the therapeutic potential of DMY in the management of PH and lays a foundation for future research and clinical applications.

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.

Construction of a novel double S-scheme structure WO3/g-C3N4/BiOI: Enhanced photocatalytic performance for antibacterial activity.

In recent years, the threat to human health from bacteria in wastewater has attracted attention, and photocatalytic technology has emerged as a promising strategy for inactivating bacteria in water. Therefore, it is of great research value to develop a novel high-efficiency photocatalytic system with the visible light response. We successfully designed a double S-scheme heterojunction composite WO3/g-C3N4/BiOI (WCB) in this paper. The preparation of WCB composites was demonstrated by a series of characterizations, including X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), Fourier transform infrared spectroscopy (FT-IR) and transmission electron microscopy (TEM). The antibacterial effects of photocatalysts against representative Gram-negative strain Escherichia coli (E. coli) and Gram-positive strain Staphylococcus aureus (S. aureus) were tested under LED light irradiation. The novel photocatalyst presented excellent antibacterial properties, inactivating E. coli in 12 min and S. aureus in 20 min. The bacterial cell inactivation process was studied by scanning electron microscopy (SEM) and Confocal Laser Scanning Microscopy (CLSM). Active species capture experiments show that the active species present in the WCB composites in the process of inactivating bacteria are h+, e-, OH and O2-. In conclusion, the synthesized double S-scheme WCB photocatalyst exhibits remarkable photocatalytic antibacterial activity under LED light and has broad prospects for practical application in water antibacterial treatment.

A novel Z-type heterojunction Bi3O4Cl/Bi4O5I2 photocatalytic composite with broad-spectrum antibacterial activity and degradation properties.

At present, the sustainable development of humans is facing health problems and ecological imbalance caused by environmental pollution. To solve the bacteria, antibiotics and other pollutants in wastewater, Bi3O4Cl and Bi4O5I2 with appropriate bandgap width were selected to prepare Z-type heterojunction Bi3O4Cl/Bi4O5I2 photocatalytic materials by calcination method. Under LED light, the best sample Bi3O4Cl/Bi4O5I2-4 could completely inactivate Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus) in 30 min, Bacillus subtilis (B. subtilis) and Pseudomonas aeruginosa (P. aeruginosa) in 20 min, and degrade 70.6% of tetracycline (TC) and 97.4% of Rhodamine B (RhB). Photocurrent and electrochemical impedance tests (EIS) confirmed the high photocurrent response and low charge transfer resistance in the Bi3O4Cl/Bi4O5I2. The photocatalytic antibacterial and degradation mechanism of Z-type Bi3O4Cl/Bi4O5I2 heterojunction was verified by capture experiments. Thus, this study provides a compact and efficient photocatalyst with broad-spectrum antibacterial activity and degradation properties.

Fabrication of n-p ß-Bi2O3@BiOI core/shell photocatalytic heterostructure for the removal of bacteria and bisphenol A under LED light.

A novel n-p ß-Bi2O3@BiOI core/shell heterostructure was successfully constructed by a facile ultrasonication method. SEM, TEM, XRD and XPS confirmed the core/shell structure. UV-vis indicated the composite had good absorption of visible light. Photocurrent and electrochemical impedance analysis (EIS) revealed effective electron (e-) and hole (h+) separation efficiency in the core/shell hybrid structure, which induced a significantly improved photocatalytic activity. The ß-Bi2O3@BiOI photocatalyst effectively treated with Escherichia coli (E. coli), Staphylococcus aureus (S. aureus) and bisphenol A (BPA) under LED light, and presented better photocatalytic antibacterial performance than ß-Bi2O3 and BiOI. Trapping experiment revealed that h+ played an important role in photocatalytic reaction. The present work provided a novel LED light-activated photocatalyst that was efficient for antibacterial application.

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.

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.

Constructing an S-scheme CuBi2O4/Bi4O5I2 heterojunction for lightemittingdiode-driven pollutant degradation and bacterial inactivation.

The CuBi2O4/Bi4O5I2 S-scheme heterojunction structure was constructed by a hydrothermal and subsequent calcination route. The combination of CuBi2O4 and Bi4O5I2 produced excellent photocatalytic performance under an LED light. A series of technical characterizations, including X-ray diffraction (XRD), scanning electron microscopy (SEM) and X-ray photoelectron spectroscopy (XPS), were used to determine the successful construction of S-scheme CuBi2O4/Bi4O5I2 composites. The improvement of photogenerated carrier separation efficiency helped to achieve the best photocatalytic performance of 37% CuBi2O4/Bi4O5I2, which can degrade tetracycline (TC) to 81.67% in 90 min, and completely inactivate Escherichia coli (E. coli) in 20 min and Staphylococcus aureus (S. aureus) in 40 min. The effects of some key parameters (such as the concentration of pollutants, the amount of catalyst, pH value of a solution, various inorganic anions and various water substrates) and the possible degradation path of tetracycline were systematically studied. Finally, the removal of pollutants and inactivation of bacterial mechanisms based on the S-scheme heterojunction (CuBi2O4/Bi4O5I2) was proposed. This study provides insight into the synthesis of S-scheme heterojunction photocatalysts, which can efficiently degrade organic pollutants and inactivate bacteria under LED light irradiation.

Facile synthesizing Z-scheme Bi12O15Cl6/InVO4 heterojunction to effectively degrade pollutants and antibacterial under light-emitting diode light.

The design of a photocatalytic system with Z-scheme heterojunction is the key to charge separation. In this paper, a simple synthesis method was used to prepare Bi12O15Cl6/InVO4 photocatalyst. The synthesized photocatalyst can effectively degrade pollutants, and inactivate bacteria under LED light irradiation. The optimal ratio of 30% Bi12O15Cl6/InVO4 material effectively degraded 78.85% of TC and 97.83% of RhB within 90 min and inactivated Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus) in 40 min. This improvement in photocatalytic performance is mainly due to the formation of a Z-scheme heterojunction between Bi12O15Cl6 and InVO4, which produces effective charge separation and improves photocatalytic degradation and antibacterial activity. The capture experiment revealed the main active substances. The effects of catalyst dosage and pollutant concentration were investigated in details. The intermediates of TC degradation were identified by mass spectrometry (MS), and the possible photocatalytic degradation pathway was proposed. Capture experiment and related measurements proposed the Z-scheme mechanism. This work emphasizes the importance of heterogeneous structure construction and proposes feasible solutions for the rational design of catalysts with photodegradation and antibacterial properties under LED light.

CFP10-loaded PLGA nanoparticles as a booster vaccine confer protective immunity against Mycobacterium bovis.

Introduction: The limited efficacy of BCG (bacillus Calmette-Guérin) urgently requires new effective vaccination approaches for the control of tuberculosis. Poly lactic-co-glycolic acid (PLGA) is a prevalent drug delivery system. However, the effect of PLGA-based nanoparticles (NPs) against tuberculosis for the induction of mucosal immune response is no fully elucidated. In this study, we hypothesized that intranasal immunization with culture filtrate protein-10 (CFP10)-loaded PLGA NPs (CFP10-NPs) could boost the protective immunity of BCG against Mycobacterium bovis in mice. Methods: The recombinant protein CFP10 was encapsulated with PLGA NPs to prepare CFP10-NPs by the classical water-oil-water solvent-evaporation method. Then, the immunoregulatory effects of CFP10-NPs on macrophages in vitro and on BCG-immunized mice in vivo were investigated. Results: We used spherical CFP10-NPs with a negatively charged surface (zeta-potential -28.5 ± 1.7 mV) having a particle size of 281.7 ± 28.5 nm in diameter. Notably, CFP10-NPs significantly enhanced the secretion of tumor necrosis factor α (TNF-α) and interleukin (IL)-1ß in J774A.1 macrophages. Moreover, mucosal immunization with CFP10-NPs significantly increased TNF-α and IL-1ß production in serum, and immunoglobulin A (IgA) secretion in bronchoalveolar lavage fluid (BALF), and promoted the secretion of CFP10-specific interferon-γ (IFN-γ) in splenocytes of mice. Furthermore, CFP10-NPs immunization significantly reduced the inflammatory area and bacterial load in lung tissues at 3-week post-M. bovis challenge. Conclusion: CFP10-NPs markedly improve the immunogenicity and protective efficacy of BCG. Our findings explore the potential of the airway mucosal vaccine based on PLGA NPs as a vehicle for targeted lung delivery.

Gut dysbacteriosis attenuates resistance to Mycobacterium bovis infection by decreasing cyclooxygenase 2 to inhibit endoplasmic reticulum stress.

The role of gut microbiota has been described as an important influencer of the immune system. Gut-lung axis is critical in the prevention of mycobacterium infection, but the specific mechanism, by which dysbiosis affects tuberculosis, has not been reported. In this study, we attempted to provide more information on how the gut-lung axis contributes to Mycobacterium bovis (M. bovis) infection. Mice are pre-treated with broad-spectrum antibiotics cocktail (Abx) to induce gut dysbiosis. Interestingly, dysbiosis of microbes showed a significant increase in the bacterial burden in the lungs and inhibited the level of COX-2. After faecal transplantation, cyclooxygenase 2 (COX-2) expression was restored and the inflammatory lesion in the lungs was reduced. Further research found that the deficiency of COX-2 inhibited endoplasmic reticulum stress (ER stress). This mechanism was completed by COX-2 interaction with BIP. Moreover, we found a positive feedback mechanism by which blocking ER stress could reduce COX-2 levels by the NF-κB pathway. Taken together, we reveal for the first time gut dysbacteriosis exacerbates M. bovis disease by limiting the COX-2/ER stress pathway. The finding strengthens the foundation of gut microbiota-targeted therapy for tuberculosis treatment.

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.