Sublethal enteroviral infection exacerbates disease progression in an ALS mouse model.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease of the motor neuron system associated with both genetic and environmental risk factors. Infection with enteroviruses, including poliovirus and coxsackievirus, such as coxsackievirus B3 (CVB3), has been proposed as a possible causal/risk factor for ALS due to the evidence that enteroviruses can target motor neurons and establish a persistent infection in the central nervous system (CNS), and recent findings that enteroviral infection-induced molecular and pathological phenotypes closely resemble ALS. However, a causal relationship has not yet been affirmed. METHODS: Wild-type C57BL/6J and G85R mutant superoxide dismutase 1 (SOD1G85R) ALS mice were intracerebroventricularly infected with a sublethal dose of CVB3 or sham-infected. For a subset of mice, ribavirin (a broad-spectrum anti-RNA viral drug) was given subcutaneously during the acute or chronic stage of infection. Following viral infection, general activity and survival were monitored daily for up to week 60. Starting at week 20 post-infection (PI), motor functions were measured weekly. Mouse brains and/or spinal cords were harvested at day 10, week 20 and week 60 PI for histopathological evaluation of neurotoxicity, immunohistochemical staining of viral protein, neuroinflammatory/immune and ALS pathology markers, and NanoString and RT-qPCR analysis of inflammatory gene expression. RESULTS: We found that sublethal infection (mimicking chronic infection) of SOD1G85R ALS mice with CVB3 resulted in early onset and progressive motor dysfunction, and shortened lifespan, while similar viral infection in C57BL/6J, the background strain of SOD1G85R mice, did not significantly affect motor function and mortality as compared to mock infection within the timeframe of the current study (60 weeks PI). Furthermore, we showed that CVB3 infection led to a significant increase in proinflammatory gene expression and immune cell infiltration and induced ALS-related pathologies (i.e., TAR DNA-binding protein 43 (TDP-43) pathology and neuronal damage) in the CNS of both SOD1G85R and C57BL/6J mice. Finally, we discovered that early (day 1) but not late (day 15) administration of ribavirin could rescue ALS-like neuropathology and symptoms induced by CVB3 infection. CONCLUSIONS: Our study identifies a new risk factor that contributes to early onset and accelerated progression of ALS and offers opportunities for the development of novel targeted therapies.

FUS/TLS Suppresses Enterovirus Replication and Promotes Antiviral Innate Immune Responses.

During viral infection, the dynamic virus-host relationship is constantly in play. Many cellular proteins, such as RNA-binding proteins (RBPs), have been shown to mediate antiviral responses during viral infection. Here, we report that the RBP FUS/TLS (fused in sarcoma/translocated in liposarcoma) acts as a host-restricting factor against infection with coxsackievirus B3 (CVB3). Mechanistically, we found that deletion of FUS leads to increased viral RNA transcription and enhanced internal ribosome entry site (IRES)-driven translation, with no apparent impact on viral RNA stability. We further demonstrated that FUS physically interacts with the viral genome, which may contribute to direct inhibition of viral RNA transcription/translation. Moreover, we identified a novel function for FUS in regulating host innate immune response. We show that in the absence of FUS, gene expression of type I interferons and proinflammatory cytokines elicited by viral or bacterial infection is significantly impaired. Emerging evidence suggests a role for stress granules (SGs) in antiviral innate immunity. We further reveal that knockout of FUS abolishes the ability to form SGs upon CVB3 infection or poly(I·C) treatment. Finally, we show that, to avoid FUS-mediated antiviral response and innate immunity, CVB3 infection results in cytoplasmic mislocalization and cleavage of FUS through the enzymatic activity of viral proteases. Together, our findings in this study identify FUS as a novel host antiviral factor which restricts CVB3 replication through direct inhibition of viral RNA transcription and protein translation and through regulation of host antiviral innate immunity.IMPORTANCE Enteroviruses are common human pathogens, including those that cause myocarditis (coxsackievirus B3 [CVB3]), poliomyelitis (poliovirus), and hand, foot, and mouth disease (enterovirus 71). Understanding the virus-host interaction is crucial for developing means of treating and preventing diseases caused by these pathogens. In this study, we explored the interplay between the host RNA-binding protein FUS/TLS and CVB3 and found that FUS/TLS restricts CVB3 replication through direct inhibition of viral RNA transcription/translation and through regulation of cellular antiviral innate immunity. To impede the antiviral role of FUS, CVB3 targets FUS for mislocalization and cleavage. Findings from this study provide novel insights into interactions between CVB3 and FUS, which may lead to novel therapeutic interventions against enterovirus-induced diseases.

SIRT4 is the molecular switch mediating cellular proliferation in colorectal cancer through GLS mediated activation of AKT/GSK3ß/CyclinD1 pathway.

Mitochondria-localized sirtuin 4 (SIRT4) is associated with malignant phenotypes in colorectal cancer (CRC). However, the molecular mechanisms that drive SIRT4-mediated carcinogenesis are unclear. Initially, we confirmed expression of SIRT4 in CRC through public database and in CRC patient tissues using quantitative real-time reverse transcription PCR. We established HCT116 colorectal cells that overexpressed SIRT4 and HT29 cells were transfected with plasmids bearing a small interfering RNA construct to silence SIRT4. Assays to determine the malignant phenotypes (proliferation, invasion and migration) were performed. Xenograft in vivo models were also constructed. A protein interactome network was built using differentially expressed proteins identified using the liquid chromatography/tandem mass spectrophotometry, the findings of which were confirmed using co-immunoprecipitation, western blotting and phenotype rescue experiments. Decreased SIRT4 expression was associated with malignant phenotypes in vitro and in vivo. The ribosomal biogenesis pathway was enriched in the interactome network. SIRT4 suppression activated glutaminase, thereby initiating AKT activation. Our research provided novel insights into the molecular mechanisms underlying CRC, and identified that SIRT4 exerts its antitumor activity in CRC possibly dependent on glutaminase to inhibit proliferation, migration and invasion via the AKT/GSK3ß/CyclinD1 pathway.

Enteroviral Infection Leads to Transactive Response DNA-Binding Protein 43 Pathology in Vivo.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that primarily affects motor neurons in the cerebral cortex, brainstem, and spinal cord, leading to progressive paralysis and eventual death. Approximately 95% of all ALS cases are sporadic without known causes. Enteroviruses have been suspected to play a role in ALS because of their ability to target motor neurons and to cause muscle weakness and paralysis. In vitro enteroviral infection results in cytoplasmic aggregation and cleavage of transactive response DNA binding protein-43, a pathologic hallmark of ALS. However, whether enteroviral infection can induce ALS-like pathologies in vivo remains to be characterized. In this study, neonatal BALB/C mice were intracranially inoculated with either a recombinant coxsackievirus B3 expressing enhanced green fluorescent protein or mock-infected for 2, 5, 10, 30, and 90 days. Histologic and immunohistochemical analysis of brain tissues demonstrated sustained inflammation (microglia and astrogliosis) and lesions in multiple regions of the brain (hippocampus, cerebral cortex, striatum, olfactory bulb, and putamen) in parallel with virus detection as early as 2 days for up to 90 days after infection. Most notably, ALS-like pathologies, including cytoplasmic mislocalization of transactive response DNA binding protein-43, p62-, and ubiquitin-positive inclusions, were observed in the areas of infection. These data provide the first pathologic evidence to support a possible link between enteroviral infection and ALS.

[Intervention effects and mechanism of Chinese herbal medicine of supplementing Qi and activating blood circulation on chronic intermittent hypoxia composite insulin resistance ApoE~(-/-) mice model].

This study aims to observe the intervention effects of Chinese herbal medicine of supplementing Qi and activating blood circulation on chronic intermittent hypoxia(CIH) composite insulin resistance(IR) mediated atherosclerosis(AS) mice model,and to observe the mechanism of SREBP-1 c signaling molecule.IR Apo E-/-mice model was induced by high-fat diet combined with STZ injection.Then the mice were treated with hypoxic animal incubator for 8 h per day and 8 weeks to establish a CIH+IR-ApoE-/-mouse model.Model mice were randomly and averagely divided into normoxic control group(NC),model group(CIH) and SREBPs inhibitor group(betulin),atorvastatin group(WM),TCM low-dose group(TCM-L),TCM middle-dose group(TCM-M) and TCM high-dose group(TCM-H) group.Chinese herbal medicine of supplementing Qi and activating blood circulation including ginsenosides combined with ligustrazine(TMP) were used as intervention drugs.The study observed the effect of drugs on IR,serum lipid,inflammation,stress,AS and SREBP-1 c related molecules.The results showed that fasting blood glucose in TCM-H group decreased compared with other experimental groups(P<0.05).HDL-C level in betulin group,WM group,TCM-H group was higher than that in CIH group(P<0.05).LDL-C level in TCM-M group,TCM-H group is lower than that in CIH group(P<0.05).The level of CRP in CIH group was higher than that in other groups(P<0.05).The level of SOD in TCM-H group was higher than that in CIH group(P<0.05).NC group and CIH group showed obvious AS aortic plaque,while betulin group,WM group,TCM-H group showed reduction in AS plaque(P<0.05).For descending aorta,AS plaque in CIH group was multiple and large,while less and smaller in WM group and TCM-H(P<0.05).The expression of SREBP-1 c and FAS in aorta and skeletal muscle in TCM-H group was lower than that in CIH group(P<0.05).In aorta,the expression of TNF-α and CD106(VCAM-1) was lower in TCM-H group than that in CIH group(P<0.05).In aorta,skeletal muscle and liver,the level of p-IRS-1 in TCM-H group was significantly higher than that in CIH group(P<0.05).In aorta and liver,the expression of HIF-1α in TCM-H group was lower than that in CIH group(P<0.05).The study demonstrated that combination ginsenosides with TMP could improve IR and serum lipid level and inhibit inflammation and oxidative stress as well as ultimately alleviate AS to some extent.And the mechanism of its interventional effects might be related to the inhibition of CIH-induced upregulation of SREBP-1 c related molecules.

[Effect of Chinese medicine of nourishing kidney and clearing liver on intermittent hypoxia induced injury model of HUVECs through p38MAPK/NF-κB signaling pathway].

This study aims to explore the intervention effect of Chinese medicine of nourishing kidney and clearing liver on intermittent hypoxia(IH) induced injury model of HUVECs through p38MAPK/NF-κB signaling pathway in vitro. HUVECs injury model was induced by modified IH treatment. The effective components of Chinese medicine of nourishing kidney and clearing liver including isochteroside, aucubin and ligustrazine were used as intervention drugs. The optimal compatibility concentration of them was screened in vitro, and then the optimal compatibility concentration was selected as the intervention dose to observe the effect on p38MAPK/NF-κB signaling pathway in IH induced injury model of HUVECs. The results showed that isochnae, aucubin and ligustrazine had the best anti-inflammatory effect at concentration of 0.01 mg•L-1. NF-κB p65 and p-IκB in the nucleus in IH group were significantly higher than those in the normal control(N) group and the other groups. Immunofluorescence staining showed significant translocation of NF-κB p65 nucleus in IH group, and HUVECs adhesion capacity in IH group was increased significantly. As compared with IH group, the expression levels of p-p38MAPK, NF-κB p65 and p-IκB in p38MAPK inhibitor(INH) group and Chinese medicine of nourishing kidney and clearing liver(GDC) group were significantly decreased, and HUVECs adhesion capacity in INH group and GDC group was significantly inhibited as well. The optimal concentration of Chinese medicine of nourishing kidney and clearing liver can inhibit the phosphorylation of p38MAPK, and then inhibit the nuclear translocation and transcription function of NF-κB. This may be the mechanism of the protective effect of Chinese medicine on IH induced injury model of HUVECs.

Enhanced enteroviral infectivity via viral protease-mediated cleavage of Grb2-associated binder 1.

Coxsackievirus B3 (CVB3), an important human causative pathogen for viral myocarditis, pancreatitis, and meningitis, has evolved different strategies to manipulate the host signaling machinery to ensure successful viral infection. We previously revealed a crucial role for the ERK1/2 signaling pathway in regulating viral infectivity. However, the detail mechanism remains largely unknown. Grb2-associated binder 1 (GAB1) is an important docking protein responsible for intracellular signaling assembly and transduction. In this study, we demonstrated that GAB1 was proteolytically cleaved after CVB3 infection at G175 and G436 by virus-encoded protease 2A(pro), independent of caspase activation. Knockdown of GAB1 resulted in a significant reduction of viral protein expression and virus titers. Moreover, we showed that virus-induced cleavage of GAB1 is beneficial to viral growth as the N-terminal proteolytic product of GAB1 (GAB1-N1-174) further enhances ERK1/2 activation and promotes viral replication. Our results collectively suggest that CVB3 targets host GAB1 to generate a GAB1-N1-174 fragment that enhances viral infectivity, at least in part, via activation of the ERK pathway. The findings in this study suggest a novel mechanism that CVB3 employs to subvert the host signaling and facilitate consequent viral replication.

Dysferlin deficiency confers increased susceptibility to coxsackievirus-induced cardiomyopathy.

Coxsackievirus infection can lead to viral myocarditis and its sequela, dilated cardiomyopathy, which represent major causes of cardiovascular mortality worldwide in children. Yet, the host genetic susceptible factors and the underlying mechanisms by which viral infection damages cardiac function remain to be fully resolved. Dysferlin is a transmembrane protein highly expressed in skeletal and cardiac muscles. In humans, mutations in the dysferlin gene can cause limb-girdle muscular dystrophy type 2B and Miyoshi myopathy. Dysferlin deficiency has also been linked to cardiomyopathy. Defective muscle membrane repair has been suggested to be an important mechanism responsible for muscle degeneration in dysferlin-deficient patients and animals. Using both naturally occurring and genetically engineered dysferlin-deficient mice, we demonstrated that loss of dysferlin confers increased susceptibility to coxsackievirus infection and myocardial damage. More interestingly, we found that dysferlin is cleaved following coxsackieviral infection through the proteolytic activity of virally encoded proteinases, suggesting an important mechanism underlying virus-induced cardiac dysfunction. Our results in this study not only identify dysferlin deficiency as a novel host risk factor for viral myocarditis but also reveal a key mechanism by which coxsackievirus infection impairs cardiac function, leading to the development of dilated cardiomyopathy.

Cytoplasmic redistribution and cleavage of AUF1 during coxsackievirus infection enhance the stability of its viral genome.

Coxsackievirus B3 (CVB3) is a causative agent of viral myocarditis, hepatitis, pancreatitis, and meningitis in humans. The adenosine-uridine (AU)-rich element RNA binding factor 1 (AUF1) is an integral component in the regulation of gene expression. AUF1 destabilizes mRNAs and targets them for degradation by binding to AU-rich elements in the 3' untranslated region (UTR) of mRNAs. The 3'-UTR of the CVB3 genome contains canonical AU-rich sequences, raising the possibility that CVB3 RNA may also be subjected to AUF1-mediated degradation. Here, we reported that CVB3 infection led to cytoplasmic redistribution and cleavage of AUF1. These events are independent of CVB3-induced caspase activation but require viral protein production. Overexpression of viral protease 2A reproduced CVB3-induced cytoplasmic redistribution of AUF1, while in vitro cleavage assay revealed that viral protease 3C contributed to AUF1 cleavage. Furthermore, we showed that knockdown of AUF1 facilitated viral RNA, protein, and progeny production, suggesting an antiviral property for AUF1 against CVB3 infection. Finally, an immunoprecipitation study demonstrated the physical interaction between AUF1 and the 3'-UTR of CVB3, potentially targeting CVB3 genome toward degradation. Together, our results suggest that cleavage of AUF1 may be a strategy employed by CVB3 to enhance the stability of its viral genome.

Synergistic Viro-chemoimmunotherapy in Breast Cancer Enabled by Bioengineered Immunostimulatory Exosomes and Dual-Targeted Coxsackievirus B3.

Breast cancer's immunosuppressive environment hinders effective immunotherapy, but oncolytic viruses hold promise for addressing this challenge by targeting tumor cells and altering the microenvironment. Yet, neutralizing antibodies and immune clearance impede their clinical utility. This study explored microRNA-modified coxsackievirus B3 (miR-CVB3), an innovative oncolytic virus, and its potential in breast cancer treatment. It investigated miR-CVB3's impact on immune-related proteins and utilized exosomes as both protective shields and delivery carriers. Results demonstrated miR-CVB3's capacity to reshape immune-related protein profiles toward a more immunostimulatory state and enhance exosome-mediated immune cell activation. Notably, cancer cell-released exosomes encapsulating miR-CVB3 (ExomiR-CVB3) maintained its antitumor cytotoxicity and bolstered its immunostimulatory effects. Moreover, ExomiR-CVB3 shielded miR-CVB3 from neutralizing antibodies and rapid immune clearance when it was systemically administered. Building on these findings, ExomiR-CVB3 was engineered with the AS1411 aptamer and doxorubicin (ExomiR-CVB3/DoxApt), enhancing therapeutic efficacy. This notable approach, combining genomic modification, aptamer surface decoration, and doxorubicin addition, demonstrated safe delivery of CVB3 to cancer cells. Comprehensive in vitro and in vivo analyses revealed selective breast cancer cell targeting, cell death induction, and significant immune cell infiltration within the tumor microenvironment while sparing healthy organs. In summary, this study highlights ExomiR-CVB3/DoxApt as a pioneering breast cancer treatment strategy adaptable for diverse cancer types, offering a potent and versatile approach to reshaping cancer immunotherapy.

Connecting atrial fibrillation to digestive neoplasms: exploring mediation via ischemic stroke and heart failure in Mendelian randomization studies.

Background: Notwithstanding the acknowledged interplay between atrial fibrillation (AF) and the emergence of digestive system neoplasms, the intricacies of this relationship remain ambiguous. By capitalizing univariable Mendelian Randomization (MR) complemented by a mediated MR tactic, our pursuit was to elucidate the causative roles of AF in precipitating digestive system malignancies and potential intermediary pathways. Method: This research endeavor seeks to scrutinize the causal clinical implications of whether genetic predispositions to AF correlate with an increased risk of digestive system malignancies, employing MR analytical techniques. Utilizing a dataset amalgamated from six studies related to AF, encompassing over 1,000,000 subjects, we performed univariable MR assessments, employing the random-effects inverse-variance weighted (IVW) methodology as our principal analytical paradigm. Subsequently, a mediated MR framework was employed to probe the potential mediating influence of AF on the nexus between hypertension (HT), heart failure (HF), ischemic stroke (IS), coronary artery disease (CAD), and digestive system neoplasms. Result: The univariable MR evaluation unveiled a notable causal nexus between the genetic inclination toward AF and the genetic susceptibility to colon, esophageal, and small intestine malignancies. The mediated MR scrutiny ascertained that the genetic inclination for AF amplifies the risk profile for colon cancer via IS pathways and partially explains the susceptibility to esophageal and small intestine tumors through the HF pathway. Conclusion: Our investigative endeavor has highlighted a definitive causative association between genetic inclination to AF and specific digestive system neoplasms, spotlighting IS and HF as instrumental mediators. Such revelations furnish pivotal perspectives on the complex genetic interconnections between cardiovascular anomalies and certain digestive tract tumors, emphasizing prospective therapeutic and diagnostic worthy of pursuit.

Phase inversion of emulsions containing a lipophilic surfactant induced by clay concentration.

Emulsions stabilized by clay particles and sorbitan monooleate (Span 80) were investigated, and an abnormal phase inversion was observed by increasing the concentration of clay particles in the aqueous phase. At a fixed concentration of Span 80 in the oil phase, the emulsions were oil-in-water (o/w) when the concentration of clay particles in the aqueous phase was low. Surprisingly, the emulsion inverted to water-in-oil (w/o) when the concentration of the hydrophilic clay particles was increased. On the basis of the results of rheological measurements and laser-induced fluorescent confocal microscopy observation, we suggest that this phase inversion is induced by the gel structures formed at high concentration of clay particles. The effects of clay concentration on the stability and the droplet size of these emulsions were also investigated.

[Fluctuant hypertension and platelet activation: current situations and control strategies with integrative medicine].

In recent years a huge amount of clinical studies have proved that fluctuant hypertension could aggravate the damage of target organs and increase the incidence of acute cardio-/cerebrovascular events, when compared with stable hypertension [increased mean artery blood pressure (MBP)]. How to prevent and treat fluctuant hypertension and its damage of target organs has become one of the hot and difficult problems in the field of hypertension studies all over the world. Hypertensive patients often suffer from thromboembolic target organ damage. Platelet activation plays a key role in this progress, but its concrete mechanisms have not been clearly clarified. Based on the in-depth discussions on progress of fluctuant hypertension, its relationship with platelet activation and blood stasis syndrome of Chinese medicine (CM) in recent three years, we proposed, under the fluctuant hypertensive state, the prethrombotic state has occurred in the organisms, i.e., a pathological state featured by platelet activation, liable to have vulnerable thrombopoiesis, and accompanied by endothelial dysfunction. Blood stasis syndrome might occupy an important position in CM syndrome typing of fluctuant hypertension. Herbs for activating blood circulation and removing stasis might have an extensive application prospect.

Engineering a facile and versatile nanoplatform to facilitate the delivery of multiple agents for targeted breast cancer chemo-immunotherapy.

There is growing evidence showing that single administration of immunotherapeutic agents has limited efficacy in a number of cancer patients mainly due to tumor heterogeneity and immunosuppressive tumor microenvironment. In this study, a novel nanoparticle-based strategy was applied to achieve efficient tumor-targeted therapy by combining chemotherapeutic agents, i.e., doxorubicin (Dox) and melittin (Mel), with an immune checkpoint inhibitor (PD-L1 DsiRNA). The proposed nanoparticle was prepared by the formation of a complex between Mel and PD-L1 DsiRNA (Dicer-substrate short-interfering RNA), followed by the loading of Dox. The surface of the resultant particles (DoxMel/PD-L1 DsiRNA) was then modified with hyaluronic acid (HA) to increase their stability and distribution. In addition, HA can also act as a tumor-targeting agent through binding to its receptor CD44 on the surface of cancer cells. We demonstrated that the surface engineering of DoxMel/PD-L1 DsiRNA with HA significantly enhances its specificity towards breast cancer cells. Moreover, we observed a noticeable reduction in PD-L1 expression together with a synergistic effect of Dox and Mel on killing cancer cells and inducing immunogenic cell death, leading to significantly diminished tumor growth in 4T1-breast tumor bearing Balb/c mice, improved survival rate and extensive infiltration of immune cells including cytotoxic T cells into the tumor microenvironment. Safety analysis revealed that there is no significant toxicity associated with the developed nanoparticle. All in all, the proposed targeted combination treatment strategy can be considered as a useful method to reduce cancer-associated mortality.

The causal relationship between sarcopenic obesity factors and benign prostate hyperplasia.

Background: Both benign prostatic hyperplasia (BPH) and sarcopenic obesity (SO) are common conditions among older adult/adults males. The prevalent lifestyle associated with SO is a significant risk factor for the development of BPH. Therefore, we investigated the causal relationship between SO factors and BPH. Method: The instrumental variables for SO factors were selected using the inverse variance-weighted method, which served as the primary approach for Mendelian randomization analysis to assess the causal effect based on summary data derived from genome-wide association studies of BPH. Result: The increase in BMR (OR = 1.248; 95% CI = (1.087, 1.432); P = 0.002) and ALM (OR = 1.126; 95% CI = (1.032, 1.228); P = 0.008) was found to be associated with an elevated risk of BPH. However, no genetic causality between fat-free mass distribution, muscle mass distribution, and BPH was observed. Conclusion: Our findings indicate that a genetic causal association between BMR, ALM and BPH. BMR and ALM are risk factors for BPH. The decrease in BMR and ALM signified the onset and progression of SO, thus SO is a protective factor for BPH.

Citalopram in the treatment of elderly chronic heart failure combined with depression: A systematic review and meta-analysis.

Background: Depression is an independent factor to predict the hospitalization and mortality in the chronic HF patients. Citalopram is known as an effective drug for depression treatment. Currently, there is no specific recommendation in the HF guidelines for the treatment of psychological comorbidity. In recent years, many studies have shown that the citalopram may be safe in treating of chronic HF with depression. Objective: To evaluate the efficacy and safety of the citalopram in the treatment of elderly chronic HF combined with depression. Methods: PubMed, EMBASE, Cochrane, Web of Science, CNKI, VIP, CBM, and Wanfang were searched from their inception to May 2022. In the treatment of elderly chronic HF combined with depression, randomized controlled studies of the citalopram were included. Independent screening and extraction of data information were conducted by two researchers, and the quality was assessed by the Cochrane bias risk assessment tool. Review manager 5.4.1 was employed for statistical analysis. Results: The results of meta-analysis prove that the citalopram treatment for depressed patients with chronic HF has a benefit for HAMD-24 (MD: -8.51, 95% CI: -10.15 to -6.88) and LVEF (MD: 2.42, 95% CI: 0.51 to 4.33). Moreover, the score of GDS decreases, and NT-proBNP (MD: -537.78, 95% CI: -718.03 to -357.54) is improved. However, the comparison with the control group indicates that there is no good effect on HAMD-17 (MD: -5.14, 95% CI: -11.60 to 1.32), MADRS (MD: -1.57, 95% CI: -3.47 to 0.32) and LVEDD (MD: -1.45, 95% CI: -3.65 to -0.76). No obvious adverse drug reactions were observed. Conclusion: Citalopram treatment for depressed patients with chronic HF has a positive effect on LVEF and NT-proBNP. It can alleviate HAMD-24 and GDS, but the relative benefits for LVEDD, HAMD-17 and MADRS still need to be verified.Systematic Review Registration: PROSPERO [CRD42021289917].

The relationship between atrial fibrillation and NLRP3 inflammasome: a gut microbiota perspective.

Atrial fibrillation (AF) is a common clinical arrhythmia whose pathogenesis has not been fully elucidated, and the inflammatory response plays an important role in the development of AF. The inflammasome is an important component of innate immunity and is involved in a variety of pathophysiologic processes. The NLRP3 inflammasome is by far the best studied and validated inflammasome that recognizes multiple pathogens through pattern recognition receptors of innate immunity and mediates inflammatory responses through activation of Caspase-1. Several studies have shown that NLRP3 inflammasome activation contributes to the onset and development of AF. Ecological dysregulation of the gut microbiota has been associated with the development of AF, and some evidence suggests that gut microbiota components, functional byproducts, or metabolites may induce or exacerbate the development of AF by directly or indirectly modulating the NLRP3 inflammasome. In this review, we report on the interconnection of NLRP3 inflammasomes and gut microbiota and whether this association is related to the onset and persistence of AF. We discuss the potential value of pharmacological and dietary induction in the management of AF in the context of the association between the NLRP3 inflammasome and gut microbiota. It is hoped that this review will lead to new therapeutic targets for the future management of AF.

Dose-dependent effects of GAT107, a novel allosteric agonist-positive allosteric modulator (ago-PAM) for the α7 nicotinic cholinergic receptor: a BOLD phMRI and connectivity study on awake rats.

Background: Alpha 7 nicotinic acetylcholine receptor (α7nAChR) agonists have been developed to treat schizophrenia but failed in clinical trials due to rapid desensitization. GAT107, a type 2 allosteric agonist-positive allosteric modulator (ago-PAM) to the α7 nAChR was designed to activate the α7 nAChR while reducing desensitization. We hypothesized GAT107 would alter the activity of thalamocortical neural circuitry associated with cognition, emotion, and sensory perception. Methods: The present study used pharmacological magnetic resonance imaging (phMRI) to evaluate the dose-dependent effect of GAT107 on brain activity in awake male rats. Rats were given a vehicle or one of three different doses of GAT107 (1, 3, and 10 mg/kg) during a 35 min scanning session. Changes in BOLD signal and resting state functional connectivity were evaluated and analyzed using a rat 3D MRI atlas with 173 brain areas. Results: GAT107 presented with an inverted-U dose response curve with the 3 mg/kg dose having the greatest effect on the positive BOLD volume of activation. The primary somatosensory cortex, prefrontal cortex, thalamus, and basal ganglia, particularly areas with efferent connections from the midbrain dopaminergic system were activated as compared to vehicle. The hippocampus, hypothalamus, amygdala, brainstem, and cerebellum showed little activation. Forty-five min post treatment with GAT107, data for resting state functional connectivity were acquired and showed a global decrease in connectivity as compared to vehicle. Discussion: GAT107 activated specific brain regions involved in cognitive control, motivation, and sensory perception using a BOLD provocation imaging protocol. However, when analyzed for resting state functional connectivity there was an inexplicable, general decrease in connectivity across all brain areas.

Double inversion of emulsions induced by salt concentration.

The effects of salt on emulsions containing sorbitan oleate (Span 80) and Laponite particles were investigated. Surprisingly, a novel double phase inversion was induced by simply changing the salt concentration. At fixed concentration of Laponite particles in the aqueous phase and surfactant in paraffin oil, emulsions are oil in water (o/w) when the concentration of NaCl is lower than 5 mM. Emulsions of water in oil (w/o) are obtained when the NaCl concentration is between 5 and 20 mM. Then the emulsions invert to o/w when the salt concentration is higher than 50 mM. In this process, different emulsifiers dominate the composition of the interfacial layer, and the emulsion type is correspondingly controlled. When the salt concentration is low in the aqueous dispersion of Laponite, the particles are discrete and can move to the interface freely. Therefore, the emulsions are stabilized by particles and surfactant, and the type is o/w as particles are in domination. At intermediate salt concentrations, the aqueous dispersions of Laponite are gel-like, the viscosity is high, and the transition of the particles from the aqueous phase to the interface is inhibited. The emulsions are stabilized mainly by lipophilic surfactant, and w/o emulsions are obtained. For high salt concentration, flocculation occurs and the viscosity of the dispersion is reduced; thus, the adsorption of particles is promoted and the type of emulsions inverts to o/w. Laser-induced fluorescent confocal micrographs and cryo transmission electron microscopy clearly confirm the adsorption of Laponite particles on the surface of o/w emulsion droplets, whereas the accumulation of particles at the w/o emulsion droplet surfaces was not observed. This mechanism is also supported by the results of rheology and interfacial tension measurements.

Current prices versus minimum costs of production for CFTR modulators.

BACKGROUND: While the clinical benefits of CFTR modulators are clear, their high prices render them inaccessible outside of the world's richest countries. Despite this, there is currently limited evidence regarding global access to these transformative therapies. Therefore, this study aims to estimate the minimum costs of production of CFTR modulators, assuming robust generic competition, and to compare them with current list prices to evaluate the feasibility of increased global access to treatment. METHODS: Minimum costs of production for CFTR modulators were estimated via an algorithm validated in previous literature and identification of cost-limiting key starting materials from published routes of chemical synthesis. This algorithm utilised per kilogram active pharmaceutical ingredient costs obtained from global import/export data. Estimated production costs were compared with published list prices in a range of countries. RESULTS: Costs of production for elexacaftor/tezacaftor/ivacaftor are estimated at $5,676 [$4,628-6,723] per year, over 90% lower than the US list price. Analysis of chemical structure and published synthetic pathways for elexacaftor/tezacaftor/ivacaftor revealed relatively straightforward routes of synthesis related to currently available products. Total cost of triple therapy for all eligible diagnosed CF patients worldwide would be $489 million per year. Comparatively, the annual cost at US list price would be $31.2 billion. CONCLUSIONS: Elexacaftor/tezacaftor/ivacaftor could be produced via generic companies for a fraction of the list price. The current pricing model restricts access to the best available therapy, thereby exacerbating existing inequalities in CF care. Urgent action is needed to increase the availability of triple combination treatment worldwide. One strategy based on previous success is originator-issued voluntary licenses.