S100A9+CD14+ monocytes contribute to anti-PD-1 immunotherapy resistance in advanced hepatocellular carcinoma by attenuating T cell-mediated antitumor function.

BACKGROUND: The paucity of reliable biomarkers for predicting immunotherapy efficacy in patients with advanced hepatocellular carcinoma (HCC) has emerged as a burgeoning concern with the expanding use of immunotherapy. This study endeavors to delve into the potential peripheral biomarkers capable of prognosticating efficacy in HCC patients who are poised to receive anti-PD-1 monotherapy within the phase III clinical trial, KEYNOTE394. Additionally, we sought to elucidate the underlying molecular mechanisms for resistance to immune checkpoint blockade (ICB) and propose innovative combination immunotherapy strategies for future clinical application. METHODS: Patient blood samples were collected for single-cell RNA sequencing to evaluate the immune cell signature before receiving ICB therapy. Subsequently, in vitro assays and in vivo murine model experiments were conducted to validate the mechanism that S100A9+CD14+ monocytes play a role in ICB resistance. RESULTS: Our study demonstrates a notable enrichment of S100A9+CD14+ monocytes in the peripheral blood of patients exhibiting suboptimal responses to anti-PD-1 therapy. Moreover, we identified the Mono_S100A9 signature as a predictive biomarker, indicative of reduced efficacy in immunotherapy and decreased survival benefits across various tumor types. Mechanistically, S100A9 activates PD-L1 transcription by directly binding to the CD274 (PD-L1) gene promoter, thereby suppressing T-cell proliferation and cytotoxicity via the PD-1/PD-L1 axis, consequently diminishing the therapeutic effectiveness of subsequent anti-PD-1 treatments. Furthermore, our in vivo studies revealed that inhibiting S100A9 can synergistically enhance the efficacy of anti-PD-1 drugs in the eradication of hepatocellular carcinoma. CONCLUSIONS: Our study underscores the significance of S100A9+CD14+ monocytes in predicting inadequate response to ICB treatment and provides insights into the monocyte cell-intrinsic mechanisms of resistance to ICB therapy. We also propose a combined therapeutic approach to enhance ICB efficacy by targeting S100A9.

Identification of potential drug targets for vascular dementia and carotid plaques by analyzing underlying molecular signatures shared by them.

Background: Vascular dementia (VaD) and carotid atherosclerotic plaques are common in the elderly population, conferring a heavy burden on families and society. Accumulating evidence indicates carotid atherosclerotic plaques to be a risk factor for VaD. However, the underlying mechanisms for this association are mainly unknown. Materials and methods: We analyzed temporal cortex gene expression data of the GSE122063 dataset and gene expression data of the GSE163154 dataset to identify commonly differentially expressed genes (DEGs). Then we performed functional enrichment analysis, immune cell infiltration and evaluation, correlation analysis between differentially expressed immune-related genes (DEIRGs) and immune cells, receiver operating characteristic (ROC) analysis, and drug-gene analysis. Results: We identified 41 overlapped DEGs between the VaD and carotid atherosclerosis plaque datasets. Functional enrichment analyses revealed that these overlapped DEGs were mainly enriched in inflammatory and immune-related processes. Immunocyte infiltration and evaluation results showed that M0 macrophages, M2 macrophages, and T cells gamma delta had a dominant abundance in carotid atherosclerosis plaque samples, and M0 macrophages showed a significantly different infiltration percentage between the early and advanced stage plaques group. Resting CD4 memory T cells, M2 macrophages, and naive B cells were the top three highest infiltrating fractions in VaD. Furthermore, B cells and NK cells showed a different infiltration percentage between VaD and matched controls. We identified 12 DEIRGs, and the result of correlation analysis revealed that these DEIRGs were closely related to differentially expressed immune cells. We identified five key DEIRGs based on ROC analysis. The drug-gene interaction analysis showed that four drugs (avacopan, CCX354, BMS-817399, and ASK-8007) could be potential drugs for VaD and carotid atherosclerotic plaques treatment. Conclusion: Collectively, these findings indicated that inflammatory and immune-related processes be a crucial common pathophysiological mechanism shared by VaD and carotid plaques. This study might provide new insights into common molecular mechanisms between VaD and carotid plaques and potential targets for the treatment.

Identification of zebrafish PLEKHF2 presents in egg/embryos as an antibacterial protein.

PLEKHF2 proteins are widespread in animals, but their functions and mechanisms remain poorly defined. Here we clearly demonstrate that PLEKHF2 is a newly identified present abundantly in the eggs/embryos of zebrafish. We also show that recombinant PLEKHF2 acts as a pattern recognition receptor capable of identifying the bacterial signature molecule PGN, LPS, and LTA, binding the bacteria, and functions as an antibacterial effector directly killing the bacteria. In brief, these results indicate that PLEKHF2 is an antibacterial protein, a novel role assigned to PLEKHF2 proteins.

Therapeutic application of GLP-1 and GIP receptor agonists in Parkinson's disease.

INTRODUCTION: Diabetes is a risk factor for Parkinson's disease (PD) and shares similar dysregulated insulin pathways. Glucagon-like peptide-1 (GLP-1) analogs originally designed to treat diabetes have shown potent neuroprotective activity in preclinical studies of PD. They are neuroprotective by inhibiting inflammation, improving neuronal survival, maintenance of synapses, and dopaminergic transmission in the brain. Building on this, three clinical studies have reported impressive effects in patients with PD, testing -4 (Exenatide, Bydureon) or liraglutide (Victoza, Saxenda). Glucose-dependent insulinotropic peptide (GIP) is another peptide hormone that has shown good effects in animal models of PD. Novel dual GLP-1/GIP agonists have been developed that can penetrate the blood-brain barrier (BBB) and show superior effects in animal models compared to GLP-1 drugs. AREAS COVERED: The review summarizes preclinical and clinical studies testing GLP-1R agonists and dual GLP-1/GIPR agonists in PD and discusses possible mechanisms of action. EXPERT OPINION: Current strategies to treat PD by lowering the levels of alpha-synuclein have not shown effects in clinical trials. It is time to move on from the 'misfolding protein' hypothesis. Growth factors such as GLP-1 that can cross the BBB have already shown impressive effects in patients and are the future of drug discovery in PD.

Association Between Stroke Characteristics and Post-Stroke Fatigue: A Meta-Analysis.

Background: Post-stroke fatigue (PSF), a highly distressing symptom, could exert an influence on the quality of life of stroke survivors. A previous meta-analysis reported that PSF was associated with mood disturbances such as depressive symptoms and anxiety. However, the association between stroke characteristics (stroke type and location) and PSF remains unclear. Objective: We performed a meta-analysis to study the association between stroke characteristics and PSF. Material and Methods: We conducted a search of electronic databases (PubMed, Web of Science, Cochrane Library) from the inception of all databases up to July 9, 2019. The quality of eligible articles was evaluated. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were applied to represent the combined effect value of each study. Results: Eight eligible studies including a total of 1816 stoke patients were identified. Three studies discussed the association between stroke type and PSF, and five studies investigated the relationship between stroke location and PSF. The results demonstrated PSF had a strong correlation with stroke type (OR = 2.42, 95% CI = [1.27, 4.61], P = 0.007) but was not relevant to stroke location, indicating that PSF was a complex, heterogeneous syndrome and that stroke characteristics may play only a very small role in the risk of developing PSF. Conclusions: Our meta-analysis indicated that PSF was closely relevant to stroke type and had no significant relationship with stroke location. However, the findings should be interpreted cautiously. Thus, we suggest an updated meta-analysis on this subject when more comprehensive studies that explore the above issue are available.

Aberrant Topological Patterns of Structural Covariance Networks in Cognitively Normal Elderly Adults With Mild Behavioral Impairment.

Mild behavioral impairment (MBI), characterized by the late-life onset of sustained and meaningful neuropsychiatric symptoms, is increasingly recognized as a prodromal stage of dementia. However, the underlying neural mechanisms of MBI remain unclear. Here, we examined alterations in the topological organization of the structural covariance networks of patients with MBI (N = 32) compared with normal controls (N = 38). We found that the gray matter structural covariance networks of both the patients with MBI and controls exhibited a small-world topology evidenced by sigma value larger than one. The patients with MBI had significantly decreased clustering coefficients at several network densities and local efficiency at densities ranging from 0.05 to 0.26, indicating decreased local segregation. No significant differences in the characteristic path length, gamma value, sigma value, or global efficiency were detected. Locally, the patients with MBI showed significantly decreased nodal betweenness centrality in the left middle frontal gyrus, right inferior frontal gyrus (opercular part), and left Heschl gyrus and increased betweenness centrality in the left gyrus rectus, right insula, bilateral precuneus, and left thalamus. Moreover, the difference in the bilateral precuneus survived after correcting for multiple comparisons. In addition, a different number and distribution of hubs was identified in patients with MBI, showing more paralimbic hubs than observed in the normal controls. In conclusion, we revealed abnormal topological patterns of the structural covariance networks in patients with MBI and offer new insights into the network dysfunctional mechanisms of MBI.

Distinct Patterns of Brain Atrophy associated with Mild Behavioral Impairment in Cognitively Normal Elderly Adults.

A cross-sectional study was conducted to evaluate patterns of gray matter changes in cognitively normal elderly adults with mild behavioral impairment (MBI). Sixteen MBI patients and 18 healthy controls were selected. All the participants underwent a neuropsychological assessment battery, including the Mini-mental State Examination (MMSE), Geriatric Depression Scale (GDS), Self-rating Anxiety Scale (SAS), and Chinese version of the mild behavioral impairment-checklist scale (MBI-C), and magnetic resonance imaging (MRI) scans. Imaging data was analyzed based on voxel-based morphometry (VBM). There was no significant difference in age, gender, MMSE score, total intracranial volume, white matter hyperdensity, gray matter volume, white matter volume between the two groups (p > 0.05). MBI group had shorter education years and higher MBI-C score, GDS and SAS scores than the normal control group (p < 0.05). For neuroimaging analysis, compared to the normal control group, the MBI group showed decreased volume in the left brainstem, right temporal transverse gyrus, left superior temporal gyrus, left inferior temporal gyrus, left middle temporal gyrus, right occipital pole, right thalamus, left precentral gyrus and left middle frontal gyrus(uncorrected p < 0.001). The grey matter regions correlated with the MBI-C score included the left postcentral gyrus, right exterior cerebellum, and left superior frontal gyrus. This suggests a link between MBI and decreased grey matter volume in cognitively normal elderly adults. Atrophy in the left frontal cortex and right thalamus in MBI patients is in line with frontal-subcortical circuit deficits, which have been linked to neuropsychiatric symptoms (NPS) in dementia. These initial results imply that MBI might be an early harbinger for subsequent cognitive decline and dementia.

40S ribosomal protein S18 is a novel maternal peptidoglycan-binding protein that protects embryos of zebrafish from bacterial infections.

Previous studies have shown that ribosomal proteins play important roles in ribosome assembly and protein translation, but other biological functions remain ill-defined. Here it is clearly demonstrated that RPS18 is a newly identified PGN-binding protein which is present abundantly in the eggs/embryos of zebrafish. Recombinant RPS18 not only identifies the bacterial signature molecule PGN, LPS, and LTA, and binds the bacteria as a pattern recognition receptor, but also kills the Gram-positive and Gram-negative bacteria as an antibacterial effector molecule. What is important is that, we reveal that microinjection of rRPS18 into early embryos significantly improved the resistance of the embryos against pathogenic Aeromonas hydrophila challenge, and co-injection of anti-RPS18 antibody could markedly reduced this improved bacterial resistance. In summary, these results indicate that RPS18 is a maternal immune factor that can protect the early embryos of zebrafish against pathogenic attacks. This work also provides another angle for understanding the biological functions of ribosomal proteins.

Identification of the 14-3-3 ß/α-A protein as a novel maternal peptidoglycan-binding protein that protects embryos of zebrafish against bacterial infections.

14-3-3 proteins are widespread in animals, but their functions and mechanisms remain poorly defined. Here we clearly demonstrate that 14-3-3 ß/α-A is a newly identified PGN-binding protein present abundantly in the eggs/embryos of zebrafish. We also show that recombinant 14-3-3 ß/α-A acts as a pattern recognition receptor capable of identifying the bacterial signature molecule PGN, binding the bacteria, and functions as an antibacterial effector molecule directly killing the bacteria. Importantly, microinjection of r14-3-3 ß/α-A into early embryos significantly enhanced the resistance of the embryos against pathogenic A. hydrophila challenge, and this enhanced bacterial resistance was markedly reduced by co-injection of anti-14-3-3 ß/α-A antibody. Collectively, these results indicate that 14-3-3 ß/α-A is a maternal PGN-binding protein that can protect the early embryos of zebrafish against pathogenic attacks, a novel role assigned to 14-3-3 ß/α-A proteins. This work also provides new insights into 14-3-3 proteins that are widely distributed in various animals.

Effects of late-onset dietary intake of salidroside on insulin/insulin-like growth factor-1 (IGF-1) signaling pathway of the annual fish Nothobranchius guentheri.

Salidroside (SDS) is the main active ingredient of Rhodiola which has many biological functions including anti-fatigue, anti-tumor, and immune regulation activities. Our last paper demonstrated that SDS prolonged longevity of the annual fish Nothobranchius guentheri, a promising vertebrate model for anti-aging research. However, little is known about its effect on insulin/insulin-like growth factor-1 (IGF-1) signaling pathway (IIS pathway). In this study, we show that SDS is able to decrease accumulation of SA-ß-Gal. We also show that SDS administraton could reduce the expression levels of Igf-1 and Igf-1R, downregulate the expressions of p-PI3K and p-Akt and upregulate the expression levels of Sirt1 and Foxo3a, both of which are the downstream regulators of the IIS pathway. We also find that SDS could alleviate DNA damage, which could result in increased expression of transcription factor Foxo3a. Collectively, these data indicate that SDS may take part in the IIS pathway.

Gedunin Degrades Aggregates of Mutant Huntingtin Protein and Intranuclear Inclusions via the Proteasomal Pathway in Neurons and Fibroblasts from Patients with Huntington's Disease.

Huntington's disease (HD) is a deadly neurodegenerative disease with abnormal expansion of CAG repeats in the huntingtin gene. Mutant Huntingtin protein (mHTT) forms abnormal aggregates and intranuclear inclusions in specific neurons, resulting in cell death. Here, we tested the ability of a natural heat-shock protein 90 inhibitor, Gedunin, to degrade transfected mHTT in Neuro-2a cells and endogenous mHTT aggregates and intranuclear inclusions in both fibroblasts from HD patients and neurons derived from induced pluripotent stem cells from patients. Our data showed that Gedunin treatment degraded transfected mHTT in Neuro-2a cells, endogenous mHTT aggregates and intranuclear inclusions in fibroblasts from HD patients, and in neurons derived from induced pluripotent stem cells from patients in a dose- and time-dependent manner, and its activity depended on the proteasomal pathway rather than the autophagy route. These findings also showed that although Gedunin degraded abnormal mHTT aggregates and intranuclear inclusions in cells from HD patient, it did not affect normal cells, thus providing a new perspective for using Gedunin to treat HD.

Minocycline attenuates the development of diabetic neuropathy by inhibiting spinal cord Notch signaling in rat.

We studied the effects of minocycline (an inhibitor of microglial activation) on the expression and activity of Notch-1 receptor, and explored the therapeutic efficacy of minocycline combined with Notch inhibitor DAPT in the treatment of diabetic neuropathic pain (DNP). Diabetic rat model was established by intraperitoneal injection (ip) of Streptozotocin (STZ). Expression and activity of Notch-1 and expression of macrophage/microglia marker Iba-1 were detected by WB. Diabetes induction significantly attenuated sciatic nerve conduction velocity, and dramatically augmented the expression and the activity of Notch-1 in the lumbar enlargement of the spinal cord. Minocycline treatment, however, accelerated the decreased conduction velocity of sciatic nerve and suppressed Notch-1expression and activity in diabetic rats. Similar to DAPT treatment, minocycline administration also prolonged thermal withdrawal latency (TWL) and increase mechanical withdrawal threshold (MWT) in diabetic rats in response to heat or mechanical stimulation via inhibition the expression and the activity of Notch-1 in spinal cord. Combination of DAPT and minocycline further inhibited Notch-1 receptor signaling and reduce neuropathic pain exhibited as improved TWL and MWT. Our study revealed a novel mechanism of Notch-1 receptor inhibition in spinal cord induced by minocycline administration, and suggested that the combination of minocycline and DAPT has the potential to treat DNP.

NOD2 mediates isoflurane preconditioning-induced protection of myocardial injury.

Anesthetic cardioprotection reduces myocardial infarct size following ischemia-reperfusion injury. However, the underlying mechanisms that drive ischemia-reperfusion injury in cardiomyocytes remain unclear. In this study, we report that isoflurane, a commonly used inhaled anesthetic, can protect cardiomyocytes from anoxia/reoxygenation injury by a nucleotide binding oligomerization domain containing 2 (NOD2)-dependent mechanism. The results showed that isoflurane increased cell viability, and decreased autophagosome generation in primary cardiomyocytes under anoxia/reoxygenation conditions. In addition, western blot revealed that isoflurane reduces the expression of NOD2. Overexpression of NOD2 is accompanied by an increased expression of autophagy-related genes, decreased cell viability, and enhanced expression of phosphorylation p38-mitogen-activated protein kinase (p38MAPK), while NOD2 knockdown exerted the opposite effect. Following preconditioning with SB203580, a p38MAPK inhibitor, the inhibitory effect of isoflurane on cardiomyocytes autophagy was further enhanced, which suggests that p38MAPK is involved in the mechanism of cardioprotection provided by isoflurane. These findings reveal a novel mechanism underlying isoflurane-afford protection of myocardial injury.

Propofol inhibits the growth and survival of gastric cancer cells in vitro through the upregulation of ING3.

Propofol is one of the most extensively used intravenous anesthetic agents and it can influence the biological behavior of gastric cancer. However, the underlying mechanism is poorly understood. In the present study, we found that propofol significantly inhibited cell proliferation, invasion and migration, and also promoted apoptosis in gastric carcinoma cell lines SGC-7901 and MGC-803, as detected using MTT, colony formation and flow cytometry assays, respectively. Moreover, propofol (10 and 20 µM) markedly upregulated the expression of inhibitor of growth 3 (ING3), which was lower in SGC-7901 and MGC-803 cells compared with that noted in normal human gastric epithelial cell lines GES-1 and HFE145. Furthermore, we transfected SGC-7901 and MGC-803 cells with ING3 overexpression vectors or ING3 small interference RNA (siING3), respectively, to assess the role of ING3 in propofol-induced antitumor activity. The siING3 transfection reversed the effects of propofol on the biological behavior of gastric cancer cells, while transfection of ING3 promoted the effects of propofol. In conclusion, our results indicate that propofol exerts an inhibitory effect on the growth and survival of gastric cancer cells by interfering with ING3 degradation.