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Neuron Apr 2022Chronic stress is a major risk factor for depression onset. However, it remains unclear how repeated stress sculpts neural circuits and finally elicits depression. Given...
Chronic stress is a major risk factor for depression onset. However, it remains unclear how repeated stress sculpts neural circuits and finally elicits depression. Given the essential role of lateral habenula (LHb) in depression, here, we attempt to clarify how LHb-centric neural circuitry integrates stress-related information. We identify lateral hypothalamus (LH) as the most physiologically relevant input to LHb under stress. LH neurons fire with a unique pattern that efficiently drives postsynaptic potential summation and a closely followed LHb bursting (EPSP-burst pairing) in response to various stressors. We found that LH-LHb synaptic potentiation is determinant in stress-induced depression. Mimicking this repeated EPSP-burst pairings at LH-LHb synapses by photostimulation, we artificially induced an "emotional status" merely by potentiating this pathway in mice. Collectively, these results delineate the spatiotemporal dynamics of chronic stress processing from forebrain onto LHb in a pathway-, cell-type-, and pattern-specific manner, shedding light on early interventions before depression onset.
Topics: Animals; Depression; Habenula; Hypothalamic Area, Lateral; Hypothalamus; Mice; Synapses
PubMed: 35114101
DOI: 10.1016/j.neuron.2022.01.011 -
Blood Nov 2022Studies have shown significantly increased thromboembolic events at high altitude. We recently reported that transferrin could potentiate blood coagulation, but the...
Studies have shown significantly increased thromboembolic events at high altitude. We recently reported that transferrin could potentiate blood coagulation, but the underlying mechanism for high altitude-related thromboembolism is still poorly understood. Here, we examined the activity and concentration of plasma coagulation factors and transferrin in plasma collected from long-term human residents and short-stay mice exposed to varying altitudes. We found that the activities of thrombin and factor XIIa (FXIIa) along with the concentrations of transferrin were significantly increased in the plasma of humans and mice at high altitudes. Furthermore, both hypoxia (6% O2) and low temperature (0°C), 2 critical high-altitude factors, enhanced hypoxia-inducible factor 1α (HIF-1α) levels to promote the expression of the transferrin gene, whose enhancer region contains HIF-1α binding site, and consequently, to induce hypercoagulability by potentiating thrombin and FXIIa. Importantly, thromboembolic disorders and pathological insults in mouse models induced by both hypoxia and low temperature were ameliorated by transferrin interferences, including transferrin antibody treatment, transferrin downregulation, and the administration of our designed peptides that inhibit the potentiation of transferrin on thrombin and FXIIa. Thus, low temperature and hypoxia upregulated transferrin expression-promoted hypercoagulability. Our data suggest that targeting the transferrin-coagulation pathway is a novel and potentially powerful strategy against thromboembolic events caused by harmful environmental factors under high-altitude conditions.
Topics: Mice; Humans; Animals; Altitude; Transferrin; Thrombin; Temperature; Hypoxia; Thrombophilia; Hypoxia-Inducible Factor 1, alpha Subunit
PubMed: 36040436
DOI: 10.1182/blood.2022016410 -
Cancer Communications (London, England) Oct 2023The efficacy of anti-programmed cell death protein 1 (PD-1) immunotherapy in various cancers, including gastric cancer (GC), needs to be potentiated by more effective...
BACKGROUND
The efficacy of anti-programmed cell death protein 1 (PD-1) immunotherapy in various cancers, including gastric cancer (GC), needs to be potentiated by more effective targeting to enhance therapeutic efficacy or identifying accurate biomarkers to predict clinical responses. Here, we attempted to identify molecules predicting or/and promoting anti-PD-1 therapeutic response in advanced GC (AGC).
METHODS
The transcriptome of AGC tissues from patients with different clinical responses to anti-PD-1 immunotherapy and GC cells was analyzed by RNA sequencing. The protein and mRNA levels of the major facilitator superfamily domain containing 2A (MFSD2A) in GC cells were assessed via quantitative real-time polymerase chain reaction, Western blotting, and immunohistochemistry. Additionally, the regulation of anti-PD-1 response by MFSD2A was studied in tumor-bearing mice. Cytometry by Time-of-Flight, multiple immunohistochemistry, and flow cytometry assays were used to explore immunological responses. The effects of MFSD2A on lipid metabolism in mice cancer tissue and GC cells was detected by metabolomics.
RESULTS
Higher expression of MFSD2A in tumor tissues of AGC patients was associated with better response to anti-PD-1 immunotherapy. Moreover, MFSD2A expression was lower in GC tissues compared to adjacent normal tissues, and its expression was inversely correlated with GC stage. The overexpression of MFSD2A in GC cells enhanced the efficacy of anti-PD-1 immunotherapy in vivo by reprogramming the tumor microenvironment (TME), characterized by increased CD8 T cell activation and reduced its exhaustion. MFSD2A inhibited transforming growth factor β1 (TGFβ1) release from GC cells by suppressing cyclooxygenase 2 (COX2)-prostaglandin synthesis, which consequently reprogrammed TME to promote anti-tumor T cell activation.
CONCLUSIONS
MFSD2A potentially serves as a predictive biomarker for anti-PD-1 immunotherapy response in AGC patients. MFSD2A may be a promising therapeutic target to potentiate the efficacy of anti-PD-1 immunotherapy by reprogramming the TME to promote T cells activation.
Topics: Humans; Animals; Mice; Stomach Neoplasms; Tumor Microenvironment; CD8-Positive T-Lymphocytes; Immunohistochemistry; Immunotherapy; Symporters
PubMed: 37539769
DOI: 10.1002/cac2.12476 -
Advances in Pharmacology (San Diego,... 202220-Hydroxyeicosatetraenoic acid (20-HETE) is a bioactive lipid generated from the ω-hydroxylation of arachidonic acid (AA) by enzymes of the cytochrome P450 (CYP)... (Review)
Review
20-Hydroxyeicosatetraenoic acid (20-HETE) is a bioactive lipid generated from the ω-hydroxylation of arachidonic acid (AA) by enzymes of the cytochrome P450 (CYP) family, primarily the CYP4A and CYP4F subfamilies. 20-HETE is most notably identified as a modulator of vascular tone, regulator of renal function, and a contributor to the onset and development of hypertension and cardiovascular disease. 20-HETE-mediated signaling promotes hypertension by sensitizing the vasculature to constrictor stimuli, inducing endothelial dysfunction, and potentiating vascular inflammation. These bioactions are driven by the activation of the G-protein coupled receptor 75 (GPR75), a 20-HETE receptor (20HR). Given the capacity of 20-HETE signaling to drive pro-hypertensive mechanisms, the CYP/20-HETE/GPR75 axis has the potential to be a significant therapeutic target for the treatment of hypertension and cardiovascular diseases associated with increases in blood pressure. In this chapter, we review 20-HETE-mediated cellular mechanisms that promote hypertension, highlight important data in humans such as genetic variants in the CYP genes that potentiate 20-HETE production and describe recent findings in humans with 20HR/GPR75 mutations. Special emphasis is given to the 20HR and respective receptor blockers that have the potential to pave a path to translational and clinical studies for the treatment of 20-HETE-driven hypertension, and obesity/metabolic syndrome.
Topics: Blood Pressure; Cardiovascular Diseases; Cytochrome P-450 CYP4A; Cytochrome P-450 Enzyme System; Humans; Hydroxyeicosatetraenoic Acids; Hypertension; Receptors, G-Protein-Coupled
PubMed: 35659370
DOI: 10.1016/bs.apha.2022.02.003 -
Proceedings of the National Academy of... Mar 2023The potentiation of antibiotics is a promising strategy for combatting antibiotic-resistant/tolerant bacteria. Herein, we report that a 5-min sublethal heat shock...
The potentiation of antibiotics is a promising strategy for combatting antibiotic-resistant/tolerant bacteria. Herein, we report that a 5-min sublethal heat shock enhances the bactericidal actions of aminoglycoside antibiotics by six orders of magnitude against both exponential- and stationary-phase . This combined treatment also effectively kills various persisters, clinical isolates, and numerous gram-negative but not gram-positive bacteria and enables aminoglycosides at 5% of minimum inhibitory concentrations to eradicate multidrug-resistant pathogens and . Mechanistically, the potentiation is achieved comprehensively by heat shock-enhanced proton motive force that thus promotes the bacterial uptake of aminoglycosides, as well as by increasing irreversible protein aggregation and reactive oxygen species that further augment the downstream lethality of aminoglycosides. Consistently, protonophores, chemical chaperones, antioxidants, and anaerobic culturing abolish heat shock-enhanced aminoglycoside lethality. We also demonstrate as a proof of concept that infrared irradiation- or photothermal nanosphere-induced thermal treatments potentiate aminoglycoside killing of in a mouse acute skin wound model. Our study advances the understanding of the mechanism of actions of aminoglycosides and demonstrates a high potential for thermal ablation in curing bacterial infections when combined with aminoglycosides.
Topics: Mice; Animals; Anti-Bacterial Agents; Aminoglycosides; Reactive Oxygen Species; Protein Aggregates; Escherichia coli; Gram-Negative Bacteria; Bacteria; Heat-Shock Response; Microbial Sensitivity Tests
PubMed: 36917671
DOI: 10.1073/pnas.2217254120 -
Science Advances Jun 2023In the face of the alarming rise in global antimicrobial resistance, only a handful of novel antibiotics have been developed in recent decades, necessitating innovations...
In the face of the alarming rise in global antimicrobial resistance, only a handful of novel antibiotics have been developed in recent decades, necessitating innovations in therapeutic strategies to fill the void of antibiotic discovery. Here, we established a screening platform mimicking the host milieu to select antibiotic adjuvants and found three catechol-type flavonoids-7,8-dihydroxyflavone, myricetin, and luteolin-prominently potentiating the efficacy of colistin. Further mechanistic analysis demonstrated that these flavonoids are able to disrupt bacterial iron homeostasis through converting ferric iron to ferrous form. The excessive intracellular ferrous iron modulated the membrane charge of bacteria via interfering the two-component system /, thereby promoting the colistin binding and subsequent membrane damage. The potentiation of these flavonoids was further confirmed in an in vivo infection model. Collectively, the current study provided three flavonoids as colistin adjuvant to replenish our arsenals for combating bacterial infections and shed the light on the bacterial iron signaling as a promising target for antibacterial therapies.
Topics: Colistin; Bacterial Proteins; Anti-Bacterial Agents; Bacteria; Iron; Homeostasis
PubMed: 37294761
DOI: 10.1126/sciadv.adg4205 -
PLoS Pathogens Aug 2023Fungal infections are rising, with over 1.5 billion cases and more than 1 million deaths recorded each year. Among these, Candida infections are frequent in at-risk...
Fungal infections are rising, with over 1.5 billion cases and more than 1 million deaths recorded each year. Among these, Candida infections are frequent in at-risk populations and the rapid development of drug resistance and tolerance contributes to their clinical persistence. Few antifungal drugs are available, and their efficacy is declining due to the environmental overuse and the expansion of multidrug-resistant species. One way to prolong their utility is by applying them in combination therapy. Here, we highlight recently described azole potentiators belonging to different categories: natural, repurposed, or novel compounds. We showcase examples of molecules and discuss their identified or proposed mode of action. We also emphasise the challenges in azole potentiator development, compounded by the lack of animal testing, the overreliance on Candida albicans and Candida auris, as well as the limited understanding of compound efficacy.
Topics: Animals; Candida; Candida albicans; Candidiasis; Antifungal Agents; Azoles
PubMed: 37651385
DOI: 10.1371/journal.ppat.1011583 -
Signal Transduction and Targeted Therapy Mar 2023Melanoma is the most lethal type of skin cancer, originating from the malignant transformation of melanocyte. While the development of targeted therapy and immunotherapy...
Melanoma is the most lethal type of skin cancer, originating from the malignant transformation of melanocyte. While the development of targeted therapy and immunotherapy has gained revolutionary advances in potentiating the therapeutic effect, the prognosis of patients with melanoma is still suboptimal. During tumor progression, melanoma frequently encounters stress from both endogenous and exogenous sources in tumor microenvironment. SIRT7 is a nuclear-localized deacetylase of which the activity is highly dependent on intracellular nicotinamide adenine dinucleotide (NAD), with versatile biological functions in maintaining cell homeostasis. Nevertheless, whether SIRT7 regulates tumor cell biology and tumor immunology in melanoma under stressful tumor microenvironment remains elusive. Herein, we reported that SIRT7 orchestrates melanoma progression by simultaneously promoting tumor cell survival and immune evasion via the activation of unfolded protein response. We first identified that SIRT7 expression was the most significantly increased one in sirtuins family upon stress. Then, we proved that the deficiency of SIRT7 potentiated tumor cell death under stress in vitro and suppressed melanoma growth in vivo. Mechanistically, SIRT7 selectively activated the IRE1α-XBP1 axis to potentiate the pro-survival ERK signal pathway and the secretion of tumor-promoting cytokines. SIRT7 directly de-acetylated SMAD4 to antagonize the TGF-β-SMAD4 signal, which relieved the transcriptional repression on IRE1α and induced the activation of the IRE1α-XBP1 axis. Moreover, SIRT7 up-regulation eradicated anti-tumor immunity by promoting PD-L1 expression via the IRE1α-XBP1 axis. Additionally, the synergized therapeutic effect of SIRT7 suppression and anti-PD-1 immune checkpoint blockade was also investigated. Taken together, SIRT7 can be employed as a promising target to restrain tumor growth and increase the effect of melanoma immunotherapy.
Topics: Humans; Endoribonucleases; Protein Serine-Threonine Kinases; Cell Survival; Immune Evasion; Cell Line, Tumor; Melanoma; Tumor Microenvironment; Sirtuins
PubMed: 36918544
DOI: 10.1038/s41392-023-01314-w -
Cellular & Molecular Immunology Aug 2022Inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis, has increased in incidence and prevalence in recent decades. Both clinical and animal...
Inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis, has increased in incidence and prevalence in recent decades. Both clinical and animal studies are critical for understanding the pathogenesis of this disease. Dextran sodium sulfate (DSS)-induced colitis is a frequently used animal model of IBD, but the underlying mechanism of the model remains incompletely understood. In this study, we found that NOD-like receptor family pyrin containing 3 (NLRP3) depletion markedly mitigated DSS-induced colitis and was accompanied by decreased activation of the inflammasome in the colons of mice. However, in vitro assays showed that DSS did not directly trigger but instead potentiated NLRP3 inflammasome assembly in macrophages in response to suboptimal ATP or nigericin stimulation. Mechanistically, DSS potentiated NLRP3 inflammasome activation in macrophages by augmenting KCa3.1-mediated potassium ion (K) efflux. Furthermore, we found that pharmacologic blockade of the K channel KCa3.1 with TRAM-34 or genetic depletion of the Kcnn4 gene (encoding KCa3.1) not only ameliorated the severity of DSS-induced colitis but also attenuated in vivo inflammasome assembly in the colonic tissues of mice, suggesting a causal link between KCa3.1-mediated augmentation of the NLRP3 inflammasome and DSS-induced inflammatory injuries. Collectively, these results indicate that KCa3.1 plays a critical role in mediating DSS-induced colitis in mice by potentiating NLRP3 inflammasome activation. Our data provide a previously unknown mechanism by which DSS induces colitis in mice and suggests that KCa3.1 is an alternative therapeutic target for treating IBD.
Topics: Animals; Colitis; Dextran Sulfate; Disease Models, Animal; Inflammasomes; Inflammatory Bowel Diseases; Intermediate-Conductance Calcium-Activated Potassium Channels; Mice; Mice, Inbred C57BL; NLR Family, Pyrin Domain-Containing 3 Protein; Potassium Channels; Sulfates
PubMed: 35799057
DOI: 10.1038/s41423-022-00891-0 -
Nature Communications Aug 2023γ-Aminobutyric acid type A (GABA) receptors mediate fast inhibitory signaling in the brain and are targets of numerous drugs and endogenous neurosteroids. A subset of...
γ-Aminobutyric acid type A (GABA) receptors mediate fast inhibitory signaling in the brain and are targets of numerous drugs and endogenous neurosteroids. A subset of neurosteroids are GABA receptor positive allosteric modulators; one of these, allopregnanolone, is the only drug approved specifically for treating postpartum depression. There is a consensus emerging from structural, physiological and photolabeling studies as to where positive modulators bind, but how they potentiate GABA activation remains unclear. Other neurosteroids are negative modulators of GABA receptors, but their binding sites remain debated. Here we present structures of a synaptic GABA receptor bound to allopregnanolone and two inhibitory sulfated neurosteroids. Allopregnanolone binds at the receptor-bilayer interface, in the consensus potentiator site. In contrast, inhibitory neurosteroids bind in the pore. MD simulations and electrophysiology support a mechanism by which allopregnanolone potentiates channel activity and suggest the dominant mechanism for sulfated neurosteroid inhibition is through pore block.
Topics: Female; Humans; Neurosteroids; Pregnanolone; Receptors, GABA-A; Binding Sites; Sulfates; gamma-Aminobutyric Acid
PubMed: 37607940
DOI: 10.1038/s41467-023-40800-1