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Genes & Diseases Jul 2024Gastric cancer is highly prevalent among digestive tract tumors. Due to the intricate nature of the gastric cancer immune microenvironment, there is currently no...
Gastric cancer is highly prevalent among digestive tract tumors. Due to the intricate nature of the gastric cancer immune microenvironment, there is currently no effective treatment available for advanced gastric cancer. However, there is promising potential for immunotherapy targeting the prostaglandin E2 receptor subtype 4 (EP4) in gastric cancer. In our previous study, we identified a novel small molecule EP4 receptor antagonist called YY001. Treatment with YY001 alone demonstrated a significant reduction in gastric cancer growth and inhibited tumor metastasis to the lungs in a mouse model. Furthermore, administration of YY001 stimulated a robust immune response within the tumor microenvironment, characterized by increased infiltration of antigen-presenting cells, T cells, and M1 macrophages. Additionally, our research revealed that YY001 exhibited remarkable synergistic effects when combined with the PD-1 antibody and the clinically targeted drug apatinib, rather than fluorouracil. These findings suggest that YY001 holds great promise as a potential therapeutic strategy for gastric cancer, whether used as a standalone treatment or in combination with other drugs.
PubMed: 38560505
DOI: 10.1016/j.gendis.2023.101164 -
Poultry Science May 2024Cadmium (Cd) and high molybdenum (Mo) are injurious to the body. Previous research has substantiated that Cd and Mo exposure caused testicular injury of ducks, but...
Cadmium (Cd) and high molybdenum (Mo) are injurious to the body. Previous research has substantiated that Cd and Mo exposure caused testicular injury of ducks, but concrete mechanism is not fully clarified. To further survey the toxicity of co-exposure to Cd and Mo in testis, 40 healthy 8-day-old Shaoxing ducks (Anas platyrhyncha) were stochasticly distributed to 4 groups and raised with basic diet embracing Cd (4 mg/kg Cd) or Mo (100 mg/kg Mo) or both. At the 16th wk, testis tissues were gathered. The characteristic ultrastructural changes related to apoptosis and ferroptosis were observed in Mo or Cd or both groups. Besides, Mo or Cd or both repressed nuclear factor erythroid 2-related factor 2 (Nrf2) pathway via decreasing Nrf2, Heme oxygenase-1 (HO-1), NAD(P)H quinone oxidoreductase 1 (NQO1), Glutamate-cysteine ligase catalytic subunit (GCLC) and Glutamate-cysteine ligase modifier subunit (GCLM) mRNA expression of and Nrf2 protein expression, then stimulated apoptosis by elevating Bcl-2 antagonist/killer-1 (Bak-1), Bcl-2-associated X-protein (Bax), Cytochrome complex (Cyt-C), caspase-3 mRNA expression, cleaved-caspase-3 protein expression and apoptosis rate, as well as reducing B-cell lymphoma-2 (Bcl-2) mRNA expression and ratio of Bcl-2 to Bax, and triggered ferroptosis by upregulating Acyl-CoA Synthetase Long Chain Family Member 4 (ACSL4), transferrin receptor (TFR1) and Prostaglandin-Endoperoxide Synthase 2 (PTGS2) expression levels, and downregulating ferritin heavy chain 1 (FTH1), ferritin light chain 1 (FTL1), ferroportin 1 (FPN1), solute carrier family 7 member 11 (SCL7A11) and glutathione peroxidase 4 (GPX4) expression levels. The most obvious changes of these indexes were observed in co-treated group. Altogether, the results announced that Mo or Cd or both evoked apoptosis and ferroptosis by inhibiting Nrf2 pathway in the testis of ducks, and co-exposure to Mo and Cd exacerbated these variations.
Topics: Animals; Male; Ducks; Cadmium; Testis; Apoptosis; Ferroptosis; NF-E2-Related Factor 2; Signal Transduction; Molybdenum; Avian Proteins
PubMed: 38537407
DOI: 10.1016/j.psj.2024.103653 -
Circulation. Heart Failure Apr 2024Prostaglandin E2 acts through 4 G-protein-coupled receptors (EP1-EP4). We previously reported that activation of the EP3 receptor reduces cardiac contractility, and its...
BACKGROUND
Prostaglandin E2 acts through 4 G-protein-coupled receptors (EP1-EP4). We previously reported that activation of the EP3 receptor reduces cardiac contractility, and its expression increases after a myocardial infarction (MI), mediating the reduction in cardiac function. In contrast, cardiac overexpression of the EP4 receptor in MI substantially improves cardiac function. Moreover, we recently reported that mice overexpressing EP3 have heart failure under basal conditions and worsened cardiac function after MI. Thus, the deleterious effects of the prostaglandin E2 EP receptors in the heart are mediated via its EP3 receptor. We, therefore, hypothesized that cardiomyocyte-specific knockout (CM-EP3 KO) or antagonism of the EP3 receptor protects the heart after MI.
METHODS
To test our hypothesis, we made the novel CM-EP3 KO mouse and subjected CM-EP3 KO or controls to sham or MI surgery for 2 weeks. In separate experiments, C57BL/6 mice were subjected to 2 weeks of MI and treated with either the EP3 antagonist L798 106 or vehicle starting 3 days post-MI.
RESULTS
CM-EP3 KO significantly prevented a decline in cardiac function after MI compared with WT animals and prevented an increase in hypertrophy and fibrosis. Excitingly, mice treated with L798 106 3 days after MI had significantly better cardiac function compared with vehicle-treated mice.
CONCLUSIONS
Altogether, these data suggest that EP3 may play a direct role in regulating cardiac function, and pharmaceutical targeting of the EP3 receptor may be a therapeutic option in the treatment of heart failure.
Topics: Mice; Animals; Dinoprostone; Receptors, Prostaglandin; Gene Deletion; Heart Failure; Mice, Inbred C57BL; Myocardial Infarction; Myocytes, Cardiac; Receptors, Prostaglandin E, EP4 Subtype; Receptors, Prostaglandin E, EP3 Subtype
PubMed: 38525608
DOI: 10.1161/CIRCHEARTFAILURE.123.011089 -
Phytomedicine : International Journal... Jun 2024Polycystic ovary syndrome is a metabolic and hormonal disorder that is closely linked to oxidative stress. Within individuals diagnosed with PCOS, changes occur in the...
BACKGROUND
Polycystic ovary syndrome is a metabolic and hormonal disorder that is closely linked to oxidative stress. Within individuals diagnosed with PCOS, changes occur in the ovaries, resulting in an excessive buildup of iron and peroxidation of lipids, both of which may be associated with the occurrence of ferroptosis. Baicalein, a flavonoid found in the roots of Scutellaria baicalensis and widely known as Chinese skullcap, is known for its anti-inflammatory and anti-ferroptotic properties, which protect against various diseases. Nevertheless, there has been no investigation into the impact of baicalein on polycystic ovary syndrome.
PURPOSE
This study aimed to correlate ferroptosis with polycystic ovary syndrome and to assess the effects of baicalein on ovarian dysfunction and placental development in pregnant patients.
STUDY DESIGN AND METHODS
Polycystic ovary syndrome was induced in a rat model through the administration of dehydroepiandrosterone, and these rats were treated with baicalein. Oxidative stress and inflammation levels were assessed in serum and ovaries, and tissue samples were collected for histological and protein analyses. Furthermore, different groups of female rats were mated with male rats to observe pregnancy outcomes and tissue samples were obtained for histological, protein, and RNA sequencing. Then, RNA sequencing of the placenta was performed to determine the key genes involved in ferroptosis negative regulation (FNR) signatures.
RESULTS
Baicalein was shown to reduce ovarian oxidative stress and pathology. Baicalein also ameliorated polycystic ovary syndrome by decreasing lipid peroxidation and chronic inflammation and modulating mitochondrial functions and ferroptosis in the ovaries. Specifically, glutathione peroxidase and ferritin heavy chain 1 were considerably downregulated in polycystic ovary syndrome gravid rats compared to their expression in the control group, and most of these differences were reversed after baicalein intervention.
CONCLUSIONS
Our findings, initially, indicated that baicalein could potentially enhance the prognosis of individuals suffering from polycystic ovary syndrome by reducing oxidative stress and ferroptosis, thus potentially influencing the formulation of a therapeutic approach to address this condition.
Topics: Polycystic Ovary Syndrome; Female; Flavanones; Ferroptosis; Animals; Oxidative Stress; Pregnancy; Placenta; Ovary; Rats; Rats, Sprague-Dawley; Scutellaria baicalensis; Disease Models, Animal; Lipid Peroxidation; Male
PubMed: 38518646
DOI: 10.1016/j.phymed.2024.155423 -
PNAS Nexus Mar 2024Cytosolic sulfotransferases (SULTs) are cytosolic enzymes that catalyze the transfer of sulfonate group to key endogenous compounds, altering the physiological functions...
Cytosolic sulfotransferases (SULTs) are cytosolic enzymes that catalyze the transfer of sulfonate group to key endogenous compounds, altering the physiological functions of their substrates. SULT enzymes catalyze the -sulfonation of hydroxy groups or -sulfonation of amino groups of substrate compounds. In this study, we report the discovery of -sulfonation of α,β-unsaturated carbonyl groups mediated by a new SULT enzyme, SULT7A1, and human SULT1C4. Enzymatic assays revealed that SULT7A1 is capable of transferring the sulfonate group from 3'-phosphoadenosine 5'-phosphosulfate to the α-carbon of α,β-unsaturated carbonyl-containing compounds, including cyclopentenone prostaglandins as representative endogenous substrates. Structural analyses of SULT7A1 suggest that the -sulfonation reaction is catalyzed by a novel mechanism mediated by His and Cys residues in the active site. Ligand-activity assays demonstrated that sulfonated 15-deoxy prostaglandin J exhibits antagonist activity against the prostaglandin receptor EP2 and the prostacyclin receptor IP. Modification of α,β-unsaturated carbonyl groups via the new prostaglandin-sulfonating enzyme, SULT7A1, may regulate the physiological function of prostaglandins in the gut. Discovery of -sulfonation of α,β-unsaturated carbonyl groups will broaden the spectrum of potential substrates and physiological functions of SULTs.
PubMed: 38487162
DOI: 10.1093/pnasnexus/pgae097 -
International Journal of Molecular... Mar 2024Adrenaline has recently been found to trigger phosphatidylserine (PS) exposure on blood platelets, resulting in amplification of the coagulation process, but the...
Adrenaline has recently been found to trigger phosphatidylserine (PS) exposure on blood platelets, resulting in amplification of the coagulation process, but the mechanism is only fragmentarily established. Using a panel of platelet receptors' antagonists and modulators of signaling pathways, we evaluated the importance of these in adrenaline-evoked PS exposure by flow cytometry. Calcium and sodium ion influx into platelet cytosol, after adrenaline treatment, was examined by fluorimetric measurements. We found a strong reduction in PS exposure after blocking of sodium and calcium ion influx via Na/H exchanger (NHE) and Na/Ca exchanger (NCX), respectively. ADP receptor antagonists produced a moderate inhibitory effect. Substantial limitation of PS exposure was observed in the presence of GPIIb/IIIa antagonist, phosphoinositide-3 kinase (PI3-K) inhibitors, or prostaglandin E, a cyclic adenosine monophosphate (cAMP)-elevating agent. We demonstrated that adrenaline may develop a procoagulant response in human platelets with the substantial role of ion exchangers (NHE and NCX), secreted ADP, GPIIb/IIIa-dependent outside-in signaling, and PI3-K. Inhibition of the above mechanisms and increasing cytosolic cAMP seem to be the most efficient procedures to control adrenaline-evoked PS exposure in human platelets.
Topics: Humans; Blood Platelets; Platelet Activation; Calcium; Epinephrine; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Sodium; Thrombin
PubMed: 38474244
DOI: 10.3390/ijms25052997 -
Scientific Reports Feb 2024A group of misfolded prone-to-aggregate domains in disease-causing proteins has recently been shown to adopt unique conformations that play a role in fundamental...
A group of misfolded prone-to-aggregate domains in disease-causing proteins has recently been shown to adopt unique conformations that play a role in fundamental biological processes. These processes include the formation of membrane-less sub-organelles, alternative splicing, and gene activation and silencing. The cellular responses are regulated by the conformational switching of prone-to-aggregate domains, independently of changes in RNA or protein expression levels. Given this, targeting the misfolded states of disease-causing proteins to redirect them towards their physiological conformations is emerging as an effective therapeutic strategy for diseases caused by protein misfolding. In our study, we successfully identified baicalein as a potent structure-correcting agent. Our findings demonstrate that baicalein can reconfigure existing TDP-43 aggregates into an oligomeric state both in vitro and in disease cells. This transformation effectively restores the bioactivity of misfolded TDP-43 proteins in cellular models of ALS and premature aging in progeria. Impressively, in progeria cells where defective lamin A interferes with TDP-43-mediated exon skipping, the formation of pathological TDP-43 aggregates is promoted. Baicalein, however, restores the functionality of TDP-43 and mitigates nuclear shape defects in these laminopathic cells. This establishes a connection between lamin A and TDP-43 in the context of aging. Our findings suggest that targeting physiological TDP-43 oligomers could offer a promising therapeutic avenue for treating aging-associated disorders.
Topics: Humans; Progeria; Lamin Type A; Aging, Premature; DNA-Binding Proteins; Flavanones
PubMed: 38409193
DOI: 10.1038/s41598-024-55229-9 -
Phytomedicine : International Journal... Apr 2024The mitochondrial unfolded protein response (UPR) is the first line of defense against mitochondrial dysfunction in several diseases. Baicalein, which is an extract of...
BACKGROUND
The mitochondrial unfolded protein response (UPR) is the first line of defense against mitochondrial dysfunction in several diseases. Baicalein, which is an extract of Scutellaria baicalensis Georgi roots, exerts mitoprotective effects on metabolic disorders and cardiovascular diseases. However, it remains unclear whether baicalein alleviates obesity-induced cardiac damage through the UPR.
PURPOSE
The present research designed to clarify the role of baicalein in lipotoxicity-induced myocardial apoptosis and investigated the UPR-related mechanism.
METHODS
In the in vitro experiment, palmitic acid (PA)-treated AC16 cardiomyocytes were established to mimic obesity-induced myocardial injury. After pretreatment of AC16 cells with baicalein, the levels of cell vitality, apoptosis, mitochondrial membrane potential, mitochondrial oxidative stress, and UPR-related proteins were determined. Additionally, AC16 cells were treated with ML385 or siRNA to explore the regulation of the UPR by NRF2 signaling. In the in vivo experiment, male db/db mice administered with baicalein for 8 weeks were used to validate the effects of baicalein on cardiac damage induced by obesity, the UPR, and the NRF2-related pathway.
RESULTS
In AC16 cardiomyocytes, PA dose-dependently increased the expression of UPR markers (HSP60, LONP1, ATF4, and ATF5). This increase was accompanied by enhanced production of mitochondrial ROS, reduced mitochondrial membrane potential, and elevated the expression levels of cytochrome c, cleaved caspase-3, and Bax/Bcl2, eventually leading to cell apoptosis. Baicalein treatment reversed UPR activation and mitochondrial damage and impeded mitochondrial-mediated cell apoptosis. Moreover, NRF2 downregulation by its inhibitor ML385 or siRNA diminished baicalein-mediated NRF2 signaling activation and UPR inhibition and triggered mitochondrial dysfunction. Additionally, NRF2 deficiency more intensely activated the UPR resulting in mitochondrial oxidative stress and apoptosis of PA-induced cardiomyocytes, thus indicating that NRF2 plays a vital role in mitochondrial homeostasis regulation. In the in vivo study in db/db mice, baicalein inhibited the UPR, enhanced the antioxidant capacity, and attenuated cardiac dysfunction through a NRF2-activated pathway.
CONCLUSION
To our best knowledge, these results provide the first insight that baicalein inhibits the UPR to induce a protective effect against lipotoxicity-induced mitochondrial damage and cardiomyocyte apoptosis via activating NRF2 signaling and suggest a new role of NRF2 in UPR regulation.
Topics: Mice; Animals; Male; NF-E2-Related Factor 2; Unfolded Protein Response; Apoptosis; Heart Diseases; RNA, Small Interfering; Mitochondrial Diseases; Oxidative Stress; Myocytes, Cardiac; Flavanones
PubMed: 38394729
DOI: 10.1016/j.phymed.2024.155441 -
International Journal of Molecular... Jan 2024The natural cyclic AMP antagonist, prostaglandylinositol cyclic phosphate (cyclic PIP), is biosynthesized from prostaglandin E (PGE) and activated inositol phosphate...
The natural cyclic AMP antagonist, prostaglandylinositol cyclic phosphate (cyclic PIP), is biosynthesized from prostaglandin E (PGE) and activated inositol phosphate (n-Ins-P), which is synthesized by a particulate rat-liver-enzyme from GTP and a precursor named inositol phosphate (pr-Ins-P), whose 5-ring phosphodiester structure is essential for n-Ins-P synthesis. Aortic myocytes, preincubated with [H] myo-inositol, synthesize after angiotensin II stimulation (30 s) [H] pr-Ins-P (65% yield), which is converted to [H] n-Ins-P and [H] cyclic PIP. Acid-treated (1 min) [H] pr-Ins-P co-elutes with inositol (1,4)-bisphosphate in high performance ion chromatography, indicating that pr-Ins-P is inositol (1:2-cyclic,4)-bisphosphate. Incubation of [H]-GTP with unlabeled pr-Ins-P gave [H]-guanosine-labeled n-Ins-P. Cyclic PIP synthase binds the inositol (1:2-cyclic)-phosphate part of n-Ins-P to PGE and releases the [H]-labeled guanosine as [H]-GDP. Thus, n-Ins-P is most likely guanosine diphospho-4-inositol (1:2-cyclic)-phosphate. Inositol feeding helps patients with metabolic conditions related to insulin resistance, but explanations for this finding are missing. Cyclic PIP appears to be the key for explaining the curative effect of inositol supplementation: (1) inositol is a molecular constituent of cyclic PIP; (2) cyclic PIP triggers many of insulin's actions intracellularly; and (3) the synthesis of cyclic PIP is decreased in diabetes as shown in rodents.
Topics: Humans; Rats; Animals; Inositol; Inositol Phosphates; Guanosine Triphosphate; Guanosine; Phosphates; Prostaglandins E
PubMed: 38338641
DOI: 10.3390/ijms25031362 -
Cardiovascular Diabetology Feb 2024Patients with diabetes mellitus have poor prognosis after myocardial ischemic injury. However, the mechanism is unclear and there are no related therapies. We aimed to...
AIM
Patients with diabetes mellitus have poor prognosis after myocardial ischemic injury. However, the mechanism is unclear and there are no related therapies. We aimed to identify regulators of diabetic myocardial ischemic injury.
METHODS AND RESULTS
Mass spectrometry-based, non-targeted metabolomic approach was used to profile coronary sinus blood from diabetic and non-diabetic Bama-mini pigs at 0.5-h post coronary artery ligation. Six metabolites had a |log (Fold Change)|> 1.3. Among them, the most changed is arachidonic acid (AA), levels of which were 32 times lower in diabetic pigs than in non-diabetic pigs. The AA-derived products, PGI and 6-keto-PGF, were also significantly reduced. AA treatment of cultured cardiomyocytes protected against cell death by 30% at 48 h of high glucose and oxygen deprivation, which coincided with increased mitophagic activity (as indicated by increased LC3II/LC3I, decreased p62 and increased parkin & PINK1), improved mitochondrial renewal (upregulation of Drp1 and FIS1), reduced ROS generation and increased ATP production. These cardioprotective effects were abolished by PINK1(a crucial mitophagy protein) knockdown or the autophagy inhibitor 3-Methyladenine. The protective effect of AA was also inhibited by indomethacin and Cay10441, a prostacyclin receptor antagonist. Furthermore, diabetic Sprague Dawley rats were subjected to coronary ligation for 40 min and AA treatment (10 mg/day per animal gavaged) decreased myocardial infarct size, cell apoptosis index, inflammatory cytokines and improved heart function. Scanning electron microscopy showed more intact mitochondria in the border zone of infarcted myocardium in AA treated rats. Lastly, diabetic patients after myocardial infarction had lower plasma levels of AA and 6-keto-PGF and reduced cardiac ejection fraction, compared with non-diabetic patients after myocardial infarction. Plasma AA level was inversely correlated with fasting blood glucose.
CONCLUSIONS
AA protects against diabetic ischemic myocardial damage by promoting mitochondrial autophagy and renewal, which is related to AA derived PGI signaling. AA may represent a new strategy to treat diabetic myocardial ischemic injury.
Topics: Humans; Rats; Animals; Swine; Rats, Sprague-Dawley; Arachidonic Acid; Swine, Miniature; Myocardial Infarction; Protein Kinases; Apoptosis; Diabetes Mellitus
PubMed: 38336692
DOI: 10.1186/s12933-024-02123-3