-
Frontiers in Immunology 2023Little is known on how metabolic reprogramming potentially prompts transition of activated and resting CD4 memory T cells infiltration in tumor microenvironment of...
BACKGROUND
Little is known on how metabolic reprogramming potentially prompts transition of activated and resting CD4 memory T cells infiltration in tumor microenvironment of gastric cancer (GC). The study aimed to evaluate their interactions and develop a risk model for predicting prognosis in GC.
METHODS
Expression profiles were obtained from TCGA and GEO databases. An immunotherapeutic IMvigor210 cohort was also enrolled. CIBERSORT algorithm was used to evaluate the infiltration of immune cells. The ssGSEA method was performed to assess levels of 114 metabolism pathways. Prognosis and correlation analysis were conducted to identify metabolism pathways and genes correlated with activated CD4 memory T cells ratio (AR) and prognosis. An AR-related metabolism gene (ARMG) risk model was constructed and validated in different cohorts. Flow cytometry was applied to validate the effect of all-trans retinoic acid (ATRA) on CD4 memory T cells.
RESULTS
Since significantly inverse prognostic value and negative correlation of resting and activated CD4 memory T cells, high AR level was associated with favorable overall survival (OS) in GC. Meanwhile, 15 metabolism pathways including retinoic acid metabolism pathway were significantly correlated with AR and prognosis. The ARMG risk model could classify GC patients with different outcomes, treatment responses, genomic and immune landscape. The prognostic value of the model was also confirmed in the additional validation, immunotherapy and pan-cancer cohorts. Functional analyses revealed that the ARMG model was positively correlated with pro-tumorigenic pathways. experiments showed that ATRA could inhibit levels of activated CD4 memory T cells and AR.
CONCLUSION
Our study showed that metabolic reprogramming including retinoic acid metabolism could contribute to transition of activated and resting CD4 memory T cells, and affect prognosis of GC patients. The ARMG risk model could serve as a new tool for GC patients by accurately predicting prognosis and response to treatment.
Topics: Humans; Stomach Neoplasms; Memory T Cells; Prognosis; CD4-Positive T-Lymphocytes; Tretinoin; Tumor Microenvironment
PubMed: 38090588
DOI: 10.3389/fimmu.2023.1275461 -
Food Research International (Ottawa,... Dec 2023Diterpenes are group of compounds of the terpenic fraction of roasted coffee and account for about 7-20 % (w/w) of the lipid fraction. Several parameters can influence...
Diterpenes are group of compounds of the terpenic fraction of roasted coffee and account for about 7-20 % (w/w) of the lipid fraction. Several parameters can influence their occurrence in coffee beans and beverages including species and post-harvest processing. Diterpenes in coffee have been studied extensively, but to the best of the authors' knowledge, there is no information in the literature on their stability over time. Coffee is a relatively stable product under optimal temperature, humidity and oxygen conditions. However, during storage it can undergo a series of chemical and physical reactions that alter its flavour and lead to rancidity, mainly due to the oxidative reactions that take place on the lipid fraction. In this study, the effect of long-term storage on the diterpene content of different commercial coffee blends and packaging is analysed and critically discussed. The Results show that the storage influences the internal environment of the capsules with an increase in moisture and a decrease in pH favouring more reactive conditions, especially for Eco capsules. Relative stability over time is observed for cafestol and kahweol. dehydro derivatives show a degradation up to T60 independently on the blends and packaging, which is not related to their precursors. The permeability of packaging and blends affect the modification of these components: while a drastic oxidation process takes place in Arabica eco compatible capsules (PC) when acidity and moisture increase, in Arabica/Robusta eco compatible capsules (IC) as well as in Arabica/Robusta and Arabica standard capsules (IS and PS) the peroxides tend to increase resulting in an autocatalytic propagation.
Topics: Aluminum; Coffea; Diterpenes; Temperature; Polymers; Lipids
PubMed: 37986525
DOI: 10.1016/j.foodres.2023.113577 -
Pharmacological Research Aug 2023The p38-MK2 signaling axis functions as an initiator of inflammation. Targeting the p38-MK2 signaling axis represents a direct therapeutic intervention of inflammatory...
The p38-MK2 signaling axis functions as an initiator of inflammation. Targeting the p38-MK2 signaling axis represents a direct therapeutic intervention of inflammatory diseases. We described here a novel role of andrographolide (AG), a small-molecule ent-labdane natural compound, as an inhibitor of p38-MK2 axis via MK2 degradation. AG was found to bind to the activation loop of MK2, located at the interface of the p38-MK2 biomolecular complex. This interaction disrupted the complex formation and predisposed MK2 to proteasome-mediated degradation. We showed that AG induced MK2 degradation in a concentration- and time-dependent manner and exerted its anti-inflammatory effects by enhancing the mRNA-destabilizing activity of tristetraprolin, thereby inhibiting pro-inflammatory mediator production (e.g., TNF-α, MCP-1). Administration of AG via intratracheal (i.t.) route to mice induced MK2 downregulation in lung alveolar macrophages, but not lung tissues, and prevented macrophage activation. Our study also demonstrated that the anti-inflammatory effects achieved by AG via MK2 degradation were more durable and sustained than that achieved by the conventional MK2 kinase inhibitors (e.g., PF-3644022). Taken together, our findings illustrated a novel mode of action of AG by modulating the p38-MK2 signaling axis and would pave the way for the development of a novel class of anti-inflammatory agents targeting MK2 for degradation by harnessing the privileged scaffold of AG.
Topics: Mice; Animals; Protein Serine-Threonine Kinases; Intracellular Signaling Peptides and Proteins; Anti-Inflammatory Agents; Diterpenes; p38 Mitogen-Activated Protein Kinases
PubMed: 37480973
DOI: 10.1016/j.phrs.2023.106861 -
PloS One 2023The credibility and wide usability of nutrition fact labels (NFLs) have increased due to the pandemic, which may lead to healthier nutritional choices. This...
Nutrition fact label (NFL) use is related to meeting the requirements for vitamins and minerals not listed on NFLs: Data from the Korea National Health and Nutritional Examination Survey VIII (2019-2021) for the prepandemic and pandemic periods.
The credibility and wide usability of nutrition fact labels (NFLs) have increased due to the pandemic, which may lead to healthier nutritional choices. This cross-sectional study aimed to evaluate the association between NFL use and meeting the estimated average requirements (EARs) for vitamins and minerals not listed on NFLs during the prepandemic (2019, n = 6606) and pandemic periods (2020 and 2021, n = 12085) using KNHANES data. Household surveys, health behavior interviews, and health checkup examinations were conducted for all participants. Subjects were included in the unAware+noUse, Aware+noUse, and Aware+Use groups according to NFL usage, and nutritional intake was analyzed by the 24-hour recall method. Complex-sample multiple logistic regression analysis was used to determine the odds ratios (ORs) and 95% confidence intervals (CIs) for meeting the EARs according to NFL usage in the crude and adjusted (including metabolic conditions) models. The primary finding was that awareness and NFL use were associated with adequate intake above the EARs for vitamin A, vitamin B2, niacin, folate, Ca, Fe, and P; this association was more evident during the pandemic. After adjusting for covariates, during the pandemic, the ORs of meeting the EARs in the Aware+noUse group and Aware+Use group were 1.25 (CI 1.06-1.47) and 1.36 (CI 1.05-1.75) for vitamin A, 1.26 (CI 1.06-1.50) and 1.54 (CI 1.19-2.00) for vitamin B2, 1.32 (CI 1.13-1.56) and 1.46 (CI 1.15-1.85) for folate, and 1.46 (CI 1.06-2.00) and 1.73 (1.09-2.75) for P, respectively. Additionally, the ORs for niacin (1.21, 1.02-1.43) and Fe (1.29, 1.08-1.54) were significant in the Aware+noUse group, and that for Ca (1.39, 1.08-1.78) was significant in the Aware+Use group (all p <0.05). In conclusion, NFL awareness and use are associated with meeting the EARs for vitamins and minerals not listed on NFLs. For future recurring health crises, effective NFL use is necessary for healthy dietary practices.
Topics: Humans; Vitamins; Vitamin A; Niacin; Cross-Sectional Studies; Pandemics; Minerals; Vitamin K; Folic Acid; Nutrition Surveys; Riboflavin; Republic of Korea
PubMed: 38153947
DOI: 10.1371/journal.pone.0296268 -
Journal For Immunotherapy of Cancer Nov 2023Multidrug resistance-1 (MDR1) transporter limits the intracellular accumulation of chemotherapies (paclitaxel, anthracyclines) used in breast cancer (BC) treatment. In...
BACKGROUND
Multidrug resistance-1 (MDR1) transporter limits the intracellular accumulation of chemotherapies (paclitaxel, anthracyclines) used in breast cancer (BC) treatment. In addition to tumor cells, MDR1 is expressed on immune cell subsets in which it confers chemoresistance. Among human T cells, MDR1 is expressed by most CD8 T cells, and a subset of CD4 T helper (Th) cells. Here we explored the expression, function and regulation of MDR1 on CD4 T cells and investigated the role of this population in response to neoadjuvant chemotherapy (NAC) in BC.
METHODS
Phenotypic and functional characteristics of MDR1 CD4 Th cells were assessed on blood from healthy donors and patients with BC by flow cytometry. These features were extended to CD4 Th cells from untreated breast tumor by flow cytometry and RNA-sequencing (RNA-seq). We performed in vitro polarization assays to decipher MDR1 regulation on CD4 Th cells. We evaluated in vitro the impact of chemotherapy agents on MDR1 CD4 Th cells. We analyzed the impact of NAC treatment on MDR1 CD4 Th cells from blood and tumors and their association with treatment efficacy in two independent BC cohorts and in a public RNA-seq data set of BC tumor biopsies before and after NAC. Finally, we performed single cell (sc) RNAseq of blood CD4 memory T cells from NAC-treated patients and combined them with an scRNAseq public data set.
RESULTS
MDR1 CD4 Th cells were strongly enriched in Th1.17 polyfunctional cells but also in Th17 cells, both in blood and untreated breast tumor tissues. Mechanistically, Tumor growth factor (TGF)-β1 was required for MDR1 induction during in vitro Th17 or Th1.17 polarization. MDR1 expression conferred a selective advantage to Th1.17 and Th17 cells following paclitaxel treatment in vitro and in vivo in NAC-treated patients. scRNAseq demonstrated MDR1 association with tumor Th1.17 and Th with features of cytotoxic cells. Enrichment in MDR1 CD4 Th1.17 and Th17 cells, in blood and tumors positively correlated with pathological response. Absence of early modulation of Th1.17 and Th17 in NAC-resistant patients, argue for its use as a biomarker for chemotherapy regimen adjustment.
CONCLUSION
MDR1 favored the enrichment of Th1.17 and Th17 in blood and tumor after NAC that correlated to clinical response.
Topics: Humans; Female; Breast Neoplasms; CD8-Positive T-Lymphocytes; Neoadjuvant Therapy; CD4-Positive T-Lymphocytes; Th17 Cells; Paclitaxel
PubMed: 37940345
DOI: 10.1136/jitc-2023-007733 -
Journal of Controlled Release :... Nov 2023While surgery represents a major therapy for most solid organ cancers, local recurrence is clinically problematic for cancers such as sarcoma for which adjuvant...
While surgery represents a major therapy for most solid organ cancers, local recurrence is clinically problematic for cancers such as sarcoma for which adjuvant radiotherapy and systemic chemotherapy provide minimal local control or survival benefit and are dose-limited due to off-target side effects. We describe an implantable, biodegradable poly(1,2-glycerol carbonate) and poly(caprolactone) film with entrapped and covalently-bound paclitaxel enabling safe, controlled, and extended local delivery of paclitaxel achieving concentrations 10,000× tissue levels compared to systemic administration. Films containing entrapped and covalently-bound paclitaxel implanted in the tumor bed, immediately after resection of human cell line-derived chondrosarcoma and patient-derived xenograft liposarcoma and leiomyosarcoma in mice, improve median 90- or 200-day recurrence-free and overall survival compared to control mice. Furthermore, mice in the experimental film arm show no film-related morbidity. Continuous, extended, high-dose paclitaxel delivery via this unique polymer platform safely improves outcomes in three different sarcoma models and provides a rationale for future incorporation into human trials.
Topics: Humans; Animals; Mice; Paclitaxel; Polymers; Sarcoma; Antineoplastic Agents, Phytogenic; Cell Line, Tumor
PubMed: 37776906
DOI: 10.1016/j.jconrel.2023.09.048 -
International Journal of Molecular... Feb 2024Free radicals (FRs) are unstable molecules that cause reactive stress (RS), an imbalance between reactive oxygen and nitrogen species in the body and its ability to... (Review)
Review
Free radicals (FRs) are unstable molecules that cause reactive stress (RS), an imbalance between reactive oxygen and nitrogen species in the body and its ability to neutralize them. These species are generated by both internal and external factors and can damage cellular lipids, proteins, and DNA. Antioxidants prevent or slow down the oxidation process by interrupting the transfer of electrons between substances and reactive agents. This is particularly important at the cellular level because oxidation reactions lead to the formation of FR and contribute to various diseases. As we age, RS accumulates and leads to organ dysfunction and age-related disorders. Polyphenols; vitamins A, C, and E; and selenoproteins possess antioxidant properties and may have a role in preventing and treating certain human diseases associated with RS. In this review, we explore the current evidence on the potential benefits of dietary supplementation and investigate the intricate connection between SIRT1, a crucial regulator of aging and longevity; the transcription factor NRF2; and polyphenols, vitamins, and selenium. Finally, we discuss the positive effects of antioxidant molecules, such as reducing RS, and their potential in slowing down several diseases.
Topics: Humans; Antioxidants; Vitamins; Selenium; Polyphenols; Oxidative Stress; Vitamin A; Vitamin K; Reactive Oxygen Species
PubMed: 38473850
DOI: 10.3390/ijms25052600 -
BioEssays : News and Reviews in... Sep 2023The photocycle of visual opsins is essential to maintain the light sensitivity of the retina. The early physical observations of the rhodopsin photocycle by Böll and... (Review)
Review
The photocycle of visual opsins is essential to maintain the light sensitivity of the retina. The early physical observations of the rhodopsin photocycle by Böll and Kühne in the 1870s inspired over a century's worth of investigations on rhodopsin biochemistry. A single photon isomerizes the Schiff-base linked 11-cis-retinylidene chromophore of rhodopsin, converting it to the all-trans agonist to elicit phototransduction through photoactivated rhodopsin (Rho*). Schiff base hydrolysis of the agonist is a key step in the photocycle, not only diminishing ongoing phototransduction but also allowing for entry and binding of fresh 11-cis chromophore to regenerate the rhodopsin pigment and maintain light sensitivity. Many challenges have been encountered in measuring the rate of this hydrolysis, but recent advancements have facilitated studies of the hydrolysis within the native membrane environment of rhodopsin. These techniques can now be applied to study hydrolysis of agonist in other opsin proteins that mediate phototransduction or chromophore turnover. In this review, we discuss the progress that has been made in characterizing the rhodopsin photocycle and the journey to characterize the hydrolysis of its all-trans-retinylidene agonist.
Topics: Humans; Rhodopsin; Photophobia; Retinaldehyde; Retina
PubMed: 37454357
DOI: 10.1002/bies.202300068 -
International Journal of Oncology Sep 2023Endometrial cancer is the most common gynecologic cancer and one of the only cancers for which incidence and mortality is steadily increasing. Although curable with...
Endometrial cancer is the most common gynecologic cancer and one of the only cancers for which incidence and mortality is steadily increasing. Although curable with surgery in the early stages, endometrial cancer presents a significant clinical challenge in the metastatic and recurrent setting with few novel treatment strategies emerging in the past fifty years. Ipatasertib (IPAT) is an orally bioavailable pan‑AKT inhibitor, which targets all three AKT isoforms and has demonstrated anti‑tumor activity in pre‑clinical models, with clinical trials emerging for many cancer types. In the present study, the MTT assay was employed to evaluate the therapeutic efficacy of IPAT or IPAT in combination with paclitaxel (PTX) in endometrial cancer cell lines and primary cultures of endometrial cancer. The effect of IPAT and PTX on the growth of endometrial tumors was evaluated in a transgenic mouse model of endometrial cancer. Apoptosis was assessed using cleaved caspase assays and cellular stress was assessed using ROS, JC1 and tetramethylrhodamine ethyl ester assays. The protein expression levels of markers of apoptosis and cellular stress, and DNA damage were evaluated using western blotting and immunohistochemistry. IPAT significantly inhibited cell proliferation, caused cell cycle G1 phase arrest, and induced cellular stress and mitochondrial apoptosis in a dose dependent manner in human endometrial cancer cell lines. Combined treatment with low doses of IPAT and PTX led to synergistic inhibition of cell proliferation and induction of cleaved caspase 3 activity in the human endometrial cancer cell lines and the primary cultures. Furthermore, IPAT effectively reduced tumor growth, accompanied by decreased protein expression levels of Ki67 and phosphorylation of S6 in the mouse model of endometrioid endometrial cancer. The combination of IPAT and PTX resulted in increased expression of phosphorylated‑H2AX and KIF14, markers of DNA damage and microtubule dysfunction respectively, as compared with IPAT alone, PTX alone or placebo‑treated mice. The results of the present study provide a biological rationale to evaluate IPAT and the combination of IPAT and PTX in future clinical trials for endometrial cancer.
Topics: Female; Animals; Humans; Mice; Paclitaxel; Proto-Oncogene Proteins c-akt; Piperazines; Cell Proliferation; Endometrial Neoplasms; Apoptosis; Cell Line, Tumor
PubMed: 37503790
DOI: 10.3892/ijo.2023.5551 -
PloS One 2023Some COVID-19 patients develop life-threatening disease accompanied by severe pneumonitis. Teprenone induces expression of heat-shock proteins (HSPs) that protect... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Some COVID-19 patients develop life-threatening disease accompanied by severe pneumonitis. Teprenone induces expression of heat-shock proteins (HSPs) that protect against interstitial pneumonia in preclinical models. We explored whether teprenone prevented worsening of COVID-19 infections.
METHODS
This open-label, randomized, pilot phase 2 clinical trial was conducted at five institutions in Japan. We randomized patients hospitalized for COVID-19 with fever to teprenone or no-teprenone groups in a 1:1 ratio. We stratified patients by sex, age < and ≥ 70 years and the existence (or not) of complications (hypertension, diabetes, ischemic heart disease, chronic pulmonary disease and active cancer). No limitation was imposed on other COVID-19 treatments. The primary endpoint was the intubation rate.
RESULTS
One hundred patients were included, 51 in the teprenone and 49 in the no- teprenone groups. The intubation rate did not differ significantly between the two groups: 9.8% (5/51) vs. 2.0% (1/49) (sub-hazard ratio [SHR] 4.99, 95% confidence interval [CI]: 0.59-42.1; p = 0.140). The rates of intra-hospital mortality and intensive care unit (ICU) admission did not differ significantly between the two groups: intra-hospital mortality 3.9% (2/51) vs. 4.1% (2/49) (hazard ratio [HR] 0.78, 95%CI: 0.11-5.62; p = 0.809); ICU admission 11.8% (6/51) vs. 6.1% (3/49) (SHR 1.99, 95%CI: 0.51-7.80; p = 0.325).
CONCLUSION
Teprenone afforded no clinical benefit.
TRIAL REGISTRATION
Japan Registry of Clinical Trials jRCTs061200002 (registered on 20/May/2020).
Topics: Humans; Aged; COVID-19; SARS-CoV-2; Diterpenes; Intensive Care Units; Treatment Outcome
PubMed: 37883347
DOI: 10.1371/journal.pone.0287501