bims-minfam Biomed News
on Inflammation and metabolism in ageing and cancer
Issue of 2022–07–03
sixteen papers selected by
Ayesh Seneviratne, Western University
  1. Human age reversal: Fact or fiction?
  2. Mitochondrial dysfunction in cell senescence and aging.
  3. Predicting frailty in older adults using vocal biomarkers: a cross-sectional study.
  4. The Achilles' heel of cancer survivors: fundamentals of accelerated cellular senescence.
  5. Use it or lose it: Protecting aging muscles with lifelong recreational exercise.
  6. Physioxia induced Downregulation of Tet2 in Hematopoietic Stem Cells contributes to Enhanced Self-renewal.
  7. BNT162b2 Vaccine Effectiveness against Omicron in Children 5 to 11 Years of Age.
  8. Calorie restriction and breast cancer treatment: a mini-review.
  9. Fourth Dose of BNT162b2 mRNA Covid-19 Vaccine. Reply.
  10. Fatty acid oxidation protects cancer cells from apoptosis by increasing mitochondrial membrane lipids.
  11. Rationale for Nicotinamide Adenine Dinucleotide (NAD+) Metabolome Disruption as a Pathogenic Mechanism of Post-Acute COVID-19 Syndrome.
  12. Relationship of frailty with excess mortality during the COVID-19 pandemic: a population-level study in Ontario, Canada.
  13. Fourth Dose of BNT162b2 mRNA Covid-19 Vaccine.
  14. Frailty in older people: Rehabilitation Treatment Research Examining Separate Settings (FORTRESS): protocol for a hybrid type II stepped wedge, cluster, randomised trial.
  15. The adverse inflammatory response of tobacco smoking in COVID-19 patients: biomarkers from proteomics and metabolomics.
  16. Targeting inflammation and redox perturbations by lisinopril mitigates Freund's adjuvant-induced arthritis in rats: role of JAK-2/STAT-3/RANKL axis, MMPs, and VEGF.
  1. Aging Cell. 2022 Jul 02. e13664
    Human age reversal: Fact or fiction?
    Adiv A Johnson, Bradley W English, Maxim N Shokhirev, David A Sinclair, Trinna L Cuellar.
      Although chronological age correlates with various age-related diseases and conditions, it does not adequately reflect an individual's functional capacity, well-being, or mortality risk. In contrast, biological age provides information about overall health and indicates how rapidly or slowly a person is aging. Estimates of biological age are thought to be provided by aging clocks, which are computational models (e.g., elastic net) that use a set of inputs (e.g., DNA methylation sites) to make a prediction. In the past decade, aging clock studies have shown that several age-related diseases, social variables, and mental health conditions associate with an increase in predicted biological age relative to chronological age. This phenomenon of age acceleration is linked to a higher risk of premature mortality. More recent research has demonstrated that predicted biological age is sensitive to specific interventions. Human trials have reported that caloric restriction, a plant-based diet, lifestyle changes involving exercise, a drug regime including metformin, and vitamin D3 supplementation are all capable of slowing down or reversing an aging clock. Non-interventional studies have connected high-quality sleep, physical activity, a healthy diet, and other factors to age deceleration. Specific molecules have been associated with the reduction or reversal of predicted biological age, such as the antihypertensive drug doxazosin or the metabolite alpha-ketoglutarate. Although rigorous clinical trials are needed to validate these initial findings, existing data suggest that aging clocks are malleable in humans. Additional research is warranted to better understand these computational models and the clinical significance of lowering or reversing their outputs.
    Keywords:  aging clock; biological age; epigenetic age; healthspan; lifespan; longevity; machine learning; mortality
    DOI:  https://doi.org/10.1111/acel.13664
  2. J Clin Invest. 2022 Jul 01. pii: e158447. [Epub ahead of print]132(13):
    Mitochondrial dysfunction in cell senescence and aging.
    Satomi Miwa, Sonu Kashyap, Eduardo Chini, Thomas von Zglinicki.
      Mitochondrial dysfunction and cell senescence are hallmarks of aging and are closely interconnected. Mitochondrial dysfunction, operationally defined as a decreased respiratory capacity per mitochondrion together with a decreased mitochondrial membrane potential, typically accompanied by increased production of oxygen free radicals, is a cause and a consequence of cellular senescence and figures prominently in multiple feedback loops that induce and maintain the senescent phenotype. Here, we summarize pathways that cause mitochondrial dysfunction in senescence and aging and discuss the major consequences of mitochondrial dysfunction and how these consequences contribute to senescence and aging. We also highlight the potential of senescence-associated mitochondrial dysfunction as an antiaging and antisenescence intervention target, proposing the combination of multiple interventions converging onto mitochondrial dysfunction as novel, potent senolytics.
    DOI:  https://doi.org/10.1172/JCI158447
  3. BMC Geriatr. 2022 Jul 01. 22(1): 549
    Predicting frailty in older adults using vocal biomarkers: a cross-sectional study.
    Yu-Chun Lin, Huang-Ting Yan, Chih-Hsueh Lin, Hen-Hong Chang.
       BACKGROUND: Frailty is a common issue in the aging population. Given that frailty syndrome is little discussed in the literature on the aging voice, the current study aims to examine the relationship between frailty and vocal biomarkers in older people.
    METHODS: Participants aged ≥ 60 years visiting geriatric outpatient clinics were recruited. They underwent frailty assessment (Cardiovascular Health Study [CHS] index; Study of Osteoporotic Fractures [SOF] index; and Fatigue, Resistance, Ambulation, Illness, and Loss of weight [FRAIL] index) and were asked to pronounce a sustained vowel /a/ for approximately 1 s. Four voice parameters were assessed: average number of zero crossings (A1), variations in local peaks and valleys (A2), variations in first and second formant frequencies (A3), and spectral energy ratio (A4).
    RESULTS: Among 277 older adults, increased A1 was associated with a lower likelihood of frailty as defined by SOF (odds ratio [OR] 0.84, 95% confidence interval [CI] 0.74-0.96). Participants with larger A2 values were more likely to be frail, as defined by FRAIL and CHS (FRAIL: OR 1.41, 95% CI 1.12-1.79; CHS: OR 1.38, 95% CI 1.10-1.75). Sex differences were observed across the three frailty indices. In male participants, an increase in A3 by 10 points increased the odds of frailty by almost 7% (SOF: OR 1.07, 95% CI 1.02-1.12), 6% (FRAIL: OR 1.06, 95% CI 1.02-1.11), or 6% (CHS: OR 1.06, 95% CI 1.01-1.11). In female participants, an increase in A4 by 0.1 conferred a significant 2.8-fold (SOF: OR 2.81, 95% CI 1.71-4.62), 2.3-fold (FRAIL: OR 2.31, 95% CI 1.45-3.68), or 2.8-fold (CHS: OR 2.82, 95% CI 1.76-4.51, CHS) increased odds of frailty.
    CONCLUSIONS: Vocal biomarkers, especially spectral-domain voice parameters, might have potential for estimating frailty, as a non-invasive, instantaneous, objective, and cost-effective estimation tool, and demonstrating sex differences for individualised treatment of frailty.
    Keywords:  Acoustic measures; Frailty; Older adults
    DOI:  https://doi.org/10.1186/s12877-022-03237-7
  4. J Clin Invest. 2022 Jul 01. pii: e158452. [Epub ahead of print]132(13):
    The Achilles' heel of cancer survivors: fundamentals of accelerated cellular senescence.
    Shameel Shafqat, Evelyn Arana Chicas, Areez Shafqat, Shahrukh K Hashmi.
      Recent improvements in cancer treatment have increased the lifespan of pediatric and adult cancer survivors. However, cancer treatments accelerate aging in survivors, which manifests clinically as the premature onset of chronic diseases, such as endocrinopathies, osteoporosis, cardiac dysfunction, subsequent cancers, and geriatric syndromes of frailty, among others. Therefore, cancer treatment-induced early aging accounts for significant morbidity, mortality, and health expenditures among cancer survivors. One major mechanism driving this accelerated aging is cellular senescence; cancer treatments induce cellular senescence in tumor cells and in normal, nontumor tissue, thereby helping mediate the onset of several chronic diseases. Studies on clinical monitoring and therapeutic targeting of cellular senescence have made considerable progress in recent years. Large-scale clinical trials are currently evaluating senotherapeutic drugs, which inhibit or eliminate senescent cells to ameliorate cancer treatment-related aging. In this article, we survey the recent literature on phenotypes and mechanisms of aging in cancer survivors and provide an up-to-date review of the major preclinical and translational evidence on cellular senescence as a mechanism of accelerated aging in cancer survivors, as well as insight into the potential of senotherapeutic drugs. However, only with time will the clinical effect of senotherapies on cancer survivors be visible.
    DOI:  https://doi.org/10.1172/JCI158452
  5. J Physiol. 2022 Jun 27.
    Use it or lose it: Protecting aging muscles with lifelong recreational exercise.
    Jonathan A Aguilera, Nicki Pourhashemi, Cooper J Sharpe, Beata Friesen.
      
    Keywords:  ageing; denervation; human skeletal muscle; lifelong exercise; sarcopenia; satellite cells
    DOI:  https://doi.org/10.1113/JP283338
  6. Blood. 2022 Jun 30. pii: blood.2022015499. [Epub ahead of print]
    Physioxia induced Downregulation of Tet2 in Hematopoietic Stem Cells contributes to Enhanced Self-renewal.
    Arafat Aljoufi, Chi Zhang, James Ropa, Wennan Chang, Lakshmi Reddy Palam, Scott Cooper, Baskar Ramdas, Maegan L Capitano, Hal E Broxmeyer, Reuben Kapur.
      Hematopoietic stem cells (HSCs) manifest impaired recovery and self-renewal with a concomitant increase in differentiation when exposed to ambient air as opposed to physioxia. Mechanism(s) behind this distinction are poorly understood but have the potential to improve stem cell transplantation. Single cell RNA-seq of HSCs in physioxia revealed upregulation of HSC self-renewal genes, and downregulation of genes involved in inflammatory pathways and HSC differentiation. HSCs under physioxia also exhibited downregulation of the epigenetic modifier Tet2. Tet2 is α-ketoglutarate (α-KG), iron and oxygen-dependent dioxygenase that converts 5-mC to 5-hmC thereby promoting active transcription. We evaluated whether loss of Tet2 affects the number and function of HSCs and hematopoietic progenitor cells (HPCs) under physioxia and ambient air. In contrast to WT-HSCs, a complete non-responsiveness of Tet2-/-HSCs and HPCs to changes in oxygen tension was observed. Unlike WT-HSCs, Tet2-/-HSCs and HPCs exhibited similar numbers and function in either physioxia or ambient air. The lack of response to changes in oxygen tension in Tet2-/- HSCs was associated with similar changes in self-renewal and quiescence genes among WT-HSC-physioxia, Tet2-/-HSC-physioxia and Tet2-/-HSC-air. We define a novel molecular program involving Tet2 in regulating HSCs under physioxia.
    DOI:  https://doi.org/10.1182/blood.2022015499
  7. N Engl J Med. 2022 Jun 29.
    BNT162b2 Vaccine Effectiveness against Omicron in Children 5 to 11 Years of Age.
    Chandra J Cohen-Stavi, Ori Magen, Noam Barda, Shlomit Yaron, Alon Peretz, Doron Netzer, Carlo Giaquinto, Ali Judd, Leonard Leibovici, Miguel A Hernán, Marc Lipsitch, Ben Y Reis, Ran D Balicer, Noa Dagan.
       BACKGROUND: Limited evidence is available on the real-world effectiveness of the BNT162b2 vaccine against coronavirus disease 2019 (Covid-19) and specifically against infection with the omicron variant among children 5 to 11 years of age.
    METHODS: Using data from the largest health care organization in Israel, we identified a cohort of children 5 to 11 years of age who were vaccinated on or after November 23, 2021, and matched them with unvaccinated controls to estimate the vaccine effectiveness of BNT162b2 among newly vaccinated children during the omicron wave. Vaccine effectiveness against documented severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and symptomatic Covid-19 was estimated after the first and second vaccine doses. The cumulative incidence of each outcome in the two study groups through January 7, 2022, was estimated with the use of the Kaplan-Meier estimator, and vaccine effectiveness was calculated as 1 minus the risk ratio. Vaccine effectiveness was also estimated in age subgroups.
    RESULTS: Among 136,127 eligible children who had been vaccinated during the study period, 94,728 were matched with unvaccinated controls. The estimated vaccine effectiveness against documented infection was 17% (95% confidence interval [CI], 7 to 25) at 14 to 27 days after the first dose and 51% (95% CI, 39 to 61) at 7 to 21 days after the second dose. The absolute risk difference between the study groups at days 7 to 21 after the second dose was 1905 events per 100,000 persons (95% CI, 1294 to 2440) for documented infection and 599 events per 100,000 persons (95% CI, 296 to 897) for symptomatic Covid-19. The estimated vaccine effectiveness against symptomatic Covid-19 was 18% (95% CI, -2 to 34) at 14 to 27 days after the first dose and 48% (95% CI, 29 to 63) at 7 to 21 days after the second dose. We observed a trend toward higher vaccine effectiveness in the youngest age group (5 or 6 years of age) than in the oldest age group (10 or 11 years of age).
    CONCLUSIONS: Our findings suggest that as omicron was becoming the dominant variant, two doses of the BNT162b2 messenger RNA vaccine provided moderate protection against documented SARS-CoV-2 infection and symptomatic Covid-19 in children 5 to 11 years of age. (Funded by the European Union through the VERDI project and others.).
    DOI:  https://doi.org/10.1056/NEJMoa2205011
  8. J Mol Med (Berl). 2022 Jun 27.
    Calorie restriction and breast cancer treatment: a mini-review.
    Meden F Isaac-Lam, Kelly M DeMichael.
      Calorie restriction (CR), referred to as a reduction in dietary calorie intake without malnutrition, has been demonstrated to be a safe way to extend longevity of yeast, worms, and laboratory animals, and to decrease the risk factors in age-related diseases including cancer in humans. Pre-clinical studies in animal models demonstrated that CR may enhance the efficacy of chemotherapy, radiation therapy, and immunotherapy during breast cancer treatment. Reduced calorie intake ameliorates risk factors and delays the onset of cancer by altering metabolism and fostering health-enhancing characteristics including increased autophagy and insulin sensitivity, and decreased blood glucose levels, inflammation, angiogenesis, and growth factor signaling. CR is not a common protocol implemented by medical practitioners to the general public due to the lack of substantial clinical studies. Future research and clinical trials are urgently needed to understand fully the biochemical basis of CR or CR mimetics to support its benefits. Here, we present a mini-review of research studies integrating CR as an adjuvant to chemotherapy, radiation therapy, or immunotherapy during breast cancer treatment.
    Keywords:  Breast cancer treatments; Calorie restriction; Chemotherapy; Immunotherapy; Intermittent fasting; Radiation therapy
    DOI:  https://doi.org/10.1007/s00109-022-02226-y
  9. N Engl J Med. 2022 Jun 29. pii: 10.1056/NEJMc2206926#sa2. [Epub ahead of print]387(2):
    Fourth Dose of BNT162b2 mRNA Covid-19 Vaccine. Reply.
    Jacob G Waxman, Ori Magen, Miguel A Hernán.
      
    DOI:  https://doi.org/10.1056/NEJMc2206926
  10. Cell Rep. 2022 Jun 28. pii: S2211-1247(22)00838-5. [Epub ahead of print]39(13): 111044
    Fatty acid oxidation protects cancer cells from apoptosis by increasing mitochondrial membrane lipids.
    Yi-Jia Li, Johannes Francois Fahrmann, Maryam Aftabizadeh, Qianqian Zhao, Satyendra C Tripathi, Chunyan Zhang, Yuan Yuan, David Ann, Samir Hanash, Hua Yu.
      
    DOI:  https://doi.org/10.1016/j.celrep.2022.111044
  11. Clin Pathol. 2022 Jan-Dec;15:15 2632010X221106986
    Rationale for Nicotinamide Adenine Dinucleotide (NAD+) Metabolome Disruption as a Pathogenic Mechanism of Post-Acute COVID-19 Syndrome.
    Tabitha Block, Jonathann Kuo.
      Many acute COVID-19 convalescents experience a persistent sequelae of infection, called post-acute COVID-19 syndrome (PACS). With incidence ranging between 31% and 69%, PACS is becoming increasingly acknowledged as a new disease state in the context of SARS-CoV-2 infection. As SARS-CoV-2 infection can affect several organ systems to varying degrees and durations, the cellular and molecular abnormalities contributing to PACS pathogenesis remain unclear. Despite our limited understanding of how SARS-CoV-2 infection promotes this persistent disease state, mitochondrial dysfunction has been increasingly recognized as a contributing factor to acute SARS-CoV-2 infection and, more recently, to PACS pathogenesis. The biological mechanisms contributing to this phenomena have not been well established in previous literature; however, in this review, we summarize the evidence that NAD+ metabolome disruption and subsequent mitochondrial dysfunction following SARS-CoV-2 genome integration may contribute to PACS biological pathogenesis. We also briefly examine the coordinated and complex relationship between increased oxidative stress, inflammation, and mitochondrial dysfunction and speculate as to how SARS-CoV-2-mediated NAD+ depletion may be causing these abnormalities in PACS. As such, we present evidence supporting the therapeutic potential of intravenous administration of NAD+ as a novel treatment intervention for PACS symptom management.
    Keywords:  Coronavirus infections; NAD; SARS virus; metabolome; mitochondria; oxidative stress
    DOI:  https://doi.org/10.1177/2632010X221106986
  12. Aging Clin Exp Res. 2022 Jul 01.
    Relationship of frailty with excess mortality during the COVID-19 pandemic: a population-level study in Ontario, Canada.
    Harindra C Wijeysundera, Husam Abdel-Qadir, Feng Qiu, Ragavie Manoragavan, Peter C Austin, Moira K Kapral, Jeffrey C Kwong, Louise Y Sun, Heather J Ross, Jacob A Udell, Idan Roifman, Amy Y X Yu, Anna Chu, Finlay A McAlister, Douglas S Lee.
       BACKGROUND: There is a paucity of the literature on the relationship between frailty and excess mortality due to the COVID-19 pandemic.
    METHODS: The entire community-dwelling adult population of Ontario, Canada, as of January 1st, 2018, was identified using the Cardiovascular Health in Ambulatory Care Research Team (CANHEART) cohort. Residents of long-term care facilities were excluded. Frailty was categorized through the Johns Hopkins Adjusted Clinical Groups (ACG® System) frailty indicator. Follow-up was until December 31st, 2020, with March 11th, 2020, indicating the beginning of the COVID-19 pandemic. Using multivariable Cox models with patient age as the timescale, we determined the relationship between frailty status and pandemic period on all-cause mortality. We evaluated the modifier effect of frailty using both stratified models as well as incorporating an interaction between frailty and the pandemic period.
    RESULTS: We identified 11,481,391 persons in our cohort, of whom 3.2% were frail based on the ACG indicator. Crude mortality increased from 0.75 to 0.87% per 100 person years from the pre- to post-pandemic period, translating to ~ 13,800 excess deaths among the community-dwelling adult population of Ontario (HR 1.11 95% CI 1.09-1.11). Frailty was associated with a statistically significant increase in all-cause mortality (HR 3.02, 95% CI 2.99-3.06). However, all-cause mortality increased similarly during the pandemic in frail (aHR 1.13, 95% CI 1.09-1.16) and non-frail (aHR 1.15, 95% CI 1.13-1.17) persons.
    CONCLUSION: Although frailty was associated with greater mortality, frailty did not modify the excess mortality associated with the pandemic.
    Keywords:  COVID-19; Excess mortality; Frailty; Population-based study
    DOI:  https://doi.org/10.1007/s40520-022-02173-1
  13. N Engl J Med. 2022 Jun 29. pii: 10.1056/NEJMc2206926#sa1. [Epub ahead of print]387(2):
    Fourth Dose of BNT162b2 mRNA Covid-19 Vaccine.
    Andrea Tumminia, Marcello Romano.
      
    DOI:  https://doi.org/10.1056/NEJMc2206926
  14. BMC Geriatr. 2022 Jun 27. 22(1): 527
    Frailty in older people: Rehabilitation Treatment Research Examining Separate Settings (FORTRESS): protocol for a hybrid type II stepped wedge, cluster, randomised trial.
    Heather Block, Alexandra Annesley, Keri Lockwood, Linda Xu, Ian D Cameron, Kate Laver, Maria Crotty, Catherine Sherrington, Annette Kifley, Kirsten Howard, Dimity Pond, Tuan A Nguyen, Susan E Kurrle.
       BACKGROUND: Frailty in older people is associated with increased risk of falls, longer length of stay in hospital, increased risk of institutionalisation and death. Frailty can be measured using validated tools. Multi-component frailty interventions are recommended in clinical practice guidelines but are not routinely implemented in clinical practice.
    METHODS: The Frailty in Older people: Rehabilitation, Treatment, Research Examining Separate Settings (FORTRESS) trial is a multisite, hybrid type II, stepped wedge, cluster, randomised trial with blinded assessment and intention-to-treat analysis being conducted in Australia. The study aims to determine the effectiveness and cost-effectiveness of an embedded individualised multicomponent frailty intervention (commencing in hospital and continuing in the community) on readmissions, frailty and quality of life when compared with usual care. Frail older people admitted to study wards with no significant cognitive impairment, who are expected to return home after discharge, will be eligible to participate. Participants will receive extra sessions of physiotherapy, pharmacy, and dietetics during their admission. A Community Implementation Facilitator will coordinate implementation of the frailty management strategies and primary network liaison. The primary outcome is number of days of non-elective hospital readmissions during 12 month follow-up period. Secondary outcomes include frailty status measured using the FRAIL scale; quality of life measured using the EQ-5D-5L; and time-to-event for readmission and readmission rates. The total cost of delivering the intervention will be assessed, and cost-effectiveness analyses will be conducted. Economic evaluation will include analyses for health outcomes measured in terms of the main clinical outcomes. Implementation outcomes will be collected as part of a process evaluation. Recruitment commenced in 2020 and we are aiming to recruit 732 participants over the three-year duration of the study.
    DISCUSSION: This study will reveal whether intervening with frail older people to address factors contributing to frailty can reduce hospital readmissions and improve frailty status and quality of life. If the FORTRESS intervention provides a clinically significant and cost-effective result, it will demonstrate an improved approach to treating frail patients, both in hospital and when they return home.
    TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (ANZCTR): ACTRN12620000760976p . ANZCTR registered 24 July 2020.
    Keywords:  Aged; Exercise; Frailty; Hospital; Implementation; Nutrition; Older people; Primary care; Transition
    DOI:  https://doi.org/10.1186/s12877-022-03178-1
  15. J Breath Res. 2022 Jun 30.
    The adverse inflammatory response of tobacco smoking in COVID-19 patients: biomarkers from proteomics and metabolomics.
    Tenglong Cui, Gan Miao, Xiaoting Jin, Haiyi Yu, Ze Zhang, Liting Xu, Yili Wu, Guangbo Qu, Guoliang Liu, Yuxin Zheng, Guibin Jiang.
      Whether tobacco smoking affects the occurrence and development of COVID-19 is still a controversial issue, and potential biomarkers to predict the adverse outcomes of smoking in the progression of COVID-19 patients have not yet been elucidated. To further uncover their linkage and explore the effective biomarkers, three proteomics and metabolomics databases (i.e. smoking status, COVID-19 status, and basic information of population) from human serum proteomic and metabolomic levels were established by literature search. Bioinformatics analysis was then performed to analyze the interactions of proteins or metabolites among the above three databases and their biological effects. Potential confounding factors (age, BMI, and gender) were controlled to improve the reliability. The obtained data indicated that smoking may increase the relative risk of conversion from non-severe to severe COVID-19 patients by inducing the dysfunctional immune response. Seven interacting proteins (C8A, LBP, FCN2, CRP, SAA1, SAA2, and VTN) were found to promote the deterioration of COVID-19 by stimulating the complement pathway and macrophage phagocytosis as well as inhibiting the associated negative regulatory pathways, which can be biomarkers to reflect and predict adverse outcomes in smoking COVID-19 patients. Three crucial pathways related to immunity and inflammation, including tryptophan, arginine, and glycerophospholipid metabolism, were considered to affect the effect of smoking on the adverse outcomes of COVID-19 patients. Our study provides novel evidence and corresponding biomarkers as potential predictors of severe disease progression in smoking COVID-19 patients, which is of great significance for preventing further deterioration in these patients.
    Keywords:  COVID-19; biomarkers; metabolomics; proteomics; smoking
    DOI:  https://doi.org/10.1088/1752-7163/ac7d6b
  16. Inflammopharmacology. 2022 Jun 28.
    Targeting inflammation and redox perturbations by lisinopril mitigates Freund's adjuvant-induced arthritis in rats: role of JAK-2/STAT-3/RANKL axis, MMPs, and VEGF.
    Hany H Arab, Sarah A Abd El-Aal, Ahmed M Ashour, Azza A K El-Sheikh, Hana J Al Khabbaz, El-Shaimaa A Arafa, Ayman M Mahmoud, Ahmed M Kabel.
       BACKGROUND: Cardiovascular disorders are major complications of rheumatoid arthritis (RA). Hence, finding effective agents that can target RA progression and its cardiovascular consequences is demanding. The present work aimed to explore the potential of lisinopril, an angiotensin-converting enzyme inhibitor, to mitigate adjuvant's-induced arthritis with emphasis on the pro-inflammatory signals, articular degradation cues, and angiogenesis alongside JAK-2/STAT-3 and Nrf2/HO-1 pathways.
    METHODS: Lisinopril (10 mg/kg/day) was administered by oral gavage for 3 weeks and the target signals were examined by biochemical assays, ELISA, histopathology, immunoblotting, and immunohistochemistry.
    RESULTS: Lisinopril attenuated the progression of arthritis as proven by lowering paw edema, arthritic index, and gait scores alongside diminishing the immune-cell infiltration/aberrant histopathology in the dorsal pouch lining. These favorable actions were associated with curtailing the production of inflammatory cytokines (TNF-α, IL-6, IL-1β, and IL-17) and the pro-inflammatory angiotensin II alongside upregulating the anti-inflammatory angiotensin-(1-7) in the hind paw of arthritic rats. At the molecular level, lisinopril inhibited the upstream JAK-2/STAT-3 pathway by downregulating the protein expression of p-JAK-2/total JAK-2 and p-STAT-3/total STAT-3 ratio and the nuclear levels of NF-κBp65. Meanwhile, lisinopril curbed the downstream cartilage degradation signals matrix metalloproteinases (MMP-3 and MMP-9) and the bone erosion cue RANKL. Equally important, the protein expression of the angiogenesis signal VEGF was downregulated in the hind paw/dorsal lining. With respect to oxidative stress, lisinopril suppressed the paw lipid peroxides and boosted GSH and Nrf-2/HO-1 pathway.
    CONCLUSION: Lisinopril attenuated adjuvant-induced arthritis via inhibition of inflammation, articular degradation cues, and angiogenesis.
    Keywords:  JAK-2; Lisinopril; RANKL; Rheumatoid arthritis; STAT-3; VEGF
    DOI:  https://doi.org/10.1007/s10787-022-00998-w
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