ISSN / EISSN: 01435221 / 14708736
Published by: Portland Press Ltd.
Total articles ≅ 10,269
Latest articles in this journal
Clinical Science, Volume 136, pp 1731-1758; https://doi.org/10.1042/cs20210862
Cardiovascular disease (CVD) remains the leading cause of death worldwide. An ongoing challenge remains the development of novel pharmacotherapies to treat CVD, particularly atherosclerosis. Effective mechanism-informed development and translation of new drugs requires a deep understanding of the known and currently unknown biological mechanisms underpinning atherosclerosis, accompanied by optimization of traditional drug discovery approaches. Current animal models do not precisely recapitulate the pathobiology underpinning human CVD. Accordingly, a fundamental limitation in early-stage drug discovery has been the lack of consensus regarding an appropriate experimental in vivo model that can mimic human atherosclerosis. However, when coupled with a clear understanding of the specific advantages and limitations of the model employed, preclinical animal models remain a crucial component for evaluating pharmacological interventions. Within this perspective, we will provide an overview of the mechanisms and modalities of atherosclerotic drugs, including those in the preclinical and early clinical development stage. Additionally, we highlight recent preclinical models that have improved our understanding of atherosclerosis and associated clinical consequences and propose model adaptations to facilitate the development of new and effective treatments.
Clinical Science, Volume 136, pp 1759-1772; https://doi.org/10.1042/cs20220547
Background: Hypertension (HTN) is associated with renal proinflammatory immune cell infiltration and increased sodium retention. We reported previously that renal lymphatic vessels, which are responsible for trafficking immune cells from the interstitial space to draining lymph nodes, increase in density under hypertensive conditions. We also demonstrated that augmenting renal lymphatic density can prevent HTN in mice. Whether renal lymphangiogenesis can treat HTN in mice is unknown. We hypothesized that genetically inducing renal lymphangiogenesis after the establishment of HTN would attenuate HTN in male and female mice from three different HTN models. Methods: Mice with inducible kidney-specific overexpression of VEGF-D (KidVD) experience renal lymphangiogenesis upon doxycycline administration. HTN was induced in KidVD+ and KidVD- mice by subcutaneous release of angiotensin II, administration of the nitric oxide synthase inhibitor L-NAME, or consumption of a 4% salt diet following a L-NAME priming and washout period. After a week of HTN stimuli treatment, doxycycline was introduced. Systolic blood pressure (SBP) readings were taken weekly. Kidney function was determined from urine and serum measures. Kidneys were processed for RT-qPCR, flow cytometry, and imaging. Results: Mice that underwent renal-specific lymphangiogenesis had significantly decreased SBP and renal proinflammatory immune cells. Additionally, renal lymphangiogenesis was associated with a decrease in sodium transporter expression and increased fractional excretion of sodium, indicating improved sodium handling efficiency. Conclusions: These findings demonstrate that augmenting renal lymphangiogenesis can treat HTN in male and female mice by improving renal immune cell trafficking and sodium handling.
Clinical Science; https://doi.org/10.1042/cs20220493
Sepsis is a leading cause of acute kidney injury (AKI), and the pathogenesis of septic AKI remains largely unclear. Parkinson disease protein 7 (PARK7) is a protein of multiple functions that was recently implicated in septic AKI, but the underlying mechanism is unknown. In the present study, we determined the role of PARK7 in septic AKI and further explored the underlying mechanism in lipopolysaccharide (LPS)-induced endotoxic models. PARK7 was induced both in vivo and in vitro following LPS treatment. Compared with wild-type mice, Park7-deficient mice experienced aggravated kidney tissue damage and dysfunction, and enhanced tubular apoptosis and inflammation following LPS treatment. Consistently, LPS-induced apoptosis and inflammation in renal tubular cells in vitro were exacerbated by Park7 knockdown, whereas they were alleviated by PARK7 overexpression. Mechanistically, silencing Park7 facilitated nuclear translocation and phosphorylation of p65 (a key component of the NF-κB complex) during LPS treatment, whereas PARK7 overexpression partially prevented these changes. Moreover, we detected PARK7 interaction with p65 in the cytoplasm in renal tubular cells, which was enhanced by LPS treatment. Collectively, these findings suggest that PARK7 is induced to protect against septic AKI through suppressing NF-κB signaling.
Clinical Science, Volume 136, pp 1691-1710; https://doi.org/10.1042/cs20220581
Lymph node (LN) metastasis affects both the management and prognosis of head and neck squamous cell carcinoma (HNSCC). Here, we explored the relationship between lymphatic metastasis and CEA family member 5 (CEACAM5), including its possible regulatory role in HNSCC. The levels of CEACAM5 in tissues from patients with HNSCC, with and without LN metastases, were assessed by transcriptome sequencing. The associations between CEACAM5 and the N stage of LN metastasis in HNSCC were predicted through The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases and a pan-cancer analysis of CEACAM5 expression in 33 common human tumors was conducted. CEACAM5 levels were analyzed in tumor and normal tissue specimens from HNSCC patients and the correlation between CEACAM5 levels and prognosis was evaluated. The influence of CEACAM5 on cell proliferation, invasion, migration, and apoptosis was investigated in HNSCC cell lines, as were the downstream regulatory mechanisms. A mouse model of LN metastasis was constructed. CEACAM5 levels were significantly higher in HNSCC tissue without LN metastasis than in that with LN metastasis. Similar findings were obtained for the clinical specimens. CEACAM5 levels were associated with better clinical prognosis. CEACAM5 was found to inhibit the proliferation and migration and promote the apoptosis of HNSCC cells. A mouse xenograft model showed that CEACAM5 inhibited LN metastasis. In conclusions, CEACAM5 inhibited epithelial–mesenchymal transition (EMT) in HNSCC by reducing murine double minute 2 (MDM2) expression and thereby suppressing LN metastasis. CEACAM5 has potential as both a prognostic marker and a therapeutic target in HNSCC.
Clinical Science, Volume 136, pp 1683-1690; https://doi.org/10.1042/cs20220203
The microbiome contributes to human development and maturation, and is essential for maintenance of health and prevention of disease. While the human genome encodes one’s identity, the microbiome – also individually unique – provides a window on one’s lifestyle and exposure to environmental variables. The microbiome thus serves as a biomarker of host health and a driver of certain diseases. However, current understanding of the gut microbiome is largely based on studies of industrialised peoples of North America and Europe. Gaps in knowledge of the microbiomes of other groups, particularly those in developing or nonindustrialised societies, are important, particularly in view of contrasting epidemiological risks of acquiring chronic inflammatory and metabolic disorders. Here, we explore underlying mechanisms of microbiome differences and whether the potential benefits of nonindustrialised microbiome can be realised in a modern world.
Clinical Science; https://doi.org/10.1042/cs20220450
Persons with cystic fibrosis (CF) exhibit a unique alteration of fatty acid composition, marked especially among polyunsaturates by relative deficiency of linoleic acid and excess of Mead acid. Relative deficiency of docosahexaenoic acid is variably found. However, the initial development of these abnormalities is not understood. We examined fatty acid composition in young CF ferrets and pigs, finding abnormalities from the day of birth onward including relative deficiency of linoleic acid in both species. Fatty acid composition abnormalities were present in both liver and serum phospholipids of newborn CF piglets even prior to feeding, including reduced linoleic acid and increased Mead acid. Serum fatty acid composition evolved over the first weeks of life in both non-CF and CF ferrets, though differences between CF and non-CF persisted. Although red blood cell phospholipid fatty acid composition was normal in newborn animals, it became perturbed in juvenile CF ferrets including relative deficiencies of linoleic and docosahexaenoic acids and excess of Mead acid. In summary, fatty acid composition abnormalities in CF pigs and ferrets exist from a young age including at birth independent of feeding and overlap extensively with the abnormalities found in humans with CF. That the abnormalities exist prior to feeding implies that dietary measures alone will not address the mechanisms of imbalance.
Clinical Science; https://doi.org/10.1042/cs20220477
Oxidative stress is vital for pathophysiology of atherosclerosis and non-alcoholic fatty liver disease (NAFLD). Monoamine oxidase (MAO) is an important source of oxidative stress in the vascular system and liver. However, the effect of MAO inhibition on atherosclerosis and NAFLD has not been explored. In this study, MAO A and B expressions were increased in atherosclerotic plaques in human and apolipoprotein E (ApoE)-deficient mice. Inhibition of MAO B (by deprenyl), but not MAO A (by clorgyline), reduced the atheroma area in the thoracic aorta and aortic sinus in ApoE-deficient mice fed the cholesterol-enriched diet for 15 weeks. MAO B inhibition attenuated oxidative stress, expression of adhesion molecules, production of inflammatory cytokines, and macrophage infiltration in atherosclerotic plaques and decreased plasma triglyceride and low-density lipoprotein (LDL) cholesterol concentrations. MAO B inhibition had no therapeutic effect on restenosis in the femoral artery wire-induced injury model in C57BL/6 mice. In the NAFLD mouse model, MAO B inhibition reduced lipid droplet deposition in the liver and hepatic total cholesterol and triglyceride levels in C57BL/6 mice fed high-fat diets for 10 weeks. Key enzymes for triglyceride and cholesterol biosynthesis (fatty acid synthase and 3-hydroxy-3-methylglutaryl-CoA reductase, HMGCR) and inflammatory markers were inhibited, and cholesterol clearance was upregulated (increased LDL receptor expression and reduced proprotein convertase subtilisin/kexin type 9, PCSK9, expression) by MAO B inhibition in the liver. These results were also demonstrated in the HepG2 liver cell model. Our data suggest that MAO B inhibition is a potential and novel treatment for atherosclerosis and NAFLD
Clinical Science, Volume 136, pp 1657-1659; https://doi.org/10.1042/cs20220040
The precise control of whole-body calcium is essential for the maintenance of normal physiological function. Disruptions in calcium homeostasis can lead to pathology including osteoporosis, kidney stone formation, and cardiac arrythmias. During the 1960s and early 1970s, a full understanding of calcium metabolism was still emerging. This commentary spotlights a seminal Clinical Science paper published in 1972 that significantly advanced the field and contributed to the eventual approval of bisphosphonate drugs commonly used to treat postmenopausal osteoporosis, cancer metastases, and other calcium disorders.
Clinical Science, Volume 136, pp 1661-1681; https://doi.org/10.1042/cs20220607
Cardiac hypertrophy is necessary for the heart to accommodate an increase in workload. Physiological, compensated hypertrophy (e.g. with exercise) is reversible and largely due to cardiomyocyte hypertrophy. Pathological hypertrophy (e.g. with hypertension) is associated with additional features including increased fibrosis and can lead to heart failure. RAF kinases (ARAF/BRAF/RAF1) integrate signals into the extracellular signal-regulated kinase 1/2 cascade, a pathway implicated in cardiac hypertrophy, and activation of BRAF in cardiomyocytes promotes compensated hypertrophy. Here, we used mice with tamoxifen-inducible cardiomyocyte-specific BRAF knockout (CM-BRAFKO) to assess the role of BRAF in hypertension-associated cardiac hypertrophy induced by angiotensin II (AngII; 0.8 mg/kg/d, 7 d) and physiological hypertrophy induced by phenylephrine (40 mg/kg/d, 7 d). Cardiac dimensions/functions were measured by echocardiography with histological assessment of cellular changes. AngII promoted cardiomyocyte hypertrophy and increased fibrosis within the myocardium (interstitial) and around the arterioles (perivascular) in male mice; cardiomyocyte hypertrophy and interstitial (but not perivascular) fibrosis were inhibited in mice with CM-BRAFKO. Phenylephrine had a limited effect on fibrosis but promoted cardiomyocyte hypertrophy and increased contractility in male mice; cardiomyocyte hypertrophy was unaffected in mice with CM-BRAFKO, but the increase in contractility was suppressed and fibrosis increased. Phenylephrine induced a modest hypertrophic response in female mice and, in contrast with the males, tamoxifen-induced loss of cardiomyocyte BRAF reduced cardiomyocyte size, had no effect on fibrosis and increased contractility. The data identify BRAF as a key signalling intermediate in both physiological and pathological hypertrophy in male mice, and highlight the need for independent assessment of gene function in females.
Clinical Science, Volume 136, pp 1653-1656; https://doi.org/10.1042/cs20220101
Over 50 years ago, John Wahren and Lennart Jorfeldt published a manuscript in Clinical Science where they detailed a series of studies of leg blood flow during exercise. They used a novel approach to indicator dye dilution: continuous arterial infusions of dye using venous samples. This technique allowed them to describe for the first time the fundamental relationships between large muscle group exercise, muscle blood flow, and pulmonary and muscle oxygen uptake. They also defined mechanical efficiency, a key measurement of muscle function. This paper formed the basis for research into muscle blood flow and exercise in health and disease and continued to be cited by modern research. In this commentary, we describe the innovations they made, the key observations that came out of their results, and the importance of this manuscript to current research.