Elisabetta Caiazzo

Background: Inflammatory chemokine receptors encompassing CCR1, CCR2, CCR3, and CCR5 orchestrate the recruitment of leukocytes during inflammation. In atherosclerosis, there is ongoing controversy surrounding the precise role each inflammatory chemokine receptor plays in the disease process. We thus performed a systematic review and meta‐analysis to examine the effects of inflammatory chemokine receptor inhibition on experimental atherosclerotic burden. Methods: We performed a systematic literature search of PubMed/MEDLINE, Embase, and Web of Science for studies on the pharmacological and/or genetic manipulation of inflammatory chemokine receptors in murine models of atherosclerosis or hyperlipidemia. We extracted data on lesion size and morphological composition as primary outcomes, and plasma lipid profile and mouse body weight as secondary outcomes. We used a random effects model to calculate the pooled effect size across studies as the standardized mean difference (SMD) with 95% CIs. Results: A total of 38 studies of experimental atherosclerosis (CCR1: n=9, CCR2: n=24, CCR5: n=13) were included. Genetic or pharmacological inhibition of CCR2 and CCR5 significantly reduced lesion size (CCR2: SMD=−1.14 [95% CI, −1.47 to −0.81]; CCR5: SMD=−1.06 [95% CI, −1.64 to −0.48]), (CCR2: SMD=−0.72 [95% CI, −1.15 to −0.29]; CCR5: SMD=−1.92 [95% CI, −2.58 to −1.26]) and macrophage load (CCR2: SMD=−1.35 [95% CI, −1.97 to −0.74], CCR5: SMD=−1.29 [95% CI, −2.39 to −0.20]), (CCR2: SMD=−0.86 [95% CI, −1.43 to −0.29]; CCR5: SMD=−1.69 [95% CI, −2.69 to −0.69]), respectively. Pharmacological (but not genetic) targeting of CCR1 significantly reduced lesion size, with protection observed only in males when both approaches were considered. Conclusions: Our analysis suggests that inhibition of either CCR2 or CCR5 is protective in experimental atherosclerosis, while the effect of CCR1 intervention is less clear with potential beneficial effects in male populations.

Introduction: Heart failure with preserved ejection fraction (HFpEF) accounts for nearly half of all heart failure cases and lacks effective therapies. Key features of HFpEF include endothelial dysfunction, fibrosis, and oxidative stress. Adenosine signaling, regulated by enzymes and receptors, is critical for vascular homeostasis and inflammation, but its role in HFpEF remains poorly understood. Adenosine receptors are abundantly expressed in the heart and kidney, modulating vascular, fibrotic, and tubular processes. Dysregulation of adenosine pathways in either organ may drive hypertension, microvascular dysfunction, and maladaptive cardio-renal crosstalk, highlighting the need to investigate adenosine signaling as a combined multi-organ target. Methods: HFpEF was induced in Dahl salt-sensitive rats by high-salt diet. Cardiac structure, function, fibrosis, oxidative stress, cytokines, renal adenosine receptors and cardiac adenosine pathway components were assessed using echocardiography, histology, proteome profiling and Western blotting. Human cardiac microvascular endothelial cells were treated with endothelin-1 in the presence of selective A _2A or A _2B agonists, or adenosine deaminase (ADA) inhibition, and profibrotic/oxidative stress genes were analyzed by qPCR. Results: Hypertensive rats exhibited diastolic dysfunction with preserved systolic function, cardiac and renal fibrosis, oxidative/nitrative stress, and elevated pro-inflammatory cytokines. Cardiac expression of CD39, CD73, and ADA enzymes was significantly reduced, indicating impaired adenosine metabolism, while transporters ENT2 and CNT2 were also downregulated, reflecting impairment of both equilibrative and concentrative adenosine transport. Adenosine receptor profiles were altered: A ₁ expression increased, A _2A decreased, and A _2B and A ₃ selectively upregulated in hypertensive, but not HFpEF, animals. In the kidney, A ₁ and A _2A receptor expression showed region-specific, time-dependent changes. In human endothelial cells, A _2A activation or ADA inhibition suppressed endothelin-1-induced COL1, COL3, and TGF-β1 expression, whereas A _2B had no effect. Both A _2A and A _2B restored MnSOD expression, while NOX4 was selectively increased by A _2B . Only A _2A activation induced CAT expression, highlighting its stronger antioxidant role. Conclusion: Impaired adenosine metabolism and transport, along with altered receptor signaling contribute to HFpEF progression. Selective A _2A activation attenuates endothelial pro-fibrotic profiles and restores antioxidant defenses, supporting its therapeutic potential. Renal receptor changes reinforce maladaptive cardio-renal crosstalk, emphasizing the importance of multi-organ adenosine modulation in HFpEF and encouraging further translational studies.

To identify the underlying mechanisms by which H. rhamnoides fruit extract exerts regulatory effects on intestinal function, we investigated its chemical composition using UHPLC Q-Orbitrap HRMS and evaluated its biological effects on Aquaporin-3 (AQP-3) expression via Western blot in the intestinal epithelial cell line (HT-29). Moreover, fecal microbiota from healthy and constipated adults was employed to mimic the in vitro fermentation of the digested extract and evaluate its effects on gut microbiota functionality. Antioxidant capacity (i.e., Total Phenolic Contents (TPC), 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS), 2,2-diphenyl-1-picrylhydrazyl (DPPH), and ferric reducing antioxidant power (FRAP) assays) was assessed prior to and after simulated digestion and fermentation processes. Short-chain fatty acids (SCFAs) were quantified using UHPLC-RID of the fermented samples. In the extract, 23 compounds belonging to a variety of classes (mainly polyphenols) were tentatively identified. The extract significantly upregulated AQP-3 expression in the absence of cytotoxicity. After in vitro fermentation with gut microbiota isolated from constipated subjects, ABTS and FRAP values significantly decreased, as well as TPC, suggesting a greater consumption of antioxidant compounds, consistent with the increased production of radical compounds associated with constipation. Fermentation with intestinal microbiota with healthy and constipated gut microbiota resulted in an increase in SCFA. These results provide preliminary insights into a non-pharmacological strategy for functional constipation.

Background Inflammation might predispose to worse outcomes after an ischemic stroke. This has not been characterized among indigenous Africans. Purpose We investigated the association between inflammatory biomarkers, stroke severity, and outcomes in Africans. Methods This is a retrospective analysis of a prospective study, including 90 participants with confirmed ischemic stroke selected from the Stroke Investigative Research & Educational Network (SIREN) cohort and 90 controls matched by age, sex, and ethnicity. Plasma concentrations of 368 protein biomarkers were analyzed (Olink® Explore 384 Inflammation panel) and compared between cases and controls. Further, we investigated the association between these proteins and stroke severity, lesion volume, and one-month post-stroke disability and fatality. Results Differential protein expression analysis revealed 23 up-regulated and 14 down-regulated proteins in stroke cases versus controls. Among the up-regulated proteins, agouti-related protein (AgRP) and tumor necrosis factor receptor superfamily member 11A (TNFRSF11A) were the most significantly up-regulated, while interleukin-1 beta (IL-1β) and integrin alpha-11 (ITGA11) were the most down-regulated proteins. Logistic regression analysis identified 72 proteins that were associated with stroke severity independent of age and sex. Among these, complement C1q subcomponent subunit A (C1qa) exhibited the strongest associations. Additionally, 14 proteins including C-C motif chemokine 23 (CCL23) were found to be associated with one-month post-stroke disability. Conclusion Stroke disability and severity were associated with inflammation in an indigenous African population. The identified biomarkers might be useful for predicting stroke outcome or serve as therapeutic target.

Despite being the most common cardiovascular risk factor, the actual burden of hypertension is poorly characterized in Africa. We meta-analysed the most extensive pooled data to determine the overall prevalence of hypertension in Africa. Following Preferred Reporting Items for Systematic Review and Meta-Analyses guidelines, we systematically searched Google Scholar, PubMed, ScienceDirect, and Web of Science databases to retrieve prevalence studies only on hypertension among Africans published between 2002 and 2023. Furthermore, we meta-analysed the crude and age-adjusted prevalences of hypertension using a random effect model due to the expected high heterogeneity, with logit transformation of the original proportions. Seventy-eight (out of an initial 779 screened) articles with complete data were included, with a total number of hypertension cases of 71 004 and a denominator population of 286 575, mostly from community-based studies in 23 countries. The pooled crude prevalence of hypertension was 28.5/100 persons [95% confidence interval (CI): 25.3–31.8%] and a 95% prediction interval of 7.6–65.6%; the pooled prevalence increased with age and was highest among the aged ≥75 years: 51.4% (95% CI: 42.0–60.6%) and remained highest in the Southern Africa region overall (34.8%) and in the last decade (2013–23; 44.5%). The point estimate of the pooled crude prevalence was higher among urban dwellers, 32.9% (95% CI: 26.8–39.5%), than rural residents, 26.3% (95% CI: 20.4–33.3%). In a subset of 21 articles reporting age stratification consistent with the World Health Organization standard population, the pooled age-standardized prevalence was 27.2/100 persons (95% CI: 20.9–33.6%). The burden of hypertension remains high, especially in urban areas and with increasing age. Frequent screening and treatment are recommended, especially in urban areas.

Background: The neutrophil-to-lymphocyte ratio (NLR) may be a useful marker of inflammation, but its associations with clinical characteristics, signs of congestion and outcome in patients with chronic heart failure (HF) are unknown. Methods and results: We enrolled 4702 ambulatory patients with HF and either left ventricular systolic dysfunction or high N-terminal pro-B-type natriuretic peptide (NTproBNP) (≥125 ng/L). Compared with those in the lowest quartile of NLR (≤2.05), patients in the highest quartile (≥4.10) were older, had higher NTproBNP, and were more likely to have HF with reduced left ventricular ejection fraction (HFrEF), atrial fibrillation and to be treated with loop diuretics. In 813 patients with detailed echocardiographic assessment, lymphocyte count correlated inversely with NTproBNP (r = −0.31) and markers of congestion [left atrial volume index (r = −0.25), inferior vena cava diameter (r = −0.24)]; neutrophil count correlated positively with high-sensitivity C-reactive protein (hsCRP) (r = 0.31, P < 0.001). During a median follow-up of 54 (29–100) months, 3015 (64%) patients died. In models adjusted for NTproBNP and HsCRP, higher NLR [hazard ratio (HR):1.05; 95% confidence interval (CI) 1.03–1.06] and neutrophil count (HR:1.07; 95%CI 1.04–1.10) were associated with higher mortality rates; higher lymphocyte count (HR:0.88; 95%CI 0.82–0.95) was associated with lower risk (all P < 0.001). Conclusions: Low lymphocyte count is associated with more congestion and high neutrophil count with more inflammation, which may explain why a greater NLR is associated with a poorer prognosis. For patients with heart failure, NLR or its components could be useful for risk stratification or for monitoring evolving risk, but might also be therapeutic targets.

Currently, the biomimetic approach of drawing inspiration from nature has frequently been employed in designing drug nanocarriers (NCs) of actively target various diseases, ranging from cancer to neuronal and inflammation pathologies. The cell-membrane coating can confer upon the inner nanomaterials a biological identity and the functions exhibited by the cells from which the membrane is derived. Monocyte- and macrophage-membrane-coated nanomaterials have emerged as an ideal delivery system to target inflamed vasculature. Herein, we developed two biomimetic NCs using a human-derived leukaemia monocytic cell line (THP-1), either undifferentiated or differentiated by phorbol 12-myristate 13-acetate (PMA) into adherent macrophage-like cells as membrane sources for NC coating. We employed a secondary oil-in-water nano-emulsion (SNE) as the inner core, which served as an optimal NC for high payloads of lipophilic compounds. Two different biomimetic systems were produced, combining the biomimetic features of biological membranes with the physicochemical and nano-sized characteristics of SNEs. These systems were named Monocyte NEsoSome (M-NEsoSome) and Macrophage NEsoSome (M0-NEsoSome). Their uptake ability was investigated in tumour necrosis factor alfa (TNFα)-treated human umbilical vein endothelial cells (HUVECs), selected as a model of inflamed endothelial cells. The M0 membrane coating demonstrated accelerated internalisation compared with the monocyte coating and notably surpassed the uptake rate of bare NCs. In conclusion, M0-NEsoSome NCs could be a therapeutic system for targeting inflamed endothelial cells and potentially delivering anti-inflammatory drugs in vascular inflammation.

Emerging evidence indicates an association between blood pressure and inflammation, yet this relationship remains unclear in older adults, despite the elevated prevalence of hypertension. We investigated the association between blood pressure, high sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6), and white blood cell (WBC) count in a cohort of 3571 older adults aged 65 and above, and 587 middle-aged participants (55–59 years old). In women aged 65 and above, the relationship between inflammatory markers and blood pressure was consistent, with hs-CRP and WBC emerging as predictors of high blood pressure. For hs-CRP, the adjusted odds ratio (OR) was 1.5 (95% CI, 1.07 to 2.10, P = 0.02), and for WBC, the adjusted OR was 1.41 (95% CI, 1.02 to 1.94, P = 0.04), comparing the highest to the lowest quartiles. In men, only the WBC count was significantly associated with an increased OR for high BP (adjusted OR 1.49, 95% CI, 1.09 to 2.02, P = 0.01) across quartiles. Across the entire study population, in a fully adjusted model, all inflammatory markers were modestly associated with blood pressure levels, while the effect of being over 65 years was the most significant predictor of high blood pressure (OR 1.84, 95% CI, 1.50 to 2.25, P < 0.001). The link between key inflammation markers and blood pressure in older adults varies by sex and biomarker type and may differ from the relationship observed in younger individuals. These relationships are likely to be affected by factors linked to age.