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Ivan Pećin,1,2 Željko Reiner1,2 1Zagreb School of Medicine, University of Zagreb, Zagreb, Croatia; 2Division of Metabolic Diseases, Department of Internal Medicine, University Hospital Center, Zagreb, CroatiaCorrespondence: Željko ReinerDivision of Metabolic Diseases, Department of Internal Medicine, University Hospital Center Zagreb Kispaticeva 12, Zagreb, 10 000, CroatiaTel + 385 1 2388772Fax + 385 1 2388623Email zreiner@kbc-zagreb.hrAbstract: Atherosclerotic cardiovascular diseases (ASCVD) are still the leading cause of morbidity and mortality in most developed countries and even more in developing countries. Dyslipidemia is a well known main risk factor for ASCVD. Lipid-lowering treatment, particularly lowering LDL-cholesterol (LDL-C), can decrease the risk for ASCVD. New data and guidelines based upon them suggest that we should go with LDL-C levels as low as we can. Therefore, conventional lipid lowering agents (statins and statins+ezetimibe) are not enough mainly because of poor compliance and statin intolerance which is in the real world mostly pseudo-intolerance. PCSK9 inhibitors provided a new hope to further decrease LDL-C but are still expensive, they have to be injected subcutaneously twice a month and their long-lasting adverse effects are not known. Therefore, there is a constant need to develop novel, more potent, more safe, less expensive, more user friendly regimens of hypolipemic agents (bempedoic acid, selective PPAR alpha receptor modulators etc). One of the ways to overcome poor compliance and increase the potency of therapy with less adverse effects are fixed combinations of established drugs (statin+ezetimibe). The future of hypolipemic agents is based on antisense therapy, ie. the use of specific oligonucleotide sequences blocking the translation of the selected protein (targeting apolipoprotein CIII, lipoprotein (a), apolipoprotein B) or RNA silencing technique (PCSK9 mRNA) and are in various stages of clinical trials. Some of them are almost ready to use in everyday clinical practice. High risk and very high risk patients (eg. familial hypercholesterolemia, familial severe chylomicronemia syndrome) will benefit most. The aim of this review is to inform about novel hypolipemic agents – potent and safe drugs for dyslipidemia which should reduce the risk of ASCVD.Keywords: dyslipidemia, novel hypolipemic drugs, cardiovascular risk, LDL-cholesterol, triglycerides, inclisiran, PCSK9 inhibitors, pemafibrate, bempedoic acid, ANGPTL3, pelacarsen

Abstract Key message We analyzed stem growth responses of Douglas-fir (Pseudotsuga menziesii (Mirb.) Franco) to severe drought in 2003/04 and 2018. The results showed high drought tolerance in sandy, loamy, and most silty soils, with limitations on clayey soils. This study indicates the susceptibility of Douglas-firs with shallow root systems to extreme drought and the importance of deep rooting for high drought resilience. Context Although Douglas-fir (Pseudotsuga menziesii (Mirb.) Franco) is considered a more drought-tolerant substitute for Norway spruce (Picea abies (L.) Karst.) in Europe, there is considerable uncertainty about the drought tolerance of Douglas-fir under climate change, specifically concerning soil properties. Aims This study aimed to assess the influence of soil texture, plant-available water capacity, and rooting characteristics on the interannual stem growth response of Douglas-fir when exposed to severe drought. Methods Along a soil texture gradient from sand to clay, we selected seven closely spaced sites at elevations of approximately 500 m a.s.l. in southern Germany. Mixed-effects models were used to analyze the effects of soil physical and rooting characteristics on growth response indices (resistance, recovery, resilience) related to the severe to extreme droughts in 2003/04 and 2018. Results Douglas-fir showed high drought tolerance in sandy, loamy, and most silty soils. However, the results suggest a higher drought stress risk on clayey soils, as well as at specific silty sites with shallow root systems. A higher effective rooting depth increased the resilience of Douglas-fir during the extreme drought in 2018. Conclusion Douglas-fir demonstrated its drought tolerance in most soil textures. In addition, this study supports the need for combined above- and below-ground investigations on factors influencing drought tolerance and the importance of rooting for drought resilience.

IntroductionDouglas-fir (Pseudotsuga menziesii (Mirb.) Franco) is considered an important non-native substitute tree species in Europe, especially for Norway spruce (Picea abies (L.) Karst.), mainly due to its higher drought tolerance. However, Douglas-fir has also shown increasing mortality in certain regions of the world. One of the main reasons is the increase in drought and heat periods due to climate change. There is still a need for research on the influence of important soil properties and rooting characteristics on the drought tolerance of Douglas-fir. Therefore, we analyzed the influence of soil texture, plant-available water capacity (PAWC), fine root density, and effective rooting depth on water status and thus drought stress in Douglas-fir during the extreme drought of 2018.MethodsWe selected seven closely spaced sites along a soil texture gradient from sand to clay at an elevation of ca. 500 m a.s.l. in southern Germany and determined soil physical and rooting characteristics. Water status parameters and growth duration were derived from dendrometer data at five Douglas-firs per site. The influence of soil and rooting characteristics on these drought stress-related parameters was analyzed using mixed-effects models. The focus was on two summer drought periods in 2018.Results and discussionIn the initial stage of the extreme summer drought of 2018 (in June), a higher PAWC and a higher fine root density reduced drought stress. However, these influences were no longer noticeable in the later stage of drought (in August), probably due to deeper soil desiccation. In August, a higher effective rooting depth reduced drought stress. Soil texture had a significant influence, particularly on growth duration. This study provides information on site selection for Douglas-fir cultivation under the predicted increase in severe drought, showing the importance of deep and intensive rooting, and points to the need for combined above- and belowground investigations for a better understanding of the drought response patterns of tree species.

IntroductionSoil drought during summer in Central Europe has become more frequent and severe over the last decades. European forests are suffering increasing damage, particularly Norway spruce. Douglas-fir (Pseudotsuga menziesii (Mirbel) Franco), a non-native tree species, is considered as a promising alternative to build drought-resilient forests. The main goal of this study was to investigate the intraannual radial stem growth and sap flow performance of Douglas-fir along a precipitation gradient across Germany under severe drought.Material and methodsSap flow and stem radial changes of up to ten trees each at four sites with different precipitation regimes were measured in combination with volumetric soil water content during the growing season of 2022. Measurements of stem radial changes were used to calculate the trees’ stem water deficit, a proxy for tree water status and drought stress.ResultsThe severe summer drought of 2022 led to an early growth cessation and a significant reduction in daily sap flow at all four sites monitored. We could identify a site-specific threshold in soil water availability ranging between 21.7 and 29.6% of relative extractable water (REW) under which stem water reserves cannot be replenished and thereby inhibiting radial growth. We could also demonstrate that at this threshold, sap flow is heavily reduced to between 43.5 and 53.3%, and for a REW below 50%, sap flow linearly decreases by 1.1–2.0% per 1% reduction in REW. This reduction tends to follow the humidity gradient, being more pronounced at the most oceanic characterized site and suggesting an adaptation to site conditions. Even though Douglas-fir is considered to be more drought stress resistant than Norway spruce, growth and sap flow are greatly reduced by severe summer drought, which became more frequent in recent years and their frequency and intensity is likely to increase.ConclusionsOur results suggest that timber production of Douglas-fir in Central Europe will decline considerably under projected climate change, and thus pointing to site specific growth constraints for a so far promising non-native tree species in Europe.

Depth filtration is a widespread technique for the separation of airborne particles. The evolution of the pressure difference within this process is determined to a significant extent by the filter structure. Simulations are an important tool for optimizing the filter structure, allowing the development of filter materials having high filtration efficiencies and low pressure differences. Because of the large number of physical phenomena and the complex structure of filter materials, simulations of the filtration kinetics are, however, challenging. In this context, one-dimensional models are advantageous for the calculation of the filtration kinetics of depth filters, due to their low computation requirements. In this work, an approach for combining a one-dimensional model with microstructural data of filter materials is presented. This enables more realistic modeling of the filtration process. Calculations were performed on a macroscopic as well as microscopic level and compared to experimental data. With the suggested approach, the influence of a measured microstructure on the results was examined and predictability was improved. Especially for small research departments and for the development of optimized filter materials adapted to specific separation tasks, this approach provides a valuable tool.

Abstract We present discrete (2‐h resolution) multi‐year (2008–2017) in situ measurements of seasonal vegetation growth and soil biophysical properties from two sites on Alaska's North Slope, USA, representing dry and wet sedge tundra. We examine measurements of vertical active soil layer temperature and soil moisture profiles (freeze/thaw status), woody shrub vegetation physiological activity, and meteorological site data to assess interrelationships within (and between) these two study sites. Vegetation phenophases (cold de‐hardening start, physiological function start, stem growth start, stem growth end, physiological function end, cold hardening completion) were found to have greater interannual day of year (DOY) occurrence variability at the dry site compared with the wet site. At the dry site, vegetation activity begins on average ~7 days earlier and ends ~11 days earlier. The mean active stem growth window lasts ~54 days for the dry site and ~51 days for the wet site. Vegetation, in both tundra environments, began cold de‐hardening functions (warm season prep) prior to atmospheric temperatures warming above 0°C. Similar results were found related to the critical soil freeze/thaw/transition dates; the dry site had a DOY phenophase occurrence range that was 8 days larger than that of the wet site. A longer continuous summer thaw period was captured at the wet site by ~26 days throughout the active layer. In addition, the dry site was measured to have longer spring and fall soil isothermal conditions than the wet site by ~9 and 5 days throughout the active layer. These results show that the dry site's willow shrub vegetation physiology and soil condition phenology is more variable than the wet site. Alongside the in situ data, a remote sensing product from NASA's MEaSUREs program was utilized; our research indicates that the AMSR‐derived satellite product is more precise over the wet tundra site with critical date alignment between remote sensing observations and in situ measurements ranging from ~4 to 11 days. Furthermore, the AMSR product was shown to preemptively estimate land surface condition change during the spring transition for both tundra types while lagging during the fall transition and freeze‐up periods.

The microscopic diffusion and the low frequency density of states (VDOS) of PIM-EA-TB(CH3) are investigated by inelastic and quasi-elastic neutron scattering where also the demethylated counterpart of PIM-EA-TB(H2) is considered. These intrinsic microporous polymers are characterized by large BET surface area values of several hundred m2/g and pore sizes between 0.5 and 2 nm. Detailed comparison is made to the archetype of polymers of intrinsic microporosity, PIM-1, and polynorbornenes also bearing a microporosity. Due to the wavelength of neutrons, the diffusion and vibrations can be addressed on microscopic length and time scales. From the inelastic neutron scattering experiments the low frequency density of states (VDOS) is estimated which shows excess contributions to the Debye-type VDOS known as Boson peak. It was found that the maximum frequency of the Boson peak decreases with increasing microporosity characterized by the BET surface area. However, besides the BET surface area, additional factors such as the backbone stiffness govern the maximum frequency of the Boson peak. Further the mean squared displacement related to microscopic motions was estimated from elastic fixed window scans. At temperatures above 175 K, the mean squared displacement PIM-EA-TB(CH3) is higher than that for the demethylated counterpart PIM-EA-TB(H2). The additional contribution found for PIM-EA-TB(CH3) is ascribed to the rotation of the methyl group in this polymer because the only difference between the two structures is that PIM-EA-TB(CH3) has methyl groups where PIM-EA-TB(H2) has none. A detailed comparison of the molecular dynamics is also made to that of PIM-1 and the microporous polynorbornene PTCNSi1. The manuscript focuses on the importance of vibrations and the localized molecular mobility characterized by the microscopic diffusion on the gas transport in polymeric separation membranes. In the frame of the random gate model localized fluctuations can open or close bottlenecks between pores to enable the diffusion of gas molecules.

To improve the representativeness of a real microstructural cut-out for modeling purposes, a numerical method named as “boundary pixel color alteration (BPCA)” is presented to modify measured 2D microstructure cut-outs. Its physical background is related to the phase growth. For the application, the precondition is that the representativeness of the microstructure is already satisfied to a certain extent. This method resolves the problem that the phase composition of a small cut-out can have a large discrepancy to the real one. The main idea is to change the pixel color among neighboring pixels belonging to different phases. Our process simultaneously maintains most of the characteristics of the original morphology and is applicable for nearly all kinds of multi-phase or polycrystalline metallic alloys, as well. From our axisymmetric finite element (FE) simulations (ABAQUS ) applied with 2D real microstructures, it shows that the volume ratios of microstructural phases, as a function of the structure position to the symmetric axis, converge to phase area ratios in the 2D cut-out, even though the axisymmetric element volume is position dependent. A mathematical proof provides the reason for the aforementioned convergence. As examples to achieve real compositions and to numerically prove the aforementioned convergence, four different materials including multiphase polycrystals are implemented. An improvement of the predicted FE result is presented for the application of a modified microstructure (with a higher representativeness) compared to the original one.

The sensitivity of Earth’s wetlands to observed shifts in global precipitation and temperature patterns and their ability to produce large quantities of methane gas are key global change questions. We present a microwave satellite-based approach for mapping fractional surface water (FW) globally at 25-km resolution. The approach employs a land cover-supported, atmospherically-corrected dynamic mixture model applied to 20+ years (1992–2013) of combined, daily, passive/active microwave remote sensing data. The resulting product, known as Surface WAter Microwave Product Series (SWAMPS), shows strong microwave sensitivity to sub-grid scale open water and inundated wetlands comprising open plant canopies. SWAMPS’ FW compares favorably (R2 = 91%–94%) with higher-resolution, global-scale maps of open water from MODIS and SRTM-MOD44W. Correspondence of SWAMPS with open water and wetland products from satellite SAR in Alaska and the Amazon deteriorates when exposed wetlands or inundated forests captured by the SAR products were added to the open water fraction reflecting SWAMPS’ inability to detect water underneath the soil surface or beneath closed forest canopies. Except for a brief period of drying during the first 4 years of observation, the inundation extent for the global domain excluding the coast was largely stable. Regionally, inundation in North America is advancing while inundation is on the retreat in Tropical Africa and North Eurasia. SWAMPS provides a consistent and long-term global record of daily FW dynamics, with documented accuracies suitable for hydrologic assessment and global change-related investigations.

Abstract Findings BMI was increased (>25) in 22% of young healthy subjects. Increased cholesterol values (>5.0 mmol/L) were found in 23% of subjects, LDL-C (>3.0 mmol/L) in 23%, triglycerides (>1.7 mmol/L) in 11% of subjects. We found statistically significant differences in subjects' weight (p = 0.015), BMI (p = 0.023), and waist-hip ratio (WHR) (p = 0.015) in regard to their diet type; subjects with Mediterranean diet had the lowest values compared to those on continental and mixed diet. Significant associations were found for: LPL genetic polymorphic variant and abdominal obesity (p = 0.013), APO epsilon4 allele and hypercholesterolemia (p = 0.003), and ESR1-TA long allele and hypercholesterolemia (p = 0.011). Background Human obesity is a multifactorial syndrome influenced also by genetic factors. Among gene variants found to be involved in body weight regulation and development of obesity, particular attention has been paid to polymorphisms in genes associated with obesity-related metabolic disorders. We explored the association of genetic polymorphisms of: estrogen receptor alpha (ESR1-TA repeats); interleukin-6 (IL-6 G-174C); apolipoprotein E (APO epsilon2, epsilon3, epsilon4); lipoprotein lipase Pvu II (LPL P+/-), with clinical variables: gender, age, body mass index (BMI), diet type and biological variables: triglycerides, cholesterol, HDL-C, LDL-C, CRP, homocysteine, urate, and glucose in 105 healthy young subjects (20-35 yrs) of Croatian origin. Methods Genotyping of IL-6, LPL was performed by PCR-RFLP, of APOE by real-time PCR, and of ESR1 by PCR and capillary electrophoresis. Association analyses were performed of alleles and genotypes with biological variables. Conclusion ESR-1, LPL, and APO E genetic polymorphic variants could represent predictive genetic risk markers for obesity-related metabolic disorders in young healthy subjects. Mediterranean type of diet is also an important protective factor against abdominal obesity.

Background: Pathogenesis of atherosclerosis is largely mediated by inflammatory process. Statins are lipid-lowering drugs which also have anti-inflammatory effects. 18 fluorine radiolabeled fluorodeoxyglucose (18 F-FDG) positron emission tomography-computed tomography (PET-CT) is considered to be a good indicator of arterial wall inflammation. Therefore, in this meta-analysis the role of statins on inflammatory process in the artery wall was evaluated using this method since its actual validity for this purpose is not yet well established., Methods: PubMed, Scopus, Web of Science, ClinicalTrials.gov, and Google Scholar databases were searched using MESH terms and keywords. Funnel plot, Begg's rank correlation, and Egger's weighted regression tests evaluated publication bias in the meta-analysis. In cases where funnel plot asymmetry was observed, the "trim and fill" method was used to check the input of potentially missing studies., Results: Findings of 10 clinical trials involving 373 subjects showed a remarkable reduction of arterial wall 18 F-FDG uptake according to target-to-background ratio (TBR) index after treatment with statins. Subgroup analysis showed a significant decrease in TBR with high-intensity and non-significant reduction of TBR with low-to-moderate-intensity statin therapy., Conclusion: Treatment with statins suppressed arterial wall inflammation as shown by using 18 F-FDG PET-CT., Competing Interests: Declarations. Ethical approval: Not applicable. Consent to participate: Not applicable. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Interest in biological therapy for cancer has surged due to its precise targeting of cancer cells and minimized impact on surrounding healthy tissues. This review discusses various biological cancer therapies, highlighting advanced alternatives over conventional chemotherapy alone. It explores DNA and RNA-based vaccines, T-cell modifications, adoptive cell transfer, CAR T cell therapy, angiogenesis inhibitors, and the combination of immunotherapy with chemotherapy, offering a holistic view of the potential in cancer treatment. Additionally, it discusses the role of nanotechnology in increasing the efficacy of cancer-targeting drugs, as well as cytokine and immunoconjugate therapies for bolstering immune system effectiveness against neoplastic cells. The potential of gene potential for precise targeting of cancer-linked genes and the application of oncolytic viruses against virus-associated cancers are also discussed. The review identifies significant advancements in the targeted treatment of cancer by biological methods. It acknowledges the challenges, including drug resistance and the need for high specificity in certain therapies, while also highlighting the effectiveness of cancer vaccines, modified T-cells, and oncolytic viruses. Biological therapies are a promising frontier in cancer treatment, offering the potential for more personalized and effective therapeutic strategies. Despite existing challenges, ongoing research and clinical trials are fundamental for overcoming current limitations and enhancing the efficacy of biological therapies in cancer care., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Cardiovascular diseases (CVD) are the leading cause of morbidity and mortality worldwide, including in Croatia. Since most patients have multiple disorders and diseases caused largely by the same risk factors, and as it is essential to approach each patient as a person with all disorders, today, we are talking about a new paradigm-cardio-renal-metabolic (CKM) syndrome and cardio-renal-metabolic health, which necessarily includes brain health. Elevated systolic blood pressure, LDL cholesterol, smoking, obesity, diabetes, impaired renal function or chronic kidney disease, which all stem from insufficient physical activity, an unhealthy diet with excessive intake of table salt, and air pollution, are the leading causes of overall morbidity and mortality from CKM diseases, especially mortality from CVD. Experts from various fields key to CKM health have written this document with the aim of integrating it as part of the national plan for the prevention of chronic non-communicable diseases with a focus on CVD, which should become mandatory and be based on the existing guidelines of professional societies.

Purpose: Statin therapy is widely used for the management of dyslipidemia and the prevention of cardiovascular diseases (CVDs). However, there is a growing concern about its potential effects on bone metabolism markers and mineral density. The aim of this systematic review and meta-analysis was to investigate the effect of statin therapy on these parameters., Methods: PubMed/MEDLINE, Scopus, and Clarivate Analytics Web of Science databases were searched from inception to August 2023, using MESH terms and keywords., Results: After screening 2450 articles, 16 studies that met the inclusion criteria were included, of which 12 randomized controlled trials (RCTs) were used for meta-analysis. The findings showed that statin therapy significantly reduced bone-specific alkaline phosphatase (B-ALP) levels (WMD=-1.1 U/L; 95% CI -2.2 to -0.07; P =0.03; I 2 =0%,), and bone mineral density (BMD) at different sites (WMD=-0.06 g/cm 2 ; 95% CI -0.08 to -0.04; P <0.001; I 2 =97.7%, P <0.001). However, this treatment did not have a significant effect on osteocalcin, serum C-terminal peptide of type I collagen (S-CTx), serum N-telopeptides of type I collagen (NTx) concentration, or overall fracture risk., Conclusion: This systematic review and meta-analysis provide evidence that statin therapy is associated with a significant reduction in B-ALP levels and BMD at different sites of the skeleton. Further studies are needed to investigate the long-term effects of statin therapy on bone health and to identify the potential underlying mechanisms., Competing Interests: All authors declare that they have no conflicts of interest., (©2024 The Author (s).)

Cardiovascular diseases, which are the leading cause of death in Croatia, are linked to the high prevalence of hypertension. Both are associated with high salt intake, which was determined almost two decades ago when Croatian Action on Salt and Health (CRASH) was launched. The main objective of the present study was to evaluate salt, potassium, and iodine intake using a single 24 h urine sample in a random sample of the adult Croatian population and to analyse trends in salt consumption after the CRASH was intensively started., Methods: In this study, we analysed data on 1067 adult participants (mean age 57.12 (SD 13.9), men 35%)., Results: Mean salt and potassium intakes were 8.6 g/day (IQR 6.2-11.2) and 2.8 g/day (IQR 2.1-3.5), respectively, with a sodium-to-potassium ratio of 2.6 (IQR 1.8-3.3). We detected a decrease of 17.6% (2 g/day less) in salt consumption compared with our previous salt-mapping study. However, only 13.7% and 8.9% met the WHO salt and potassium recommended targets of 5 g/day and 3.5 g/day, respectively. Salt intake was higher, and potassium ingestion was lower, in rural vs. urban regions and in continental vs. Mediterranean parts of Croatia. Moderate to severe iodine insufficiency was determined in only 3% of the adult participants., Conclusion: In the last fifteen years, salt consumption has been significantly reduced in the Croatian adult population because of the intensive and broad CRASH program. However, salt intake is still too high, and potassium ingestion is too low. Salt reduction programs are the most cost-effective methods of cardiovascular disease prevention and merit greater consideration by the government and health policy makers.

Dyslipidaemia is a complex disorder characterised by abnormal lipid levels in the blood, including cholesterol and triglycerides, and plays an important role in the development of atherosclerotic cardiovascular disease. Most risk factors for cardiovascular disease are modifiable, and dyslipidaemia is a key factor among them. It can result from a combination of genetic and environmental factors. A distinction is made between primary dyslipidaemia, which is mainly caused by inherited genetic changes, and secondary dyslipidaemia, which is due to underlying diseases or certain medications. The treatment of dyslipidaemia has evolved over the years. In the past, statins were the first choice, but newer drugs, such as proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors, have gained prominence due to their effectiveness in lowering lipids. Although recent guidelines recommend PCSK9 inhibitors for high-risk patients and patients who cannot tolerate statins, their widespread use is limited because of cost. Several meta-analyses have confirmed the efficacy and safety of PCSK9 inhibitors and have shown a significant reduction in low-density lipoprotein (LDL) cholesterol levels. However, the long-term side effects and interactions with other risk factors for cardiovascular disease remain uncertain. In addition, cost-effectiveness analyses have shown mixed results, with some countries considering PCSK9 inhibitors to be cost-effective for certain patient groups, while others consider them less economical. Meanwhile, initial data from patients using PCSK9 inhibitors support the results of the clinical trials. To summarise, PCSK9 inhibitors represent a revolutionary solution for lowering LDL cholesterol, but their cost-effectiveness remains controversial. Despite the controversy, they offer clear benefits for high-risk patients and should therefore be considered in the treatment of dyslipidaemia., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Mercep, Strikic, Hrabac, Pecin and Reiner.)

The World Health Organization recommends adjusting salt intake as a part of the nine global targets to reduce premature mortality from non-communicable chronic diseases as a priority and the most cost-effective intervention. In 2006, the main aim of the Croatian Action on Salt and Health was to decrease salt intake by 16% because of its critical intake and consequences on human health. We have organized educative activities to increase awareness on salt harmfulness, define food categories of prime interest, collaborate with industries and determine salt intake (24 h urine sodium excretion). It was determined that the proportion of salt in ready-to-eat baked bread should not exceed 1.4%. In the period 2014-2022, salt in semi-white bread was reduced by 14%, 22% in bakery and 25% in the largest meat industry. Awareness of the harmfulness of salt on health increased from 65.3% in 2008 to 96.9% in 2023 and salt intake was reduced by 15.9-1.8 g/day (22.8% men, 11.7% women). In the last 18 years, a significant decrease in salt intake was achieved in Croatia, awareness of its harmfulness increased, collaboration with the food industry was established and regulatory documents were launched. However, salt intake is still very high, underlying the need for continuation of efforts and even stronger activities., Competing Interests: The authors declare no conflicts of interest.

Cancer poses a significant global health challenge, with predictions of increasing prevalence in the coming years due to limited prevention, late diagnosis, and inadequate success with current therapies. In addition, the high cost of new anti-cancer drugs creates barriers in meeting the medical needs of cancer patients, especially in developing countries. The lengthy and costly process of developing novel drugs further hinders drug discovery and clinical implementation. Therefore, there has been a growing interest in repurposing approved drugs for other diseases to address the urgent need for effective cancer treatments. The aim of this comprehensive review is to provide an overview of the potential of approved non-oncology drugs as therapeutic options for cancer treatment. These drugs come from various chemotherapeutic classes, including antimalarials, antibiotics, antivirals, anti-inflammatory drugs, and antifungals, and have demonstrated significant antiproliferative, pro-apoptotic, immunomodulatory, and antimetastatic properties. A systematic review of the literature was conducted to identify relevant studies on the repurposing of approved non-oncology drugs for cancer therapy. Various electronic databases, such as PubMed, Scopus, and Google Scholar, were searched using appropriate keywords. Studies focusing on the therapeutic potential, mechanisms of action, efficacy, and clinical prospects of repurposed drugs in cancer treatment were included in the analysis. The review highlights the promising outcomes of repurposing approved non-oncology drugs for cancer therapy. Drugs belonging to different therapeutic classes have demonstrated notable antitumor effects, including inhibiting cell proliferation, promoting apoptosis, modulating the immune response, and suppressing metastasis. These findings suggest the potential of these repurposed drugs as effective therapeutic approaches in cancer treatment. Repurposing approved non-oncology drugs provides a promising strategy for addressing the urgent need for effective and accessible cancer treatments. The diverse classes of repurposed drugs, with their demonstrated antiproliferative, pro-apoptotic, immunomodulatory, and antimetastatic properties, offer new avenues for cancer therapy. Further research and clinical trials are warranted to explore the full potential of these repurposed drugs and optimize their use in treating various cancer types. Repurposing approved drugs can significantly expedite the process of identifying effective treatments and improve patient outcomes in a cost-effective manner., (© 2023. BioMed Central Ltd., part of Springer Nature.)

One of the greatest burdens on the healthcare systems of modern civilization is cardiovascular diseases (CVDs). Therefore, the medical community is looking for ways to reduce the incidence of CVDs. Simple lifestyle changes from an unhealthy to a healthy lifestyle are the cornerstone of prevention, but other risk factors for cardiovascular disease are also being currently targeted, most notably dyslipidaemia. It is well known that lowering serum lipid levels, and in particular lowering elevated LDL-cholesterol, leads to a reduction in major cardiovascular events. Although the focus to date has been on LDL-cholesterol levels and lowering them with statin therapy, this is often not enough because of increased concentrations of other lipoprotein particles in the serum and residual cardiovascular risk. Since lowering LDL-cholesterol levels is successful in most cases, there has been a recent focus on lowering residual cardiovascular risk. In recent years, new therapeutic options have emerged that target triglyceride-rich lipoproteins, lipoprotein (a) and apolipoproteins C and B. The effects of these drugs on serious adverse cardiovascular events are not yet known, but recent studies with some of these drugs have shown significant results in lowering total lipid levels. The aim of this review is to present the current therapeutic options for the treatment of dyslipidaemia and to describe the newly approved drugs as well as the drugs that are still in development. Although at this stage we cannot say with certainty whether these agents will be approved and widely used, it is safe to say that our views on the treatment of dyslipidaemia are certainly changing.

Introduction: There are several pathologic mechanisms involved in diabetic nephropathy, but the role of oxidative stress seems to be one of the most important. Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a relatively new class of antidiabetic drugs that might also have some other effects in addition to lowering glucose. The aim of this study was to evaluate the possible effects of the SGLT2 inhibitor empagliflozin on oxidative stress and renal function in diabetes., Methods: Male Wistar rats were randomly divided into four groups: control, control-treated, diabetic, and diabetic-treated ( n = 8 per group). Diabetes was induced by a single intraperitoneal dose of streptozotocin (50 mg/kg). The treated animals received empagliflozin for 5 weeks (20 mg/kg/day/po). All groups were sacrificed on the 36th day, and blood and tissue samples were collected. Serum levels of urea, uric acid, creatinine, and glucose levels were determined. The level of malondialdehyde (MDA) and glutathione (GLT), as well as the activity of catalase (CAT) and superoxide dismutase (SOD), was measured in all groups. Data were analyzed using one-way Anova and paired T-tests, and p ≤ 0.05 was considered significant., Results: Diabetes significantly increased urea ( p < 0.001), uric acid ( p < 0.001), and creatinine ( p < 0.001) in the serum, while the activities of CAT ( p < 0.001) and SOD ( p < 0.001) were reduced. GLT was also reduced ( p < 0.001), and MDA was increased ( p < 0.001) in non-treated animals. Treatment with empagliflozin improved renal function, as shown by a reduction in the serum levels of urea ( p = 0.03), uric acid ( p = 0.03), and creatinine ( p < 0.001). Empagliflozin also increased the antioxidant capacity by increasing CAT ( p = 0.035) and SOD ( p = 0.02) activities and GLT content ( p = 0.01) and reduced oxidative damage by lowering MDA ( p < 0.001)., Conclusions: It seems that uncontrolled diabetes induces renal insufficiency by decreasing antioxidant defense mechanisms and inducing oxidative stress. Empagliflozin might have additional benefits in addition to lowering glucose--reversing these processes, improving antioxidative capacity, and improving renal function.

Introduction: Dyslipidemia frequently occurs in women with polycystic ovary syndrome (PCOS), but it is unclear whether dyslipidemia is due to obesity and insulin resistance (IR) or is inherent to PCOS. To address this, proteomic analysis of proteins important in lipid metabolism, particularly for high-density lipoprotein cholesterol (HDL-C), was performed in non-obese, non-insulin resistant PCOS women compared to matched controls., Methods: Weight and aged-matched non-obese subjects with PCOS (n=24) and without IR were compared with control women (n=24). 19 proteins were measured by Somalogic proteomic analysis: alpha-1-antichymotrypsin, alpha-1-antitrypsin, apolipoproteins A-1, B, D, E, E2, E3, E4, L1, M, clusterin, complement C3, hemopexin, heparin cofactor-II (HCFII), kininogen-1, serum amyloid A-1, amyloid beta A-4 and paraoxonase-1., Results: Women with PCOS had a higher free androgen index (FAI) (p<0.001) and anti-Mullerian hormone (AMH) (p<0.001), but IR and C-reactive protein (CRP), a marker of inflammation, did not differ from controls (p>0.05). The triglyceride:HDL-cholesterol ratio was elevated (p=0.03) in PCOS. Alpha-1-antitrypsin levels were lower (p<0.05) and complement C3 levels were higher (p=0.001) in PCOS. C3 correlated with body mass index (BMI) (r=0.59, p=0.001), IR (r=0.63, p=0.0005) and CRP (r=0.42, p=0.04) in women with PCOS, though no correlations of these parameters with alpha-1-antitrypsin were found. Total cholesterol, triglycerides, HDL-cholesterol, LDL-cholesterol and levels of the other 17 lipoprotein metabolism-associated proteins did not differ between the two groups (p>0.05). However, in PCOS, alpha-1-antichymotrypsin correlated negatively with BMI (r=-0.40, p<0.04) and HOMA-IR (r=-0.42, p<0.03), apoM correlated positively with CRP (r=0.36, p<0.04) and HCFII correlated negatively with BMI (r=-0.34, p<0.04)., Conclusion: In PCOS subjects, when obesity, IR and inflammation confounders were absent, alpha-1-antitrypsin was lower and complement C3 was higher than in non-PCOS women, suggesting increased cardiovascular risk; however, subsequent obesity related IR/inflammation likely stimulates other HDL-associated protein abnormalities, thus increasing cardiovascular risk further., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Butler, Moin, Reiner, Sathyapalan, Jamialahmadi, Sahebkar and Atkin.)

Introduction: Serum lipoproteins, with the exception of high-density lipoprotein cholesterol (HDL-C), are increased in polycystic ovary syndrome (PCOS) and their levels may reflect the associated obesity and insulin resistance, but the nature of this association is not fully explained. Therefore, proteomic analysis of key proteins in lipoprotein metabolism was performed., Methods: In this cohort study, plasma was collected from 234 women (137 with PCOS and 97 controls without PCOS). Somalogic proteomic analysis was undertaken for the following 19 proteins involved in lipoprotein, and particularly HDL, metabolism: alpha-1-antichymotrypsin; alpha-1-antitrypsin; apolipoproteins A-1, B, D, E, E2, E3, E4, L1, and M; clusterin; complement C3; hemopexin; heparin cofactor II; kininogen-1; serum amyloid A-1; amyloid beta A-4; and paraoxonase-1., Results: The levels of apolipoprotein E were higher in PCOS ( p = 0.012). However, the other isoforms of ApoE, ApoE2, E3, and E4, did not differ when compared with controls. ApoM was lower in PCOS ( p = 0.000002). Complement C3 was higher in PCOS ( p = 0.037), as was heparin cofactor II (HCFII) ( p = 0.0004). The levels of the other proteins associated with lipoprotein metabolism did not differ between PCOS and controls., Conclusions: These data contribute to the concern of the deleterious dyslipidemia found in PCOS, with the novel combination reported here of higher levels of ApoE, C3 and HCFII together with lower ApoM. The dysregulation of these proteins could circumvent the protective effect of HDL-C and contribute to a more atherogenic profile that may increase cardiovascular risk.

Background : MCP-1 (monocyte chemoattractant protein) plays an important role in early phases of atherogenesis as well as in plaque destabilization, which causes cardiovascular events to play an important role in low-grade inflammation. Obesity, particularly extreme obesity, is a pivotal risk factor for atherosclerosis and many other diseases. In the early stages, bariatric surgery might stop or slow atherogenesis by suppressing inflammation, but also in later stages, preventing plaque destabilization. The aim of this meta-analysis was to provide an answer as to whether bariatric surgery has a significant effect on circulating MCP-1 level or not. Methods : A systematic literature search in PubMed, Scopus, Embase, and Web of Science was performed from inception to 1 January 2022. Meta-analysis was performed using Comprehensive Meta-Analysis (CMA) V2 software. In order to heterogeneity compensation of studies in terms of study design and treatment duration, the characteristics of the studied populations random-effects model and the generic inverse variance weighting method were used. To investigate the relationship with the estimated effect size, a random-effect meta-regression model was used. To assess the exitance of publication bias in the meta-analysis, the funnel plot, Begg's rank correlation, and Egger's weighted regression tests were used. Results : Meta-analysis of 25 studies with 927 subjects included demonstrated a significant decrease of MCP-1 concentration after bariatric surgery. The data of meta-regression did not indicate any association between the alterations in body mass index (BMI) and absolute difference in MCP-1 levels, but a linear relationship between the changes in MCP-1 and length of follow-up was proven. Conclusions : Bariatric surgery significantly decreases MCP-1 concentration, but there was no association between the changes in BMI and absolute difference in MCP-1 levels before and after the surgery.

Chronic hyperglycemia induces pathophysiologic pathways with negative effects on the metabolism of most substrates as well as lipids and lipoproteins, and thereby induces dyslipidemia. Thus, the diabetic milieu is commonly accompanied by different levels of atherogenic dyslipidemia, which is per se a major risk factor for subsequent complications such as atherosclerosis, coronary heart disease, acute myocardial infarction, ischemic stroke, and nephropathy. Therefore, readjusting lipid metabolism in the diabetic milieu is a major goal for preventing dyslipidemia-induced complications. Sodium-glucose cotransporter-2 (SGLT2) inhibitors are a class of relatively newly introduced antidiabetes drugs (including empagliflozin, canagliflozin, dapagliflozin, etc.) with potent hypoglycemic effects and can reduce blood glucose by inducing glycosuria. However, recent evidence suggests that they could also provide extra-glycemic benefits in lipid metabolism. It seems that they can increase fat burning and lipolysis, normalizing the lipid metabolism and preventing or improving dyslipidemia. Nevertheless, the exact mechanisms involved in this process are not well-understood. In this review, we tried to explain how these drugs could regulate lipid homeostasis and we presented the possible involved cellular pathways supported by clinical evidence.

Abdominal aortic aneurysm (AAA) is a prevalent condition which causes progressive growth and rupture of aortic wall with a high death rate. Several studies have found that treatment with statins may decrease the progress of AAA and the risk of rupture by suppressing the inflammatory mediators, decreasing oxidative stress, and inhibiting mechanisms involved in extracellular matrix (ECM) degradation. Moreover, some studies have reported that prehospital therapy with statins can decrease mortality after surgery. The novelty of this paper is that different studies including those performed in humans and animals were reviewed and the potential mechanisms by which statins can have an effect on AAA were summarized. Overall, the evidence suggested an association between treatment with statins and improvement of AAA., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflict of interest., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Obesity, and in particular extreme obesity, as a global health problem is an important risk factor for many diseases, including atherosclerotic cardiovascular disease (ACVD). Bariatric surgery might stop or slow atherogenesis by decreasing excessive weight in the early stages of atherogenesis, by suppressing low-grade systemic inflammation as well as by inhibiting oxidative stress and endothelial dysfunction. The aim of this meta-analysis was to provide an answer to whether bariatric surgery has a significant effect on intima-media thickness (IMT) which is a surrogate marker of early atherosclerosis and has a good correlation with atherosclerotic coronary heart disease., Methods: A systematic literature search in PubMed, Scopus, Embase, and Web of Science as well as grey literature was performed from inception to 1 July 2022. The meta-analysis was performed using Comprehensive Meta-Analysis (CMA) V3 software. Overall, the estimate of effect size was measured by a random effects meta-analysis. To account for the heterogeneity of studies regarding study design, characteristics of the populations, and treatment duration, a random-effects model (using the DerSimonian-Laird method) and the generic inverse variance weighting approach were used. To assess the existence of publication bias in the meta-analysis, the funnel plot, Begg's rank correlation, and Egger's weighted regression tests were used., Results: The meta-analysis of 30 trials, including 1488 subjects, demonstrated a significant decrease in IMT after bariatric surgery. The reduction in IMT was also robust in the leave-one-out sensitivity analysis. It must be stressed that the results of the random-effects meta-regression did not suggest any relationship between the changes in IMT and delta body mass index (BMI) or duration of follow-up after the bariatric surgery. However, the subgroup analyses showed a better IMT reduction after laparoscopic sleeve gastrectomy (LSG) when compared to Roux-en-Y gastric bypass (RYGB). Within a year, the IMT follow-up values showed a further improvement., Conclusions: Bariatric surgery significantly reduced IMT. Significant associations were found between the surgery type and IMT changes, as well as a significant effect of follow-up duration on the changes of IMT after bariatric surgery.