Exploring the Role of Vitamin D, Vitamin D-Dependent Proteins, and Vitamin D Receptor Gene Variation in Lung Cancer Risk.

Lung cancer has an unfavorable prognosis with a rate of low overall survival, caused by the difficulty of diagnosis in the early stages and resistance to therapy. In recent years, there have been new therapies that use specific molecular targets and are effective in increasing the survival chances of advanced cancer. Therefore, it is necessary to find more specific biomarkers that can identify early changes in carcinogenesis and allow the earliest possible treatment. Vitamin D (VD) plays an important role in immunity and carcinogenesis. Furthermore, the vitamin D receptor (VDR) regulates the expression of various genes involved in the physiological functions of the human organism. The genes encoding the VDR are extremely polymorphic and vary greatly between human populations. To date, there are significant associations between VDR polymorphism and several types of cancer, but the data on the involvement of VDR polymorphism in lung cancer are still conflicting. Therefore, in this review, our aim was to investigate the relationship between VDR single-nucleotide polymorphisms in humans and the degree of risk for developing lung cancer. The studies showcased different gene polymorphisms to be associated with an increased risk of lung cancer: TaqI, ApaI, BsmI, FokI, and Cdx2. In addition, there is a strong positive correlation between VD deficiency and lung cancer development. Still, due to a lack of awareness, the assessment of VD status and VDR polymorphism is rarely considered for the prediction of lung cancer evolution and their clinical applicability, despite the fact that studies have shown the highest risk for lung cancer given by TaqI gene polymorphisms and that VDR polymorphisms are associated with more aggressive cancer evolution.

Genetically modified rodent models and celiac, non-celiac gluten sensitivity: a minireview.

Celiac disease (CD) is a disorder that affects both children and adults. Over the few last decades, several new atypical cases have been identified through improved diagnostic tools. On the other hand, the onset of CD at a later age, including atypical CD forms whose clinical picture overlaps with other autoimmune diseases, shows that currently there are several unknown gene mutations, which could be responsible for the disease development. Non-celiac gluten sensitivity (NCGS) is entity included by the ingestion of gluten leading to intestinal, or extraintestinal symptoms that improve once the gluten is removed from the nutrition. In this article relationships between genetically modified rodent animals with previously unknown multiple organ changes and CD, respectively NCGS are reviewed. Relationships between the small bowel histological changes and other organs pathology are discussed. Results of research document that changes have similar genetic background and can develop to serious autoimmune systematic diseases, including small bowel inflammation resembling atypical CD or NCGS. These may have extra-intestinal symptomatology but without a clear explanation of causes and differences in their manifestations. Research on animal models helps to discover links between several disorders associated with gastrointestinal damage. New methods based on individual gene mutations can help in atypical adult CD and NCGS recognitions in the future.

MiRNAs roles in the diagnosis, prognosis and treatment of colorectal cancer.

Introduction: The liver is the main location for metastasization in stage IV colorectal cancers. Areas covered: This review intends to comprehensively present the most important studies conducted in the past few years concerning the role of miRNAs in colorectal cancer liver metastases, trying to clarify some aspects regarding tumor biology and favorite liver metastasization site. Expert commentary: Recent advances in tissue and serum RNA extraction has considerably improved the field of microRNAs studies. These molecules known to play a crucial role in the metastatic stage indicate a starting point in the development of clinical biomarkers with a possible role in the stratification of high-risk patients for adequate treatment.

Vitamin K Dependent Proteins in Kidney Disease.

Patients with chronic kidney disease (CKD) have an increased risk of developing vascular calcifications, as well as bone dynamics impairment, leading to a poor quality of life and increased mortality. Certain vitamin K dependent proteins (VKDPs) act mainly as calcification inhibitors, but their involvement in the onset and progression of CKD are not completely elucidated. This review is an update of the current state of knowledge about the relationship between CKD and four extrahepatic VKDPs: matrix Gla protein, osteocalcin, growth-arrest specific protein 6 and Gla-rich protein. Based on published literature in the last ten years, the purpose of this review is to address fundamental aspects about the link between CKD and circulating VKDPs levels as well as to raise new topics about how the interplay between molecular weight and charge could influence the modifications of circulating VKDPs at the glomerular level, or whether distinct renal etiologies have effect on VKDPs. This review is the output of a systematic literature search and may open future research avenues in this niche domain.

BONE MARKERS IN ARTHROPATHIES.

Bone endures a lifelong course of construction and destruction, with bone marker (BM) molecules released during this cycle. The field of measuring BM levels in synovial fluid and peripheral blood is a cardinal part of bone research within modern clinical medicine and has developed extensively in the last years. The purpose of our work was to convey an up-to-date overview on synovial fluid and serum BMs in the most common arthropathies.

Prognosis and Treatment of Gastric Cancer: A 2024 Update.

Due to the high death rate associated with gastric cancer, a great deal of research has been conducted on this disease. The goal of this paper was to start a trimestral review of 2024 for the year that had just started. The scientific literature from 1 January 2024 was chosen with consideration of the the guidelines of the European Society of Medical Oncology (ESMO), which are updated with new findings but not systematically reviewed annually. We used the search term "gastric cancer" to find the most current publications in the PubMed database related to the prognosis and treatment of gastric cancer. As previously said, the only articles that satisfied the inclusion criteria were those from 2024. Articles with case reports were eliminated since they had nothing to do with our research. The treatment of gastric cancer is the focus of the majority of articles from 2024. The primary research axes include surgery and immunonutrition, immunotherapy and Helicobacter pylori, and therapeutic targets. Patients with GC may experience less psychological, social, and financial hardship if the recently identified markers discovered in circulation are better assessed and validated. This could be achieved by either including the markers in an artificial intelligence-based diagnostic score or by using them in conjunction with traditional diagnostic methods. Due to the rising death rate associated with GC, funding for research into diagnosis, prognosis, therapy, and therapeutic targets is essential.

Helicobacter pylori Infection in Patients with Gastric Cancer: A 2024 Update.

Numerous studies have been performed on Helicobacter pylori infection because of the high death rate linked to this illness and gastric cancer. An update on the key developments in recent years in the investigation of Helicobacter pylori and gastric cancer is the goal of this review. Using the search term "Helicobacter pylori, gastric cancer", the PubMed database was searched. Only papers published in 2024 fulfilled the inclusion criteria. Because case report papers were not part of our investigation, they satisfied the exclusion criteria. Most of the research on the variable genes of Helicobacter pylori is guided by genetics to determine potential treatments. Studies on clinical treatments for the eradication of H. pylori with promising therapeutic options are needed. We found the fewest studies related to the immunopathology of H. pylori infection, which is still unknown. In conclusion, priority should be given to this kind of research.

Assessing seasonal variations of biomarkers in inflammatory bowel disease.

OBJECTIVE: Inflammatory bowel diseases are chronic pathologies characterized by a complex interplay of genetic and environmental factors, as well as aberrant immune responses. This study aimed to investigate inflammation markers' seasonality and association with disease exacerbation episodes in patients with Crohn's disease and ulcerative colitis. METHODS: 284 patients were classified based on clinical, endoscopic, and histopathological criteria. Systemic inflammation was evaluated using C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and chitotriosidase, while fecal calprotectin was measured to assess intestinal inflammation. Serum vitamin D levels and the seasonality of an activity score that combines several clinical and biological parameters were also evaluated. RESULTS: The peak number of patients reporting endoscopic activity occurred in autumn for Crohn's disease (82%) and spring for ulcerative colitis (95%). Regarding histological activity, spring saw the highest number of patients for both diseases (72% for Crohn's disease; 87% for ulcerative colitis). Most of the inflammatory markers exhibited lower values during winter. Systemic inflammatory markers follow a slightly different trend than fecal calprotectin and differ in the two pathologies. The maximum values of intestinal inflammation were observed in autumn for Crohn's disease (784 µg/g) and in spring for ulcerative colitis (1269 µg/g). Serum vitamin D concentrations were consistently low throughout the year. Statistical analysis revealed differences between the seasons for CRP and ESR (P < 0.05). CONCLUSION: The evolution of flares and inflammatory markers in Crohn's disease and ulcerative colitis displayed distinct seasonal patterns. Systemic inflammation did not consistently parallel intestinal inflammation.

Low Vitamin K Status in Patients with Psoriasis Vulgaris: A Pilot Study.

Psoriasis vulgaris (PV) is a disease characterized by skin manifestations and systemic inflammation. There are no published studies to date on vitamin K status assessed by extrahepatic vitamin K-dependent proteins [e.g., osteocalcin (OC) and matrix Gla protein (MGP)] in patients with PV, even if vitamin K was found to promote wound contraction and decrease the healing time of the skin. Metabolic syndrome (MS), a comorbidity of PV, was found to influence vitamin K status, and vitamin D was found to be involved in the pathogenesis of PV. Therefore, our aim was to assess the status of vitamins K and D in subjects with PV. We enrolled 44 patients with PV and 44 age- and sex-matched subjects as a control group (CG), of which individuals with MS were designated the CG with MS subgroup. Furthermore, the PV patients were stratified into two subgroups: those with MS (n = 20) and those without MS (n = 24). In addition to the quantification of vitamin D and MGP in all subjects, the uncarboxylated OC/carboxylated OC (ucOC/cOC) ratio was also assessed as an inversely proportional marker of vitamin K status. We found an increased ucOC/cOC ratio in the PV group compared to CG but also a greater ucOC/cOC ratio in the PV with MS subgroup than in the CG with MS subgroup. MGP was decreased in the PV with MS subgroup compared to CG with MS subgroup. There was no difference in the vitamin D concentration between the groups. This is the first study to report decreased vitamin K status in patients with PV, independent of the presence of MS.

Circulating matrix Gla protein: a potential tool to identify minor carotid stenosis with calcification in a risk population.

BACKGROUND: Carotid calcification is an independent marker for future ischemic events, which are more frequently encountered in postmenopausal women as the prevalence of type 2 diabetes mellitus (T2DM) and hypertension (HT) increases. Matrix Gla protein (MGP) is a major inhibitor of vascular calcification. Here, we report on the prospect of serum MGP to become an identifying tool for minor carotid stenosis (minCAS) with calcification in a risk population. METHODS: Based on carotid ultrasound examination, out of 72 enrolled postmenopausal women, 33 had minCAS with carotid calcification (minCAS group) and 39 were without minCAS and carotid calcification (non-minCAS group). Serum total MGP, high-sensitivity C-reactive protein (hs-CRP), bone mineral density (BMD) and carotid intima-media thickness (CIMT) were determined. RESULTS: We found significantly elevated serum MGP levels in the minCAS compared to the non-minCAS group (p < 0.05). MGP was independently associated with hs-CRP (unstandardized ß -regression coefficient = 2.6; 95 % CI 0.007 ­ 5.3; p = 0.049) and CIMT ( ß = ­ 611.3; 95 % CI ­ 1172.6 ­ ­ 49.9; p = 0.034) within the minCAS group, but not with BMD. Furthermore, significantly higher MGP levels were determined in two minCAS subgroups (one with HT or T2DM and second with both diseases) compared to a non-minCAS subgroup with HT or T2DM (p < 0.05 and p < 0.01, respectively). A threshold of 87.9 µ g/L serum MGP (area under the receiver operating characteristic = 0.72 } 0.06; 95 % CI 0.60 ­ 0.84; p = 0.001) may identify minCAS with calcification in postmenopausal women with 63 % precision. CONCLUSIONS: Higher circulating MGP levels could help identify minCAS with calcification in a relatively homogenous risk population (i.e., postmenopausal women), regardless of underlying cardiovascular risk factors.

An Improved Score for the Evaluation of Mucosal Healing in Inflammatory Bowel Disease-A Pilot Study.

Inflammatory bowel diseases are chronic conditions characterized by periods of remission, alternating with episodes of exacerbation, in which the primary therapeutic target is mucosal healing. Although colonoscopy is currently considered the gold standard for assessing disease activity, it presents a significant number of disadvantages. Over time, various inflammatory biomarkers have been proposed to detect disease activation, but current biomarkers have many limitations. Our study aimed to analyze the most commonly used biomarkers for patient monitoring and follow-up both independently and taken together as a group, in order to propose an improved activity score that more accurately reflects the changes occurring at the intestinal level, in order to limit the number of colonoscopic interventions. By applying logistic regression as a method of statistical analysis to the retrospectively collected data, we obtained an easy-to-calculate improved score that quantifies the chance that a given patient may be in remission or in a period of endoscopic activity. To achieve a widely accessible score that is easily accessible in clinical practice, we have included only the most commonly used clinical and biological parameters.

First Comparative Evaluation of Short-Chain Fatty Acids and Vitamin-K-Dependent Proteins Levels in Mother-Newborn Pairs at Birth.

BACKGROUND: The interplay between vitamin K (vitK) (as carboxylation cofactor, partially produced by the gut microbiota) and short-chain fatty acids (SCFAs), the end-product of fiber fermentation in the gut, has never been assessed in mother-newborn pairs, although newborns are considered vitK deficient and with sterile gut. METHODS: We collected venous blood from 45 healthy mothers with uncomplicated term pregnancies and umbilical cord blood from their newborns at birth. The concentrations of total SCFAs and hepatic/extra-hepatic vitK-dependent proteins (VKDPs), as proxies of vitK status were assayed: undercarboxylated and total matrix Gla protein (ucMGP and tMGP), undercarboxylated osteocalcin (ucOC), undercarboxylated Gla-rich protein (ucGRP), and protein induced by vitK absence II (PIVKA-II). RESULTS: We found significantly higher ucOC (18.6-fold), ucMGP (9.2-fold), and PIVKA-II (5.6-fold) levels in newborns, while tMGP (5.1-fold) and SCFAs (2.4-fold) were higher in mothers, and ucGRP was insignificantly modified. In mother-newborn pairs, only ucGRP (r = 0.746, p < 0.01) and SCFAs (r = 0.428, p = 0.01) levels were correlated. Conclusions: We report for the first time the presence of SCFAs in humans at birth, probably transferred through the placenta to the fetus. The increased circulating undercarboxylated VKDPSs in newborns revealed a higher vitamin K deficiency at the extrahepatic level compared to liver VKDPs.

Targeted EGFR Nanotherapy in Non-Small Cell Lung Cancer.

Non-small cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality worldwide. Despite advances in treatment, the prognosis remains poor, highlighting the need for novel therapeutic strategies. The present review explores the potential of targeted epidermal growth factor receptor (EGFR) nanotherapy as an alternative treatment for NSCLC, showing that EGFR-targeted nanoparticles are efficiently taken up by NSCLC cells, leading to a significant reduction in tumor growth in mouse models. Consequently, we suggest that targeted EGFR nanotherapy could be an innovative treatment strategy for NSCLC; however, further studies are needed to optimize the nanoparticles and evaluate their safety and efficacy in clinical settings and human trials.

Diet-Related Changes of Short-Chain Fatty Acids in Blood and Feces in Obesity and Metabolic Syndrome.

Obesity-related illnesses are one of the leading causes of death worldwide. Metabolic syndrome has been associated with numerous health issues. Short-chain fatty acids (SCFAs) have been shown to have multiple effects throughout the body, both directly as well as through specific G protein-coupled receptors. The main SCFAs produced by the gut microbiota are acetate, propionate, and butyrate, which are absorbed in varying degrees from the large intestine, with some acting mainly locally and others systemically. Diet has the potential to influence the gut microbial composition, as well as the type and amount of SCFAs produced. High fiber-containing foods and supplements increase the production of SCFAs and SCFA-producing bacteria in the gut and have been shown to have bodyweight-lowering effects. Dietary supplements, which increase SCFA production, could open the way for novel approaches to weight loss interventions. The aim of this review is to analyze the variations of fecal and blood SCFAs in obesity and metabolic syndrome through a systematic search and analysis of existing literature.

Early Preeclampsia Effect on Preterm Newborns Outcome.

BACKGROUND: An early form of preeclampsia is rare. Abnormal placentation, placental perfusion disorders, and inflammatory cytokine release will have an effect on the fetus and newborn. MATERIAL AND METHODS: The study group consisted of preterm newborns whose mothers had a history of preeclampsia and a gestational age of between 30 weeks and 34 weeks + 6 days. The control group consists of neonates matched for gestational age with the case group, whose mothers had normal blood pressure. The incidence and severity of respiratory distress syndrome (RDS), intraventricular hemorrhage, hypoglycemia, pH gas changes, and hematological parameters were analyzed in the two groups. RESULTS: The study group of preterm neonates had a lower birth weight than the control group (p < 0.001). Most of the deliveries in the group of newborns exposed to preeclampsia were performed by cesarean section. Severe forms of RDS were two times more frequent in the group of newborns exposed to preeclampsia compared to those in the control group. Even though we expected to see a lower incidence, owing to the high number of deliveries by cesarean section, we still observed a higher rate of intraventricular hemorrhage in the preeclampsia group (16 cases in the study group vs. 7 in the control, p = 0.085). Neutropenia and thrombocytopenia were more frequent in preterm newborns exposed to preeclampsia. CONCLUSIONS: The study shows that early preeclampsia increases the risk of complications in preterm neonates. RDS was more frequent in the exposed group than in the control group. The severity of preeclampsia correlates with hematological changes.

The First Evaluation of Serum Levels of MGP, Gas6 and EGFR after First Dose of Chemotherapy in Lung Cancer.

BACKGROUND: Vitamin K-dependent proteins (VKDPs) and the epidermal growth factor receptor (EGFR) are involved in lung cancer progression. Therefore, we aimed to study the serum concentration of Matrix Gla protein (MGP), Growth Arrest-specific 6 (Gas6), and EGFR before and after the first cycle of chemotherapy and to investigate how MGP, Gas6, and EGFR are modified after one cycle of chemotherapy. METHODS: We performed an observational study on twenty patients diagnosed with lung cancer, by assessing the serum concentration of vitaminK1 (VitK1), MGP, Gas6, and EGFR using the ELISA technique before and after three weeks of the first cycle of chemotherapy. Patients were evaluated using RECIST 1.1 criteria. RESULTS: Serum levels of MGP, Gas6, EGFR, and VK1 before and after treatment were not changed significantly. Regarding the pre-treatment correlation of the MGP values, we found a strong positive relationship between MGP and VK1 pre-treatment values (r = 0.821, 95%CI 0.523; 0.954, p < 0.001). Furthermore, there was a moderately negative correlation between VK1 and EGFR pre-treatment values, with the relationship between them being marginally significant (r = -0.430, 95%CI -0.772; 0.001, p = 0.058). Post-treatment, we found a strong positive relationship between MGP and VK1 post-treatment values (r = 0.758, 95%CI 0.436; 0.900, p < 0.001). We also found a moderate positive relationship between Gas6 and EGFR post-treatment values, but the correlation was only marginally significant (r = 0.442, p = 0.051).

Assessment of Specific Tumoral Markers, Inflammatory Status, and Vitamin D Metabolism before and after the First Chemotherapy Cycle in Patients with Lung Cancer.

BACKGROUND: We aimed to investigate the changes of inflammatory status reflected by serum levels of chitotriosidase (CHT) and neopterin, and how specific tumor markers such as neuron-specific enolase (NSE) and squamous cell carcinoma antigen (SCCA), as well as vitamin D metabolism assessed by vitamin D receptor (VDR) and 25-hydroxy vitamin D3 (25OHD3), were modified after the first cycle of chemotherapy in patients with lung cancer. METHODS: We performed this first pilot study on twenty patients diagnosed with lung cancer by investigating the serum concentrations of CHT, neopterin, NSE, SCCA, VDR and 25OHD3 before and after the first cycle of chemotherapy. RESULTS: The post-treatment values of NSE were significantly lower compared to the pre-treatment levels (14.37 vs. 17.10 ng/mL, p = 0.031). We noticed a similar trend in neopterin levels, but the difference was only marginally significant (1.44 vs. 1.17 ng/mL, p = 0.069). On the contrary, the variations of circulating SCCA, CHT, neopterin, VDR and 25OHD3, before and after treatment, did not reach statistical significance. CONCLUSION: Only circulating NSE was treatment responsive to the first chemotherapy cycle in patients with lung cancer, while inflammatory markers and vitamin D status were not significantly modified.

Nanocarriers for Drug Delivery: An Overview with Emphasis on Vitamin D and K Transportation.

Mounting evidence shows that supplementation with vitamin D and K or their analogs induces beneficial effects in various diseases, e.g., osteoarticular, cardiovascular, or carcinogenesis. The use of drugs delivery systems via organic and inorganic nanocarriers increases the bioavailability of vitamins and analogs, enhancing their cellular delivery and effects. The nanotechnology-based dietary supplements and drugs produced by the food and pharmaceutical industries overcome the issues associated with vitamin administration, such as stability, absorption or low bioavailability. Consequently, there is a continuous interest in optimizing the carriers' systems in order to make them more efficient and specific for the targeted tissue. In this pioneer review, we try to circumscribe the most relevant aspects related to nanocarriers for drug delivery, compare different types of nanoparticles for vitamin D and K transportation, and critically address their benefits and disadvantages.

Synovial and serum levels of uncarboxylated matrix Gla-protein (ucMGP) in patients with arthritis.

BACKGROUND: Matrix Gla-protein (MGP) is a calcification inhibitor produced by cartilage and vessel walls. Arthritis is defined by inflammation, cartilage and bone destruction/formation and articular calcifications. Our objectives were to evaluate ucMGP levels in synovial fluid (SF) in arthritis patients and to investigate the relationship between local and circulating ucMGP and their association with age and inflammation. METHODS: Arthritis patients (n=26) with knee joint effusion and controls (n=30) underwent an ultrasonographic knee examination for articular calcifications assessment. Patients were divided into inflammatory and non-inflammatory groups. ucMGP levels were determined in serum and SF using a competitive ELISA assay. RESULTS: Within the arthritis patients, the inflammatory group had the lowest ucMGP serum levels, and the highest levels of synovial ucMGP. Furthermore, the inflammatory group had significantly (p<0.05) higher RucMGP (synovial ucMGP/serum ucMGP*100) than the non-inflammatory group [36 (17-69) vs. 24 (5-55)], and this parameter positively correlated (r=0.4; p<0.05) with the erythrocyte sedimentation rate (ESR). No correlation was found between age and local or circulating ucMGP in patients and controls. CONCLUSIONS: The ucMGP assay can be used for determination of MGP in SF, and combined assessment of ucMGP in serum and SF could potentially serve as a joint inflammatory marker in arthritis patients.

Sirtuin 3 (SIRT3) Pathways in Age-Related Cardiovascular and Neurodegenerative Diseases.

Age-associated cardiovascular and neurodegenerative diseases lead to high morbidity and mortality around the world. Sirtuins are vital enzymes for metabolic adaptation and provide protective effects against a wide spectrum of pathologies. Among sirtuins, mitochondrial sirtuin 3 (SIRT3) is an essential player in preserving the habitual metabolic profile. SIRT3 activity declines as a result of aging-induced changes in cellular metabolism, leading to increased susceptibility to endothelial dysfunction, hypertension, heart failure and neurodegenerative diseases. Stimulating SIRT3 activity via lifestyle, pharmacological or genetic interventions could protect against a plethora of pathologies and could improve health and lifespan. Thus, understanding how SIRT3 operates and how its protective effects could be amplified, will aid in treating age-associated diseases and ultimately, in enhancing the quality of life in elders.