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Breast cancer is a serious health problem worldwide, representing the second cause of death through malignancies among women in developed countries. Population, endogenous and exogenous hormones, and physiological, genetic and breast-related factors are involved in breast cancer pathogenesis. The phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) is a signaling pathway involved in cell proliferation, survival, invasion, migration, apoptosis, glucose metabolism and DNA repair. In breast tumors, PIK3CA somatic mutations have been reported, located in exon 9 and exon 20. Up to 40% of PIK3CA mutations are estrogen receptor (ER) positive and human epidermal growth factor receptor 2 (HER2) -negative in primary and metastatic breast cancer. HER2 is overexpressed in 20–30% of breast cancers. HER1, HER2, HER3 and HER4 are membrane receptor tyrosine kinases involved in HER signaling to which various ligands can be attached, leading to PI3K/AKT activation. Currently, clinical studies evaluate inhibitors of the PI3K/AKT/mTOR axis. The main purpose of this review is to present general aspects of breast cancer, the components of the AKT signaling pathway, the factors that activate this protein kinase B, PI3K/AKT-breast cancer mutations, PI3K/AKT/mTOR-inhibitors, and the relationship between everolimus, temsirolimus and endocrine therapy.

Colorectal cancer (CRC) is a predominant malignancy worldwide, being the fourth most common cause of mortality and morbidity. The CRC incidence in adolescents, young adults, and adult populations is increasing every year. In the pathogenesis of CRC, various factors are involved including diet, sedentary life, smoking, excessive alcohol consumption, obesity, gut microbiota, diabetes, and genetic mutations. The CRC tumor microenvironment (TME) involves the complex cooperation between tumoral cells with stroma, immune, and endothelial cells. Cytokines and several growth factors (GFs) will sustain CRC cell proliferation, survival, motility, and invasion. Epidermal growth factor receptor (EGFR), Insulin-like growth factor -1 receptor (IGF-1R), and Vascular Endothelial Growth Factor -A (VEGF-A) are overexpressed in various human cancers including CRC. The phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) and all the three major subfamilies of the mitogen-activated protein kinase (MAPK) signaling pathways may be activated by GFs and will further play key roles in CRC development. The main aim of this review is to present the CRC incidence, risk factors, pathogenesis, and the impact of GFs during its development. Moreover, the article describes the relationship between EGF, IGF, VEGF, GFs inhibitors, PI3K/AKT/mTOR-MAPK signaling pathways, and CRC.

Although pancreatic cancer (PC) was considered in the past an orphan cancer type due to its low incidence, it may become in the future one of the leading causes of cancer death. Pancreatic ductal adenocarcinoma (PDAC) is the most frequent type of PC, being a highly aggressive malignancy and having a 5-year survival rate of less than 10%. Non-modifiable (family history, age, genetic susceptibility) and modifiable (smoking, alcohol, acute and chronic pancreatitis, diabetes mellitus, intestinal microbiota) risk factors are involved in PC pathogenesis. Chronic inflammation induced by various factors plays crucial roles in PC development from initiation to metastasis. In multiple malignant conditions such as PC, cytokines, chemokines, and growth factors activate the class I phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) (PI3K/AKT/mTOR) signaling pathway, which plays key roles in cell growth, survival, proliferation, metabolism, and motility. Currently, mTOR, AKT, and PI3K inhibitors are used in clinical studies. Moreover, PI3K/mTOR dual inhibitors are being tested in vitro and in vivo with promising results for PC patients. The main aim of this review is to present PC incidence, risk factors, tumor microenvironment development, and PI3K/AKT/mTOR dysregulation and inhibitors used in clinical, in vivo, and in vitro studies.

There is a growing interest in the development of organic nanomaterials for biomedical applications. An increasing number of studies focus on the uses of nanomaterials with organic structure for regeneration of bone, cartilage, skin or dental tissues. Solid evidence has been found for several advantages of using natural or synthetic organic nanostructures in a wide variety of dental fields, from implantology, endodontics, and periodontics, to regenerative dentistry and wound healing. Most of the research is concentrated on nanoforms of chitosan, silk fibroin, synthetic polymers or their combinations, but new nanocomposites are constantly being developed. The present work reviews in detail current research on organic nanoparticles and their potential applications in the dental field.

Periodontitis represents a complex inflammatory disease that compromises the integrity of the tooth-supporting tissue through the interaction of specific periodontal pathogens and the host’s immune system. Experimental data help to outline the idea that the molecular way towards periodontitis initiation and progression presents four key steps: bacterial infection, inflammation, oxidative stress, and autophagy. The aim of this review is to outline the autophagy involvement in the pathogenesis and evolution of periodontitis from at least three points of view: periodontal pathogen invasion control, innate immune signaling pathways regulation and apoptosis inhibition in periodontal cells. The exact roles played by reactive oxygen species (ROS) inside the molecular mechanisms for autophagy initiation in periodontitis still require further investigation. However, clarifying the role and the mechanism of redox regulation of autophagy in the periodontitis context may be particularly beneficial for the elaboration of new therapeutic strategies.

A wide range of mediators are released from the pulp tissue because of bacterial invasion which causes inflammation. Interleukins (ILs) and matrix metalloproteinases (MMPs) have a leading role in initiating and spreading of inflammation because of their synergic action. Biomarkers such as ILs and MMPs can be identified via several methods, establishing the inflammatory response of the dental pulp. The aim of this systematic review is to evaluate the levels of ILs and/or MMPs in human dental pulp. PubMed, OVID, Cochrane, Scopus, Web of Science and Wiley online library databases were searched for original clinical studies. After applying inclusion and exclusion criteria, a quality assessment of studies was performed based on a modified Newcastle-Ottawa scale. In the review were included articles that evaluated the presence of ILs and/or MMPs in pulp tissue using enzyme-linked immunosorbent assay (ELISA) or western blot or multiplex assay. Six articles were included in the present synthesis. Although various diagnostic methods were used, statistically significant higher levels of ILs and/or MMPs were mostly found in the experimental groups compared to healthy pulp samples. The biomarkers studied can be a promising tool to evaluate pulp tissue health or even in pulpitis treatment.

Worldwide, diabetes mellitus (DM) and cardiovascular diseases (CVDs) represent serious health problems associated with unhealthy diet and sedentarism. Metabolic syndrome (MetS) is characterized by obesity, dyslipidemia, hyperglycemia, insulin resistance (IR) and hypertension. The mammalian target of rapamycin (mTOR) is a serine/threonine kinase with key roles in glucose and lipid metabolism, cell growth, survival and proliferation. mTOR hyperactivation disturbs glucose metabolism, leading to hyperglycemia and further to IR, with a higher incidence in the Western population. Metformin is one of the most used hypoglycemic drugs, with anti-inflammatory, antioxidant and antitumoral properties, having also the capacity to inhibit mTOR. mTOR inhibitors such as rapamycin and its analogs everolimus and temsirolimus block mTOR activity, decrease the levels of glucose and triglycerides, and reduce body weight. The link between mTOR dysregulation, IR, hypertension and mTOR inhibitors has not been fully described. Therefore, the main aim of this narrative review is to present the mechanism by which nutrients, proinflammatory cytokines, increased salt intake and renin–angiotensin–aldosterone system (RAAS) dysregulation induce mTOR overactivation, associated further with IR and hypertension development, and also mTOR inhibitors with higher potential to block the activity of this protein kinase.

NOABSTRACTAcute kidney injury (AKI), a medical condition associated with increased hospitalization rates which requires interdisciplinary management, is a major health concern because of the burden it places on the health systems of different countries. Biomarkers represent the focus of recent years in furthering the early diagnosis of AKI, providing new opportunities for correct prophylaxis or early therapeutic intervention so that the evolution of patients with this pathology is favorable and the risk of life-threatening complications is negligible.We performed an extensive literature search on PubMed and ScienceDirect databases, using keywords related to bio-markers for AKI. We searched for acute kidney injury (AKI), cystatin C (CYS-C), galectin-3 (GAL-3), kidney injury molecule-1 (KIM-1), neutrophil-gelatinase-associated lipocalin (NGAL), interleukin-8 (IL-8), and liver-type fatty acid-binding protein (L-FABP). We included a high number of papers, with an emphasis on more recent publications.Studies that analyzed the biomarkers for AKI show that CYS-C, GAL-3, KIM-1, NGAL, IL-8, calprotectin, and proteinuria were noted as potential biomarkers for early diagnosis of AKI.Biomarkers represent the focus of recent years in furthering an early diagnosis of AKI, providing new opportunities for correct prophylaxis or early therapeutic intervention.

Inflammation in primary teeth (PT) is commonly associated with a lower sensibility to painful stimuli, compared to permanent teeth, and usually leads to late presentation for dental treatment. Data obtained on the molecular assessments of dental pulp and clinical examinations could guide practitioners to conduct precise diagnoses and correct treatments. The aim of our pilot study was to assess the levels of several biomarkers (e.g., mineralization, oxidative stress, and inflammation) in primary teeth. The research included 46 dental pulp specimens collected from the primary teeth of children and adolescents between the ages of 6 and 12. The experimental groups consisted of 18 samples collected from primary teeth with acute pulpitis and 15 samples from chronically inflamed pulp tissues. The control group was represented by 13 specimens acquired from clinically healthy primary teeth. The enzyme-linked immunosorbent assay (ELISA) technique was used to determine the protein expression of tumor necrosis factor-α (TNF-α), superoxide dismutase-3 (SOD-3), osteocalcin, and transforming growth factor-β1 (TGF-β1) in the lysates. Our results revealed that all of the studied parameters presented statistically significant (p ≤ 0.05) increased levels in both experimental groups compared to the control samples. Furthermore, osteocalcin presented statistically significant increased concentrations in chronically- versus acute-inflamed pulp samples (p ≤ 0.05). The studied molecules may have an influential role in acute and chronic pulp inflammation in primary teeth.

Dental pulp inflammation, caused by the evolution of caries, involves numerous interrelated activities at a cellular and molecular level. Cytokines, proteases, growth factors, and other biomarkers of the host response may take part in dental pulp’s immune defense. The aim of this pilot study was to determine the levels of inflammation, oxidative stress, and extracellular matrix degradation biomarkers in healthy and symptomatic irreversibly inflamed dental pulp samples from children and adolescents. Twenty-three dental pulp samples were collected from permanent teeth with irreversible inflammation, while nineteen healthy dental pulp samples were obtained from teeth extracted for orthodontic reasons. Pulp lysates were obtained and the levels of IL-2, IL-17, TNF-α, SOD3, TGF-β1, catalase, osteocalcin, MMP-7, and MMP-9 were determined using the enzyme-linked immunosorbent assay (ELISA) technique. We detected significantly higher levels (p < 0.001) of IL-2, IL-17, TNF-α, SOD3, osteocalcin, and TGF-β1 in pulp samples with irreversible inflammation than in controls. Catalase and MMP-7 showed higher levels in the experimental group, while MMP-9 showed slightly increased levels in the control group, but none of these differences were statistically significant (p = 0.064/p = 0.061/p = 0.625). Inflamed dental pulp samples showed an up-regulation of IL-2, IL-17, TNF-α, SOD3, osteocalcin, and TGF-β1. These biomarkers appear to have a powerful role in the inflammation process of human dental pulp.