Low-Density Lipoproteins Increase Proliferation, Invasion, and Chemoresistance via an Exosome Autocrine Mechanism in MDA-MB-231 Chemoresistant Cells.

Dyslipidemias involving high concentrations of low-density lipoproteins (LDLs) increase the risk of developing triple-negative breast cancer (TNBC), wherein cholesterol metabolism and protein translation initiation mechanisms have been linked with chemoresistance. Doxorubicin (Dox) treatment, a member of the anthracycline family, represents a typical therapeutic strategy; however, chemoresistance remains a significant challenge. Exosomes (Exs) secreted by tumoral cells have been implicated in cell communication pathways and chemoresistance mechanisms; the content of exosomes is an outcome of cellular cholesterol metabolism. We previously induced Dox resistance in TNBC cell models, characterizing a variant denominated as variant B cells. Our results suggest that LDL internalization in parental and chemoresistant variant B cells is associated with increased cell proliferation, migration, invasion, and spheroid growth. We identified the role of eIF4F translation initiation factor and the down-regulation of tumor suppressor gene PDCD4, an inhibitor of eIF4A, in chemoresistant variant B cells. In addition, the exomes secreted by variant B cells were characterized by the protein content, electronic microscopy, and cell internalization assays. Critically, exosomes purified from LDL-treated variant B cell promoted cell proliferation, migration, and an increment in lactate concentration. Our results suggest that an autocrine phenomenon induced by exosomes in chemoresistant cells may induce modifications on signaling mechanisms of the p53/Mdm2 axis and activation of p70 ribosomal protein kinase S6. Moreover, the specific down-regulated profile of chaperones Hsp90 and Hsp70 secretion inside the exosomes of the chemoresistant variant could be associated with this phenomenon. Therefore, autocrine activation mediated by exosomes and the effect of LDL internalization may influence changes in exosome chaperone content and modulate proliferative signaling pathways, increasing the aggressiveness of MDA-MB-231 chemoresistant cells.

Celecoxib Decreases the Need for Rescue Analgesics after Total Knee Arthroplasty: A Meta-Analysis.

This systematic review and meta-analysis aimed to evaluate the analgesic efficacy and adverse effects of celecoxib after total knee arthroplasty. Keywords in the PubMed and Scopus databases were used to find article abstracts. Each included clinical trial was assessed using the Cochrane Collaboration risk of bias tool, and we extracted data on postoperative pain assessment using the Visual Analogue Scale (VAS) at rest, ambulation, and active range of motion, rescue analgesic intake, and adverse effects. Inverse variance tests with mean differences were used to analyze the numerical variables. The Mantel-Haenszel statistical method and the odds ratio were used to evaluate the dichotomous data. According to this qualitative assessment (n = 482), two studies presented conclusions in favor of celecoxib (n = 187), one showed similar results between celecoxib and the placebo (n = 44), and three clinical trials did not draw conclusions as to the effectiveness of celecoxib versus the placebo (n = 251). Moreover, the evaluation of the rescue analgesic intake showed that the patients receiving celecoxib had a lower intake compared to patients receiving a placebo (n = 278, I2 = 82%, p = 0.006, mean difference = -6.89, 95% IC = -11.76 to -2.02). In conclusion, the pooled analysis shows that administration of celecoxib alone results in a decrease in rescue analgesic consumption compared to a placebo after total knee surgery.

Modulation of myeloid-derived suppressor cell functions by oral inflammatory diseases and important oral pathogens.

The oral cavity presents a diverse microbiota in a dynamic balance with the host. Disruption of the microbial community can promote dysregulation of local immune response which could generate oral diseases. Additionally, alterations in host immune system can result in inflammatory disorders. Different microorganisms have been associated with establishment and progression of the oral diseases. Oral cavity pathogens/diseases can modulate components of the inflammatory response. Myeloid-derived suppressor cells (MDSCs) own immunoregulatory functions and have been involved in different inflammatory conditions such as infectious processes, autoimmune diseases, and cancer. The aim of this review is to provide a comprehensive overview of generation, phenotypes, and biological functions of the MDSCs in oral inflammatory diseases. Also, it is addressed the biological aspects of MDSCs in presence of major oral pathogens. MDSCs have been mainly analyzed in periodontal disease and Sjögren's syndrome and could be involved in the outcome of these diseases. Studies including the participation of MDSCs in other important oral diseases are very scarce. Major oral bacterial and fungal pathogens can modulate expansion, subpopulations, recruitment, metabolism, immunosuppressive activity and osteoclastogenic potential of MDSCs. Moreover, MDSC plasticity is exhibited in presence of oral inflammatory diseases/oral pathogens and appears to be relevant in the disease progression and potentially useful in the searching of possible treatments. Further analyses of MDSCs in oral cavity context could allow to understand the contribution of these cells in the fine-tuned balance between host immune system and microorganism of the oral biofilm, as well as their involvement in the development of oral diseases when this balance is altered.

Increased Expression of lncRNA AC000120.7 and SENP3-EIF4A1 in Patients with Acute Respiratory Distress Syndrome Induced by SARS-CoV-2 Infection: A Pilot Study.

COVID-19, a disease caused by the SARS-CoV-2 virus, poses significant threats to the respiratory system and other vital organs. Long non-coding RNAs have emerged as influential epigenetic regulators and promising biomarkers in respiratory ailments. The objective of this study was to identify candidate lncRNAs in SARS-CoV-2-positive individuals compared to SARS-CoV-2-negative individuals and investigate their potential association with ARDS-CoV-2 (acute respiratory distress syndrome). Employing qRT-PCR, we meticulously examined the expression profiles of a panel comprising 84 inflammation-related lncRNAs in individuals presenting upper respiratory infection symptoms, categorizing them into those testing negative or positive for SARS-CoV-2. Notably, first-phase PSD individuals exhibited significantly elevated levels of AC000120.7 and SENP3-EIF4A1. In addition, we measured the expression of two lncRNAs, AC000120.7 and SENP3-EIF4A1, in patients with ARDS unrelated to SARS-CoV-2 (n = 5) and patients with ARDS induced by SARS-CoV-2 (ARDS-CoV-2, n = 10), and interestingly, expression was also higher among patients with ARDS. Intriguingly, our interaction pathway analysis unveiled potential interactions between lncRNA AC000120.7, various microRNAs, and genes associated with inflammation. This study found higher expression levels of lncRNAs AC000120.7 and SENP3-EIF4A1 in the context of infection-positive COVID-19, particularly within the complex landscape of ARDS.

Isobolographic analysis of the ciprofloxacin-gentamicin combination against beta-lactamase-producing Staphylococcus aureus.

BACKGROUND: Bacterial multi-resistance is a serious global problem that continues to worsen over time due to multiple factors. Among these factors, it is important to highlight the clinical misuse of antibiotics and the mechanisms that microorganisms have developed to protect themselves from these drugs. In this sense, Staphylococcus aureus (S. aureus) is a pathogen that has found a way to resist many of the drugs currently in use, so infections by this bacterium represent a serious clinical problem. OBJECTIVES: The purpose of this study was to determine the type of interaction between ciprofloxacin and gentamicin against beta-lactamase-producing S. aureus using isobolographic analysis. METHODS: Ciprofloxacin (0.5-0.05 mg/mL) and gentamicin (10-1 mg/mL) were used to make concentration-dependent curves for each individual drug. Thereafter, the 50 inhibitory concentration (IC50 ) of each drug was obtained, and different proportions of the ciprofloxacin-gentamicin combination-0.5:0.5, 0.8:0.2, 0.2:0.8, 0.9:0.1, 0.1:0.9, 0.95:0.05, and 0.05:0.95-were evaluated. The isobolographic analysis and the interaction index were used to analyze the data. RESULTS: The isobolographic evaluation of the combination showed that the ratios 0.5:0.5, 0.8:0.2, 0.2:0.8, and 0.9:0.1 produced a synergistic anti-staphylococcal effect, and the 0.95:0.05 ratio induced an additive antibacterial effect. Finally, the 0.1:0.9 and 0.05:0.95 ratios of the combination presented antagonistic effects against S. aureus. On the other hand, the interaction index showed similar results to the isobolographic analysis. CONCLUSION: The isobolographic results of this in vitro assay show that the ciprofloxacin-gentamicin combination induces synergistic, additive, and antagonistic antimicrobial effects against S. aureus.

Analgesic Efficacy of COX-2 Inhibitors in Periodontal Surgery: A Systematic Review and Meta-Analysis.

The objective of this systematic review and meta-analysis was to evaluate the analgesic efficacy of COX-2 inhibitors versus other drugs in periodontal surgery. Two researchers searched PubMed, Google Scholar, ACM Digital, BASE, EBSCOhost, Scopus, or Web of Science for clinical trials using various combinations of words. All articles that met the selection criteria were assessed using the Cochrane Collaboration's risk of bias tool. For data analysis, the inverse variance and mean difference statistical method was used with Review Manager 5.3 software for Windows. According to the conclusion of each study (qualitative evaluation), only one clinical trial had results in favor of a COX-2 inhibitor when compared to placebo, one clinical study informed that a COX-2 was better that an active control, four studies showed similar analgesic efficacy to active controls, and one clinical study informed the analgesic effect of one celecoxib-caffeine combination in comparison with celecoxib alone and placebo (n = 337). The COX-2 inhibitors showed a decrease in the rescue analgesic consumption (n = 138; I2 = 15%; mean difference = -0.31; 95%CIs = -0.6 to -0.01), and lower pain intensity at four hours (n = 178; I2 = 0%; mean difference = -2.25; 95%CIs = -2.94 to -1.55; p = 0.00001) when compared to active controls after periodontal surgery. In conclusion, the data indicate that COX-2 agents produce better pain relief in comparison to placebo and other drugs after periodontal surgery.

Emerging avenues linking myeloid-derived suppressor cells to periodontal disease.

Periodontal disease is one of the most common inflammatory disorders in humans. Gingivitis is the mildest form of periodontal disease and its progression can lead to periodontitis, an inflammatory disease characterized by soft tissue damage that can lead to progressive destruction of the periodontal ligament and alveolar bone. Diverse populations of immune cells are involved in periodontal disease. Myeloid-derived suppressor cells (MDSCs) represent a heterogeneous group of immature myeloid cells derived from hematopoietic precursor cells and exhibit T cell immunosuppressive functions that are thought to be involved in periodontal disease. Therefore, MDSCs have been recently analyzed in the context of this disease. In this review, we discuss the most recent advances in the characterization of the biological aspects, subpopulations, and traffic of MDSCs, as well as their immunosuppressive and osteoclastogenic activity in the context of periodontal disease and in the presence of key periodontal pathogens.

Antagonistic, synergistic, and additive antibacterial interaction between ciprofloxacin and amoxicillin against Staphylococcus aureus.

The aim of this in vitro study was to evaluate the interaction between ciprofloxacin and amoxicillin against beta-lactamase-producing Staphylococcus aureus. Concentration-dependent curves for each individual drug were carried out to obtain the mean inhibitory concentration in the agar well diffusion assay. Then, different ratios of the ciprofloxacin-amoxicillin combination (0.5:0.5, 0.8:0.2, 0.2:0.8, 0.9:0.1, 0.1:0.9, 0.95:0.05, and 0.05:0.95) were assessed. Data were analyzed using the isobolographic analysis and interaction index. The isobolographic evaluation shows that the 0.9:0.1 and 0.95:0.05 ratios of the ciprofloxacin-amoxicillin combination produced a synergistic antimicrobial interaction, the 0.8:0.2, 0.2:0.8, 0.1:0.9, and 0.05:0.95 proportions showed an additive antibacterial effect, and the 0.5:0.5 proportion induced antagonistic antimicrobial effects. The interaction index showed similar outcomes to the isobolographic analysis. In conclusion, the data of this study mainly show antimicrobial additive results of the ciprofloxacin-amoxicillin combination against beta-lactamase-producing S. aureus.

eIF4A/PDCD4 Pathway, a Factor for Doxorubicin Chemoresistance in a Triple-Negative Breast Cancer Cell Model.

Cells employ several adaptive mechanisms under conditions of accelerated cell division, such as the unfolded protein response (UPR). The UPR is composed of a tripartite signaling system that involves ATF6, PERK, and IRE1, which maintain protein homeostasis (proteostasis). However, deregulation of protein translation initiation could be associated with breast cancer (BC) chemoresistance. Specifically, eukaryotic initiation factor-4A (eIF4A) is involved in the unfolding of the secondary structures of several mRNAs at the 5' untranslated region (5'-UTR), as well as in the regulation of targets involved in chemoresistance. Importantly, the tumor suppressor gene PDCD4 could modulate this process. This regulation might be disrupted in chemoresistant triple negative-BC (TNBC) cells. Therefore, we characterized the effect of doxorubicin (Dox), a commonly used anthracycline medication, on human breast carcinoma MDA-MB-231 cells. Here, we generated and characterized models of Dox chemoresistance, and chemoresistant cells exhibited lower Dox internalization levels followed by alteration of the IRE1 and PERK arms of the UPR and triggering of the antioxidant Nrf2 axis. Critically, chemoresistant cells exhibited PDCD4 downregulation, which coincided with a reduction in eIF4A interaction, suggesting a sophisticated regulation of protein translation. Likewise, Dox-induced chemoresistance was associated with alterations in cellular migration and invasion, which are key cancer hallmarks, coupled with changes in focal adhesion kinase (FAK) activation and secretion of matrix metalloproteinase-9 (MMP-9). Moreover, eIF4A knockdown via siRNA and its overexpression in chemoresistant cells suggested that eIF4A regulates FAK. Pro-atherogenic low-density lipoproteins (LDL) promoted cellular invasion in parental and chemoresistant cells in an MMP-9-dependent manner. Moreover, Dox only inhibited parental cell invasion. Significantly, chemoresistance was modulated by cryptotanshinone (Cry), a natural terpene purified from the roots of Salvia brandegeei. Cry and Dox co-exposure induced chemosensitization, connected with the Cry effect on eIF4A interaction. We further demonstrated the Cry binding capability on eIF4A and in silico assays suggest Cry inhibition on the RNA-processing domain. Therefore, strategic disruption of protein translation initiation is a druggable pathway by natural compounds during chemoresistance in TNBC. However, plasmatic LDL levels should be closely monitored throughout treatment.

Local Tramadol Improves the Anesthetic Success in Patients with Symptomatic Irreversible Pulpitis: A Meta-Analysis.

Symptomatic irreversible pulpitis is a painful clinical condition with a broad inflammatory component. Dental anesthesia in these patients is affected by the inflammatory process, reporting a high incidence of anesthesia failure. The aim of this systematic review and meta-analytical evaluation was to determine the effect of pre-treatment with tramadol in patients with symptomatic irreversible pulpitis, as well as for pain control and adverse effects. This study was registered in PROSPERO (ID: CRD42021279262). PubMed was consulted to identify clinical investigations comparing tramadol and placebo/local anesthetics in patients with symptomatic irreversible pulpitis. Data about the anesthesia, pain control, and adverse effects were extracted. Both the anesthetic success index and the adverse effects of local tramadol and placebo were compared with the Mantel−Haenszel test and odds ratio. Data analysis showed that the local administration of tramadol increased the anesthetic success rate when compared to placebo in patients with symptomatic irreversible pulpitis (n = 228; I2 = 0; OR = 2.2; 95% CIs: 1.30 to 3.79; p < 0.004). However, local administration of tramadol increased the risk of adverse effects when compared to placebo/local anesthetics (n = 288; I2 = 0; OR = 7.72; 95% CIs: 1.37 to 43.46; p < 0.02). In conclusion, this study shows that the local administration of tramadol increases the anesthetic success index when compared to placebo in patients with symptomatic irreversible pulpitis.

Roles of microRNAs and Long Non-Coding RNAs Encoded by Parasitic Helminths in Human Carcinogenesis.

Infectious agents such as viruses, bacteria, and parasites can lead to cancer development. Infection with the helminthic parasite Schistosoma haematobium can cause cancer of the urinary bladder in humans, and infection with the parasites Clonorchis sinensis and Opisthorchis viverrini can promote cholangiocarcinoma. These three pathogens have been categorized as "group 1: carcinogenic to humans" by the International Agency for Research on Cancer (IARC). Additionally, the parasite Schistosoma japonicum has been associated with liver and colorectal cancer and classified as "group 2B: possibly carcinogenic to humans". These parasites express regulatory non-coding RNAs as microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), which modulate genic expression in different biological processes. In this review, we discuss the potential roles of miRNAS and lncRNAs encoded by helminthic parasites that are classified by the IARC as carcinogenic and possibly carcinogenic to humans. The miRNAs of these parasites may be involved in carcinogenesis by modulating the biological functions of the pathogen and the host and by altering microenvironments prone to tumor growth. miRNAs were identified in different host fluids. Additionally, some miRNAs showed direct antitumoral effects. Together, these miRNAs show potential for use in future therapeutic and diagnostic applications. LncRNAs have been less studied in these parasites, and their biological effects in the parasite-host interaction are largely unknown.

Dexamethasone Increases the Anesthetic Success in Patients with Symptomatic Irreversible Pulpitis: A Meta-Analysis.

Inferior alveolar nerve block (IANB) has a high failure rate in subjects with symptomatic irreversible pulpitis (SIP). It has been suggested that drugs with anti-inflammatory activity could improve the efficacy of the anesthetic used for IANB. The aim of this study was to assess the effect of dexamethasone on the success of dental anesthesia in patients with SIP. An information search was performed using PubMed and Google Scholar. The risk of bias of the included studies was evaluated with the Cochrane Collaboration's risk-of-bias tool. The anesthetic success rate, pain intensity (VAS), and adverse effects were extracted. Data were analyzed using the Mantel−Haenszel test and odds ratio or the inverse variance and standardized mean difference. Dexamethasone increased the anesthetic success in comparison with placebo (n = 502; p < 0.001; OR = 2.59; 95% CIs: 1.46 to 4.59). Moreover, patients who were given dexamethasone had lower pain scores at 6 h (n = 302; p < 0.001; MD= −1.43; 95% CIs: −2.28 to −0.58), 12 h (n = 302; p < 0.0001; MD = −1.65; 95% CIs: −2.39 to −0.92), and 24 h (n = 302; p < 0.0008; MD = −1.27; 95% CIs: −2.01 to −0.53) when compared with placebo. In conclusion, the systemic administration of dexamethasone increases the anesthetic success rate and improves pain management in patients with SIP.

Postoperative administration of ketorolac compared to other drugs for pain control after third molar surgery: A meta-analysis of double-blind, randomized, clinical trials.

AIMS: The aim of this study was to evaluate the analgesic effectiveness and adverse reactions of ketorolac in comparison with other drugs when administered postoperatively after third molar surgery. METHODS: PubMed and Google Scholar were utilized to search for articles comparing the efficacy and safety of ketorolac and other analgesic agents after third molar surgery. Data from papers with a lower risk of bias were recorded. The overall evaluation of analgesia onset, general and subgroup evaluation of the number of patients requiring rescue analgesic medication, general and subgroup assessment of the study medication (satisfaction on the study drugs), and the overall estimation of adverse effects were performed using the Review Manager Software 5.3 to analyse the data and obtain the meta-analysis plot. RESULTS: The subgroup evaluation of the study medication showed that patients who received ketorolac 30 mg were more satisfied than those who were given parecoxib 1 mg (odds ratio [OR] = 8.57, 95% confidence interval [CI] = 3.66-20.08, P = .00001), parecoxib 2 mg (OR = 7.17, 95% CI = 2.88-17.86, P = .0001), parecoxib 5 mg (OR = 3.03, 95% CI = 1.69-5.41, P = .0002), and parecoxib 10 mg (OR = 2.42, 95% CI = 1.36-4.32, P = .003). Moreover, patients who received ketorolac reported fewer adverse reactions compared with those who had received opioid analgesics (OR = 0.14, 95% CI = 0.32-1.76, P = .0001). CONCLUSIONS: The data from this study demonstrates that the postoperative administration of ketorolac 30 mg presents better results on patient satisfaction when compared to parecoxib 1 mg to 10 mg, and presents a similar satisfaction to parecoxib 20 mg following third molar removal.

Vitamin A deficiency in K14E7HPV expressing transgenic mice facilitates the formation of malignant cervical lesions.

Infection with high-risk human papillomavirus (HR-HPV) is the main cause of cervical cancer (CC), but viral infection alone does not guarantee the development of this malignancy. Indeed, deficiencies of dietary micronutrients could favor cervical cancer development in individuals that harbor HR-HPV infections. The status of retinoid levels, natural and synthetic derivatives of vitamin A, is important in maintaining cellular differentiation of the cervical epithelium. Moreover, many studies show a link between deficient intake of retinoids or alteration of the retinoid receptors and CC development. In spite of this, the effect of vitamin A deficiency (VAD) in presence of HR-HPV oncoproteins on cervical carcinogenesis in vivo has not been reported. Transgenic mice expressing E6 or E7 oncoproteins (K14E6 or K14E7 mice, respectively) were used to evaluate the possible role of VAD in the development of malignant cervical lesions. The survival of the mice in VAD condition was studied, and histopathological analysis and immunohistochemical detection of molecular cancer markers such as the tumor suppressor retinoic acid receptor beta (RARß), proliferating cell nuclear antigen (PCNA), cleaved caspase 3, and the tumor suppressor protein p16INK4A (inhibitor of CDK4) were performed. Our results show that K14E6/VAD mice showed moderate cervical dysplasia; notably, K14E7/VAD mice developed severe cervical dysplasia and cervical in situ carcinoma at an early age. VAD synergizes with HPV16E7 oncoprotein expression favoring cervical carcinogenesis in vivo.

Is periodontal disease a risk factor for severe COVID-19 illness?

Periodontal disease (PD) comprises a group of diseases involving inflammatory aspects of the host and dysbiotic events that affect periodontal tissues and could have systemic implications. Diverse factors and comorbidities have been closely associated with PD such as diabetes, obesity, aging, hypertension, and so on; although, underlying mechanisms or causal associations have not been established completely. Interestingly, these same factors have been widely associated with progression or severe coronavirus disease 2019 (COVID-19), an illness caused by coronavirus SARS-CoV-2. Since inflammatory and dysbiotic factors as well as comorbidities affect systemic health, it is possible that periodontal status indicates the risk of complication of COVID-19. However, assessment of oral health history including periodontal status in COVID-19 patients has not been reported. Knowing PD is associated with severe COVID-19 could help identify risk groups and establish pertinent recommendations.

TIE2 Induces Breast Cancer Cell Dormancy and Inhibits the Development of Osteolytic Bone Metastases.

Breast cancer (BCa) cells disseminating to the bone can remain dormant and resistant to treatments for many years until relapsing as bone metastases. The tyrosine kinase receptor TIE2 induces the dormancy of hematopoietic stem cells, and could also induce the dormancy of BCa cells. However, TIE2 is also a target for anti-angiogenic treatments in ongoing clinical trials, and its inhibition could then restart the proliferation of dormant BCa cells in bone. In this study, we used a combination of patient data, in vitro, and in vivo models to investigate the effect of TIE2 in the dormancy of bone metastases. In BCa patients, we found that a higher TIE2 expression is associated with an increased time to metastases and survival. In vitro, TIE2 decreased cell proliferation as it increased the expression of cyclin-dependent kinase inhibitors CDKN1A and CDKN1B and arrested cells in the G0/G1 phase. Expression of TIE2 also increased the resistance to the chemotherapeutic 5-Fluorouracil. In mice, TIE2 expression reduced tumor growth and the formation of osteolytic bone metastasis. Together, these results show that TIE2 is sufficient to induce dormancy in vitro and in vivo, and could be a useful prognostic marker for patients. Our data also suggest being cautious when using TIE2 inhibitors in the clinic, as they could awaken dormant disseminated tumor cells.

Long Non-coding RNAs: Regulators of the Activity of Myeloid-Derived Suppressor Cells.

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous cell population with potent immunosuppressive functions. They play major roles in cancer and many of the pathologic conditions associated with inflammation. Long non-coding RNAs (lncRNAs) are untranslated functional RNA molecules. The lncRNAs are involved in the control of a wide variety of cellular processes and are dysregulated in different diseases. They can participate in the modulation of immune function and activity of inflammatory cells, including MDSCs. This mini review focuses on the emerging role of lncRNAs in MDSC activity. We summarize how lncRNAs modulate the generation, recruitment, and immunosuppressive functions of MDSCs and the underlying mechanisms.

Protein translation associated to PERK arm is a new target for regulation of metainflammation: A connection with hepatocyte cholesterol.

Endoplasmic reticulum stress is a cellular phenomenon that has been associated with metabolic disorders, contributing to the development of obesity, fatty liver disease, and dyslipidemias. Under metabolic overload conditions, in cells with a high protein-secretory activity, such as hepatocytes and Langerhans ß cells, the unfolded protein response (UPR) is critical in to maintain protein homeostasis (proteostasis). UPR integrated by a tripartite signaling system, through activating transcription factor 6, protein kinase R-like endoplasmic reticulum kinase (PERK), and inositol-requiring enzyme 1, regulates gene transcription and translation to resolve stress and conserve proteostasis. In the current study, we demonstrated in hepatocytes under metabolic overload by saturated palmitic and stearic fatty acids, through activation of PERK signaling and CCAAT-enhancer-binding protein homologous protein (CHOP) transcription factor, an association with the expression of cyclooxygenase 2. More important, isolated exosomes from supernatants of macrophages exposed to lipopolysaccharides can also induce a metainflammation phenomenon, and when treated on hepatocytes, induced a rearrangement in cholesterol metabolism through sterol regulatory element-binding protein 2 (SREBP2), low-density lipoprotein receptor (LDLR), apolipoprotein A-I, and ABCA1. Moreover, we demonstrate the cellular effect of terpene-derived molecules, such as cryptotanshinone, isolated of plant Salvia brandegeei, regulating metainflammatory conditions through PERK pathway in both hepatocytes and ß cells. Our data suggest the presence of a modulatory mechanism on specific protein translation process. This effect could be mediated by eukaryotic initiation factor-4A, evaluating salubrinal as a control molecule. Likewise, the protective mechanisms of unsaturated fatty acids, such as oleic and palmitoleic acid were confirmed. Therefore, modulation of metainflammation suggests a new target through PERK signaling in cells with a high secretory activity, and possibly the regulation of cholesterol in hepatocytes is promoted via exosomes.

Pharmacological Control of Complications Following to Third Molar Removal: Evidence Based on A Meta-Analysis.

AIMS: The purpose of this meta-analysis was to evaluate the clinical efficacy of non-steroidal anti-inflammatory drugs and dexamethasone on the trismus, postsurgical pain, facial swelling, as well as the analgesic consumption after third molar surgery. MATERIAL AND METHODS: The reports were identified in the most important medical databases. Those studies that met the requirements were fully assessed according to the inclusion and exclusion criteria. The quality of each report was evaluated with the Oxford Quality Scale and using the Cochrane Collaboration's risk of bias tool. Each meta-analysis was done using the technique of mean difference and 95% confidence intervals employing a random effects model with the Review Manager 5.3., from the Cochrane Library. Significant statistical difference was accepted when the p value was less than 0.05 on the test of overall effect (Z value). RESULTS: Qualitative evaluation was done using the data of 330 patients extracted from seven articles and the quantitative assessment with data of 200 patients from three reports. It was not observed difference among non-steroidal anti-inflammatory drugs and dexamethasone in any of the clinical effectiveness indicators. CONCLUSION: The outcomes of our meta-analysis indicate that non-steroidal anti-inflammatory drugs and dexamethasone have good therapeutic effect for the management of inflammatory complications following to third molar surgery.

Molecular Markers of Anticancer Drug Resistance in Head and Neck Squamous Cell Carcinoma: A Literature Review.

This manuscript provides an update to the literature on molecules with roles in tumor resistance therapy in head and neck squamous cell carcinoma (HNSCC). Although significant improvements have been made in the treatment for head and neck squamous cell carcinoma, physicians face yet another challenge-that of preserving oral functions, which involves the use of multidisciplinary therapies, such as multiple chemotherapies (CT) and radiotherapy (RT). Designing personalized therapeutic options requires the study of genes involved in drug resistance. This review provides an overview of the molecules that have been linked to resistance to chemotherapy in HNSCC, including the family of ATP-binding cassette transporters (ABCs), nucleotide excision repair/base excision repair (NER/BER) enzymatic complexes (which act on nonspecific DNA lesions generated by gamma and ultraviolet radiation by cross-linking and forming intra/interchain chemical adducts), cisplatin (a chemotherapeutic agent that causes DNA damage and induces apoptosis, which is a paradox because its effectiveness is based on the integrity of the genes involved in apoptotic signaling pathways), and cetuximab, including a discussion of the genes involved in the cell cycle and the proliferation of possible markers that confer resistance to cetuximab.