Genetic influence on treatment outcomes in patients with pain-related temporomandibular disorders.

BACKGROUND: Single nucleotide polymorphisms (SNPs) may influence pain susceptibility and impact treatment response in pain-related temporomandibular disorders (TMDp). OBJECTIVE: Explore the role of COMT (rs4646310, rs6269, rs4818, rs4680) and OPRM1 (rs1799971) genotypes in regulating treatment response. METHODS: Sixty TMDp patients (55 females and 5 males), diagnosed with the Diagnostic Criteria for TMD (DC/TMD), underwent standardised treatment (information and education, home physical therapy, occlusal splint) for 6 months. Treatment outcomes included: pain intensity, pain-free mouth opening, jaw functional limitation, depression, and anxiety. Genotyping for COMT and OPRM1 SNPs was performed using DNA from buccal mucosa swabs and TaqMan assays. Statistical analysis was carried out to compare the changes in treatment outcomes and the influence of genotypes on treatment response. RESULTS: Significantly less pain reduction was observed in minor allele carriers of rs4646310, and rs4680 compared to dominant homozygous (p < .025). Minor allele carriers of rs1799971 and rs4646310 demonstrated worsening in pain-free mouth opening while dominant homozygous exhibited improvement (p < .025). Significantly less anxiety reduction was observed in minor allele carriers of rs4646310 compared to dominant homozygous (p = .003). Of the all variables assessed in the regression model, carrying a minor allele of rs1799971 predicted a poorer treatment response considering pain-free mouth opening while carrying a minor allele of rs4646310 predicted less pain and less anxiety reduction. CONCLUSION: Our findings indicate that certain SNP variants of the COMT and OPRM1 genes were associated with poorer treatment response and may therefore play a significant role in the classification of TMDp patients. Also, assessment of patient genotype could potentially aid in predicting treatment response.

Nicotinamide N-Methyltransferase in Acquisition of Stem Cell Properties and Therapy Resistance in Cancer.

The activity of nicotinamide N-methyltransferase (NNMT) is tightly linked to the maintenance of the nicotinamide adenine dinucleotide (NAD+) level. This enzyme catalyzes methylation of nicotinamide (NAM) into methyl nicotinamide (MNAM), which is either excreted or further metabolized to N1-methyl-2-pyridone-5-carboxamide (2-PY) and H2O2. Enzymatic activity of NNMT is important for the prevention of NAM-mediated inhibition of NAD+-consuming enzymes poly-adenosine -diphosphate (ADP), ribose polymerases (PARPs), and sirtuins (SIRTs). Inappropriately high expression and activity of NNMT, commonly present in various types of cancer, has the potential to disrupt NAD+ homeostasis and cellular methylation potential. Largely overlooked, in the context of cancer, is the inhibitory effect of 2-PY on PARP-1 activity, which abrogates NNMT's positive effect on cellular NAD+ flux by stalling liberation of NAM and reducing NAD+ synthesis in the salvage pathway. This review describes, and discusses, the mechanisms by which NNMT promotes NAD+ depletion and epigenetic reprogramming, leading to the development of metabolic plasticity, evasion of a major tumor suppressive process of cellular senescence, and acquisition of stem cell properties. All these phenomena are related to therapy resistance and worse clinical outcomes.

Cell-Type Specific Metabolic Response of Cancer Cells to Curcumin.

In order to support uncontrolled proliferation, cancer cells need to adapt to increased energetic and biosynthetic requirements. One such adjustment is aerobic glycolysis or the Warburg effect. It is characterized by increased glucose uptake and lactate production. Curcumin, a natural compound, has been shown to interact with multiple molecules and signaling pathways in cancer cells, including those relevant for cell metabolism. The effect of curcumin and its solvent, ethanol, was explored on four different cancer cell lines, in which the Warburg effect varied. Vital cellular parameters (proliferation, viability) were measured along with the glucose consumption and lactate production. The transcripts of pyruvate kinase 1 and 2 (PKM1, PKM2), serine hydroxymethyltransferase 2 (SHMT2) and phosphoglycerate dehydrogenase (PHGDH) were quantified with RT-qPCR. The amount and intracellular localization of PKM1, PKM2 and signal transducer and activator of transcription 3 (STAT3) proteins were analyzed by Western blot. The response to ethanol and curcumin seemed to be cell-type specific, with respect to all parameters analyzed. High sensitivity to curcumin was present in the cell lines originating from head and neck squamous cell carcinomas: FaDu, Detroit 562 and, especially, Cal27. Very low sensitivity was observed in the colon adenocarcinoma-originating HT-29 cell line, which retained, after exposure to curcumin, a higher levels of lactate production despite decreased glucose consumption. The effects of ethanol were significant.

Implementing Curcumin in Translational Oncology Research.

Most data published on curcumin and curcumin-based formulations are very promising. In cancer research, the majority of data has been obtained in vitro. Less frequently, researchers used experimental animals. The results of several clinical studies are conclusive, and these studies have established a good foundation for further research focusing on implementing curcumin in clinical oncology. However, the issues regarding timely data reporting and lack of disclosure of the exact curcumin formulations used in these studies should not be neglected. This article is a snapshot of the current status of publicly available data on curcumin clinical trials and a detailed presentation of results obtained so far with some curcumin formulations. Phenomena related to the observed effects of curcumin shown in clinical trials are presented, and its modifying effect on gut microbiota and metabolic reprogramming is discussed. Based on available data, there is a strong indication that curcumin and its metabolites present molecules that do not necessarily need to be abundant in order to act locally and benefit systemically. Future clinical studies should be designed in a way that will take that fact into consideration.

Curcumin and its Potential for Systemic Targeting of Inflamm-Aging and Metabolic Reprogramming in Cancer.

Pleiotropic effects of curcumin have been the subject of intensive research. The interest in this molecule for preventive medicine may further increase because of its potential to modulate inflamm-aging. Although direct data related to its effect on inflamm-aging does not exist, there is a strong possibility that its well-known anti-inflammatory properties may be relevant to this phenomenon. Curcumin's binding to various proteins, which was shown to be dependent on cellular oxidative status, is yet another feature for exploration in depth. Finally, the binding of curcumin to various metabolic enzymes is crucial to curcumin's interference with powerful metabolic machinery, and can also be crucial for metabolic reprogramming of cancer cells. This review offers a synthesis and functional links that may better explain older data, some observational, in light of the most recent findings on curcumin. Our focus is on its modes of action that have the potential to alleviate specific morbidities of the 21st century.

Curcuminoids as Anticancer Drugs: Pleiotropic Effects, Potential for Metabolic Reprogramming and Prospects for the Future.

The number of published studies on curcuminoids in cancer research, including its lead molecule curcumin and synthetic analogs, has been increasing substantially during the past two decades. Insights on the diversity of inhibitory effects they have produced on a multitude of pathways involved in carcinogenesis and tumor progression have been provided. As this wealth of data was obtained in settings of various experimental and clinical data, this review first aimed at presenting a chronology of discoveries and an update on their complex in vivo effects. Secondly, there are many interesting questions linked to their pleiotropic effects. One of them, a growing research topic, relates to their ability to modulate metabolic reprogramming. This review will also cover the use of curcuminoids as chemosensitizing molecules that can be combined with several anticancer drugs to reverse the phenomenon of multidrug resistance. Finally, current investigations in these three complementary research fields raise several important questions that will be put among the prospects for the future research related to the importance of these molecules in cancer research.

Prognostic Significance of Amino Acid Metabolism-Related Genes in Prostate Cancer Retrieved by Machine Learning.

Prostate cancer is among the leading cancers according to both incidence and mortality. Due to the high molecular, morphological and clinical heterogeneity, the course of prostate cancer ranges from slow growth that usually does not require immediate therapeutic intervention to aggressive and fatal disease that spreads quickly. However, currently available biomarkers cannot precisely predict the course of a disease, and novel strategies are needed to guide prostate cancer management. Amino acids serve numerous roles in cancers, among which are energy production, building block reservoirs, maintenance of redox homeostasis, epigenetic regulation, immune system modulation and resistance to therapy. In this article, by using The Cancer Genome Atlas (TCGA) data, we found that the expression of amino acid metabolism-related genes is highly aberrant in prostate cancer, which holds potential to be exploited in biomarker design or in treatment strategies. This change in expression is especially evident for catabolism genes and transporters from the solute carrier family. Furthermore, by using recursive partitioning, we confirmed that the Gleason score is strongly prognostic for progression-free survival. However, the expression of the genes SERINC3 (phosphatidylserine and sphingolipids generation) and CSAD (hypotaurine generation) can refine prognosis for high and low Gleason scores, respectively. Therefore, our results hold potential for novel prostate cancer progression biomarkers.

Association of Oxidative-Stress-Related Gene Polymorphisms with Pain-Related Temporomandibular Disorders and Oral Behavioural Habits.

The frequency of selected polymorphisms, one in each gene coding for proteins with antioxidative properties (CAT(rs1001179), SOD2(rs4880), GPX1(rs1050450), and NQO1(rs689452)), was compared between patients suffering from pain-related temporomandibular disorders (TMDp; n = 85) and control subjects (CTR; n = 85). The same was evaluated when participants were divided with respect to oral behavioural habits frequency into high-frequency parafunction (HFP; n = 98) and low-frequency parafunction (LFP; n = 72) groups. Another aim was to investigate whether polymorphisms in these genes can be associated with participants' psychological and psychosomatic characteristics. Polymorphisms were genotyped using the genomic DNA extracted from buccal mucosa swabs and real-time TaqMan genotyping assays. No differences in genotype distribution between TMDp patients and control subjects were found. Still, TMDp patients who were homozygous for minor allele A, related to the GPX1 polymorphism rs1050450, reported significantly more waking-state oral behaviours than GA + GG genotype carriers (score: 30 vs. 23, p = 0.019). The frequency of genotype AA for rs1050450 polymorphism was higher in HFP than in LFP participants (14.3% vs. 4.2%, p = 0.030). The most important predictors of waking-state oral behaviours were depression, anxiety, AA genotype (rs1050450), and female sex. The explored gene polymorphisms were not found to be significant risk factors for either TMDp or sleep-related oral behaviours. The association of waking-state oral behaviours with selected gene polymorphisms additionally supports previous assumptions that daytime bruxism is more closely linked to various stress manifestations, which might also be reflected through the variability related to the cellular antioxidative activity.

EZH2 Inhibition and Cisplatin as a Combination Anticancer Therapy: An Overview of Preclinical Studies.

Anticancer monotherapies are often insufficient in eradicating cancer cells because cancers are driven by changes in numerous genes and pathways. Combination anticancer therapies which aim to target several cancer traits at once represent a substantial improvement in anticancer treatment. Cisplatin is a conventional chemotherapy agent widely used in the treatment of different cancer types. However, the shortcomings of cisplatin use include its toxicity and development of resistance. Therefore, from early on, combination therapies that include cisplatin were considered and used in a variety of cancers. EZH2, an epigenetic regulator, is frequently upregulated in cancers which, in general, potentiates cancer cell malignant behavior. In the past decade, numerous EZH2 inhibitors have been explored for their anticancer properties. In this overview, we present the studies that discuss the joint action of cisplatin and EZH2 inhibitors. According to the data presented, the use of cisplatin and EZH2 inhibitors may be beneficial in the treatment of lung, ovarian, and breast cancers, since there is a substantial amount of published evidence that suggests their concerted action. However, in testicular germ cell tumors, such a combination would not be recommended because cisplatin resistance seems to be associated with decreased expression of EZH2 in this tumor type.

Expression of nm23-H1 and COX-2 in thyroid papillary carcinoma and microcarcinoma.

The expression of non-metastatic expressed/non-metastatic 23 nucleoside diphosphate kinase 1 (nm23-H1) and cyclooxygenase 2 (COX-2) proteins in thyroid carcinoma have been analysed in a number of previous studies, but this requires further study. The current study focused on the expression levels of nm23-H1 and COX-2 in 130 human thyroid papillary carcinoma (PTC) tissues. Of the 130 PTC tissues, 55 were classified as microcarcinoma and may provide information on the development of the specific characteristics of this tumour type. Routine histopathological examination and immunohistochemical detection of nm23-H1 and COX-2 expression was performed on 130 PTC tissues from patients treated in the Clinical Hospital for Tumours (Zagreb, Croatia) between January 2000 and December 2007. The stain intensity of nm23-H1 and COX-2 proteins was compared with the characteristics of the patients and the tumour. The highest overall expression rate of nm23-H1 and COX-2 was 90 and 67.6%, respectively, and the joint expression of these proteins was statistically significant. The median expression level of nm23-H1 was significantly increased in the classical and follicular histological group of the PTC tissues compared with tissues from other histological groups. The median expression level of COX-2 was significantly increased in the follicular histological group, and reduced in the diffuse-sclerosing group of PTC tissues. All the metastatic microcarcinoma tissues had increased expression levels of the two proteins in comparison with microcarcinoma tissues without lymph node metastases; however, this variation was only statistically significant for COX-2 expression levels. Therefore the results of the current study indicate that COX-2 protein levels may be able to differentiate which thyroid papillary microcarcinoma tumours possess metastatic potential.

Selected attributes of polyphenols in targeting oxidative stress in cancer.

Various plant polyphenols have been recognized as redox active molecules. This review discusses some aspects of polyphenols' modes of redox action, corresponding structure-activity relationships and their potential to be applied as adjuvants to conventional cytostatic drugs. Polyphenols' antioxidative capacity has been discussed as the basis for targeting oxidative stress and, consequently, for their chemopreventive and anti-inflammatory activities, which may alleviate side-effects on normal cells arising from oxidative stress caused by cytostatics. Some polyphenols may scavenge various free radicals directly, and some of them are found to suppress free radical production through inhibiting NADPH oxidases and xanthine oxidase. Additionally, polyphenols may increase antioxidative defense in normal cells by increasing the activity of NRF2, transcription factor for many protective proteins. The activation of the NRF2-mediated signaling pathways in cancer cells results in chemoresistance. Luteolin, apigenin and chrysin reduce NRF2 expression and increase the chemosensitivity of cancer cells to cytostatic drugs. Their common 5,7-dihydroxy-4H-chromen-4-one moiety, may represent a starting pharmacophore model for designing novel, non-toxic compounds for overcoming chemoresistance. However, prooxidative activity of some polyphenols (quercetin, EGCG) may also provide a basis for their use as chemotherapeutic adjuvants since they may enhance cytotoxic effects of cytostatics selectively on cancer cells. However, considerable caution is needed in applying polyphenols to anticancer therapy, since their effects greatly depend on the applied dose, the cell type, exposure time and environmental conditions.

Curcumin in combined cancer therapy.

The mechanisms of beneficial preventive and therapeutic effects achieved by traditional and complementary medicine are currently being deciphered in molecular medicine. Curcumin, a yellow-colored polyphenol derived from the rhizome of turmeric (Curcuma longa), influences a wide variety of cellular processes through the reshaping of many molecular targets. One of them, nuclear factor kappa B (NF-κB), represents a strong mediator of inflammation and, in a majority of systems, supports the pro-proliferative features of cancer cells. The application of various anticancer drugs, cytostatics, triggers signals which lead to an increase in cellular NF-κB activity. As a consequence, cancer cells often reshape their survival signaling pathways and, over time, become resistant to applied therapy. Curcumin was shown to be a strong inhibitor of NF-κB activity and its inhibitory effect on NF-κB related pathways often leads to cellular apoptotic response. All these facts, tested and confirmed in many different biological systems, have paved the way for research aimed to elucidate the potential beneficial effects of combining curcumin and various anti-cancer drugs in order to establish more efficient and less toxic cancer treatment modalities. This review addresses certain aspects of NF-κB-related inflammatory response, its role in carcinogenesis and therapy benefits that may be gained through silencing NF-κB by selectively combining curcumin and various anticancer drugs.

Single nucleotide polymorphisms in the interleukin-6 gene promoter, tumor necrosis factor-alpha gene promoter, and transforming growth factor-beta1 gene signal sequence as predictors of time to onset of aseptic loosening after total hip arthroplasty: preliminary study.

BACKGROUND: Aseptic loosening resulting from inflammatory response to the implant wear debris is the major cause of late total hip arthroplasty (THA) failure. We examined single nucleotide polymorphisms in genes encoding for three involved cytokines--interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), and transforming growth factor-beta1 (TGF-beta1)--as potential predictors of time to onset of aseptic instability. METHODS: A total of 41 patients/45 total hip endoprostheses (same type, same surgeon) were followed up for as long as 18 years. They were genotyped for the IL-6 promoter (-597G-->A) and (-572G-->C), TNF-alpha promoter (-308G-->A), and TGF-beta1 signal sequence (29T-->C) transitions. Cox regression was performed on the prosthesis survival. RESULTS: Overall, 22 of 45 prostheses developed aseptic instability. Cumulative survivals at 10 and 15 years after THA were 95.6% and 66.6%, respectively. The effect of a particular polymorphic site was estimated with adjustment for sex, age at THA, reason for THA, and the effects of other analyzed sites. The hazard ratio (HR) for genotype T/T versus "C-allele carriage" at the TGF-beta1 site was 8.23 [95% confidence interval (CI) 1.45-46.8] (P=0.017) or 5.70 (1.39-23.4) (P=0.016) when the IL-6 promoter sites were considered as a "combination of genotypes (-597)|(-572)." The most prevalent combination of genotypes at IL-6 sites was G/A (-597)|C/C (-572). HR for this combination (versus other combinations) was 5.43 (1.73-17.0) (P=0.004) when "TGF-beta1 (29T-->C)" was considered as a three-level factor (three possible genotypes), and 4.92 (1.71-14.1) (P=0.003) when TGF-beta1 site was considered as a two-level factor (T/T and "C-allele carriage"). The HR for the "A-allele carriage" at TNF-alpha (-308G-->A) could not be determined (only two patients had the G/G genotype). CONCLUSIONS: This preliminary study is the first to suggest that the TGF-beta1 signal sequence (29T-->C) and IL-6 promoter (-597G-->A)|(-572G-->C) transitions are predictive for the time to onset of aseptic instability after THA.