Effectiveness of gold nanoparticles in prevention and treatment of oral mucositis in animal models: a systematic review

Background: Oral mucositis remains a significant complication during cancer therapy with no effective treatment. Gold nanoparticles offer anti-inflammatory, antioxidant properties with low toxicity. This study systematically reviews the literature assessing gold nanoparticles in the management of oral mucositis in animal models. Methods: A literature search was undertaken using MEDLINE, Embase, PubMed, and Web of Science databases, using the format for Systematic Review Centre for Laboratory Animal Experimentation. Prior to the review, the protocol was registered in the systematic review register, PROSPERO (registration no. CRD42021272169). Outcome measures included ulceration, histopathological scores, inflammatory mediators, microbial growth, and pain. Study quality was analysed by SYRCLE risk-of-bias tool. Results: Only one study met the inclusion criteria, documenting reduction in ulceration, inflammatory, and oxidative biomarkers. Exposure to AuNPs prevented inflammatory response induced by 5-fluorouracil in oral mucosa of hamsters. However, a high risk of bias necessitates further research. Conclusion: This review identifies a potential therapeutic strategy for prevention and management of oral mucositis. It also provides future direction for gold nanoparticle research in oral mucositis; however, there is lack of sufficient evidence to derive any conclusion. Research with standardized parameters including nanoparticle size, capping agent, surface charge, and appropriate oral mucositis animal models will establish risk–benefit balance and margin of safety for therapeutic use of gold nanoparticles for oral mucositis

Social Value Orientation, Expectations, and Cooperation in Social Dilemmas:A Meta-analysis

Interdependent situations are pervasive in human life. In these situations, it is essential to form expectations about the others' behaviour to adapt one's own behaviour to increase mutual outcomes and avoid exploitation. Social value orientation, which describes the dispositional weights individuals attach to their own and to another person's outcome, predicts these expectations of cooperation in social dilemmas—an interdependent situation involving a conflict of interests. Yet, scientific evidence is inconclusive about the exact differences in expectations between prosocials, individualists, and competitors. The present meta-analytic results show that, relative to proselfs (individualists and competitors), prosocials expect more cooperation from others in social dilemmas, whereas individualists and competitors do not significantly differ in their expectations. The importance of these expectations in the decision process is further highlighted by the finding that they partially mediate the well-established relation between social value orientation and cooperative behaviour in social dilemmas. In fact, even proselfs are more likely to cooperate when they expect their partner to cooperate

Arrhythmic effects of Epac-mediated ryanodine receptor activation in Langendorff-perfused murine hearts are associated with reduced conduction velocity

Recent papers have attributed arrhythmic substrate in murine RyR2-P2328S hearts to reduced action potential (AP) conduction velocities (CV), reflecting acute functional inhibition and/or reduced expression of sodium channels. We explored for acute effects of direct exchange protein directly activated by cAMP (Epac)-mediated ryanodine receptor-2 (RyR2) activation on arrhythmic substrate and CV. Monophasic action potential (MAP) recordings demonstrated that initial steady (8 Hz) extrinsic pacing elicited ventricular tachycardia (VT) in 0 of 18 Langendorff-perfused wild-type mouse ventricles before pharmacological intervention. The Epac activator 8-CPT (8-(4-chlorophenylthio)-2′-O-methyladenosine-3′,5′-cyclic monophosphate) (VT in 1 of 7 hearts), and the RyR2 blocker dantrolene, either alone (0 of 11) or with 8-CPT (0 of 9) did not then increase VT incidence (P>.05). Both progressively increased pacing rates and programmed extrasystolic (S2) stimuli similarly produced no VT in untreated hearts (n=20 and n=9 respectively). 8-CPT challenge then increased VT incidences (5 of 7 and 4 of 8 hearts respectively; P.05). 8-CPT but not dantrolene, whether alone or combined with 8-CPT, correspondingly increased AP latencies (1.14±0.04 (n=7), 1.04±0.03 (n=10), 1.09±0.05 (n=8) relative to respective control values). In contrast, AP durations, conditions for 2:1 conduction block and ventricular effective refractory periods remained unchanged throughout. We thus demonstrate for the first time that acute RyR2 activation reversibly induces VT in specific association with reduced CV.We thank the Medical Research Council (UK) (CLH), Wellcome Trust (UK) (CLH), British Heart Foundation (UK) (CLH), McVeigh Benefaction (CLH and AG), and Sudden Arrhythmic Death Syndrome (SADS) UK (CLH and AG) for support

Estradiol during (analogue-)trauma: Risk- or protective factor for intrusive re-experiencing?

Intrusions, a key symptom of posttraumatic stress disorder (PTSD), can occur in the form of images but also as pain sensations. Similar to audiovisual intrusions, the frequency and persistence of pain intrusions varies greatly between individuals. In the current study, we examined whether peritraumatic circulating 17β-estradiol (E2) levels are a biologic factor associated with subsequent audiovisual (i.e., film) and pain intrusion development, and whether peritraumatic stress levels modulate this relationship. Forty-one free-cycling women participated in an ecologically informed trauma-pain-conditioning (TPC) paradigm, using trauma-films and pain as unconditioned stimuli. Independent variables were salivary peritraumatic E2 levels and stress indexed by salivary cortisol and self-reported state-anxiety during TPC. Outcomes were film- and pain-intrusions occurring during daily-life in the week following TPC and a Memory-Triggering-Task in response to conditioned stimuli 24 h after TPC. In the week after analogue-trauma, higher peritraumatic E2 levels were associated with a greater probability of experiencing film-intrusions in the beginning of the week, which switched to a lower probability toward the end of the week. This time-dependent relationship between E2 and film-intrusions only held for higher state-anxious women. In contrast, results indicated a consistent inverse relationship between peritraumatic E2 levels and pain-intrusions during daily-life and Memory-Triggering-Task. Together, these data suggest that higher peritraumatic E2 levels could be associated with lower long-term visual trauma intrusions, as well as lower pain-intrusions, and thereby possibly constitute a protective biologic factor for PTSD and potentially also for chronic pain

Social Value Orientation, Expectations, and Cooperation in Social Dilemmas:A Meta-analysis

Interdependent situations are pervasive in human life. In these situations, it is essential to form expectations about the others’ behaviour to adapt one’s own behaviour to increase mutual outcomes and avoid exploitation. Social value orientation, which describes the dispositional weights individuals attach to their own and to another person’s outcome, predicts these expectations of cooperation in social dilemmas—an interdependent situation involving a conflict of interests. Yet, scientific evidence is inconclusive about the exact differences in expectations between prosocials, individualists, and competitors. The present meta-analytic results show that, relative to proselfs (individualists and competitors), prosocials expect more cooperation from others in social dilemmas, whereas individualists and competitors do not significantly differ in their expectations. The importance of these expectations in the decision process is further highlighted by the finding that they partially mediate the well-established relation between social value orientation and cooperative behaviour in social dilemmas. In fact, even proselfs are more likely to cooperate when they expect their partner to cooperate

Attempting to distinguish between endogenous and contaminating cytokeratins in a corneal proteomic study

<p>Abstract</p> <p>Background</p> <p>The observation of cytokeratins (CK's) in mass spectrometry based studies raises the question of whether the identified CK is a true endogenous protein from the sample or simply represents a contaminant. This issue is especially important in proteomic studies of the corneal epithelium where several CK's have previously been reported to mark the stages of differentiation from corneal epithelial stem cell to the differentiated cell.</p> <p>Methods</p> <p>Here we describe a method to distinguish very likely endogenous from uncertain endogenous CK's in a mass spectrometry based proteomic study. In this study the CK identifications from 102 human corneal samples were compared with the number of human CK identifications found in 102 murine thymic lymphoma samples.</p> <p>Results</p> <p>It was anticipated that the CK's that were identified with a frequency of <5%, <it>i.e. </it>in less than one spot for every 20 spots analysed, are very likely to be endogenous and thereby represent a 'biologically significant' identification. CK's observed with a frequency >5% are uncertain endogenous since they may represent true endogenous CK's but the probability of contamination is high and therefore needs careful consideration. This was confirmed by comparison with a study of mouse samples where all identified human CK's are contaminants.</p> <p>Conclusions</p> <p>CK's 3, 4, 7, 8, 11, 12, 13, 15, 17, 18, 19, 20 and 23 are very likely to be endogenous proteins if identified in a corneal study, whilst CK's 1, 2e, 5, 6A, 9, 10, 14 and 16 may be endogenous although some are likely to be contaminants in a proteomic study. Further immunohistochemical analysis and a search of the current literature largely supported the distinction.</p

CDK-Mediated Regulation of Cell Functions via c-Jun Phosphorylation and AP-1 Activation

Cyclin-dependent kinases (CDKs) and their targets have been primarily associated with regulation of cell-cycle progression. Here we identify c-Jun, a transcription factor involved in the regulation of a broad spectrum of cellular functions, as a newly recognized CDK substrate. Using immune cells from mouse and human, and several complementary in vitro and in vivo approaches including dominant negative protein expression, pharmacologic inhibitors, kinase assays and CDK4 deficient cells, we demonstrate the ability of CDK4 to phosphorylate c-Jun. Additionally, the activity of AP-1, a ubiquitous transcription factor containing phosphorylated c-Jun as a subunit, was inhibited by abrogating CDK4. Surprisingly, the regulation of c-Jun phosphorylation by CDK4 occurred in non-dividing cells, indicating that this pathway is utilized for cell functions that are independent of proliferation. Our studies identify a new substrate for CDK4 and suggest a mechanism by which CDKs can regulate multiple cellular activation functions, not all of which are directly associated with cell cycle progression. These findings point to additional roles of CDKs in cell signaling and reveal potential implications for therapeutic manipulations of this kinase pathway

Malignant hyperthermia

Malignant hyperthermia (MH) is a pharmacogenetic disorder of skeletal muscle that presents as a hypermetabolic response to potent volatile anesthetic gases such as halothane, sevoflurane, desflurane and the depolarizing muscle relaxant succinylcholine, and rarely, in humans, to stresses such as vigorous exercise and heat. The incidence of MH reactions ranges from 1:5,000 to 1:50,000–100,000 anesthesias. However, the prevalence of the genetic abnormalities may be as great as one in 3,000 individuals. MH affects humans, certain pig breeds, dogs, horses, and probably other animals. The classic signs of MH include hyperthermia to marked degree, tachycardia, tachypnea, increased carbon dioxide production, increased oxygen consumption, acidosis, muscle rigidity, and rhabdomyolysis, all related to a hypermetabolic response. The syndrome is likely to be fatal if untreated. Early recognition of the signs of MH, specifically elevation of end-expired carbon dioxide, provides the clinical diagnostic clues. In humans the syndrome is inherited in autosomal dominant pattern, while in pigs in autosomal recessive. The pathophysiologic changes of MH are due to uncontrolled rise of myoplasmic calcium, which activates biochemical processes related to muscle activation. Due to ATP depletion, the muscle membrane integrity is compromised leading to hyperkalemia and rhabdomyolysis. In most cases, the syndrome is caused by a defect in the ryanodine receptor. Over 90 mutations have been identified in the RYR-1 gene located on chromosome 19q13.1, and at least 25 are causal for MH. Diagnostic testing relies on assessing the in vitro contracture response of biopsied muscle to halothane, caffeine, and other drugs. Elucidation of the genetic changes has led to the introduction, on a limited basis so far, of genetic testing for susceptibility to MH. As the sensitivity of genetic testing increases, molecular genetics will be used for identifying those at risk with greater frequency. Dantrolene sodium is a specific antagonist of the pathophysiologic changes of MH and should be available wherever general anesthesia is administered. Thanks to the dramatic progress in understanding the clinical manifestation and pathophysiology of the syndrome, the mortality from MH has dropped from over 80% thirty years ago to less than 5%

Identification of Intracellular and Plasma Membrane Calcium Channel Homologues in Pathogenic Parasites

Ca2+ channels regulate many crucial processes within cells and their abnormal activity can be damaging to cell survival, suggesting that they might represent attractive therapeutic targets in pathogenic organisms. Parasitic diseases such as malaria, leishmaniasis, trypanosomiasis and schistosomiasis are responsible for millions of deaths each year worldwide. The genomes of many pathogenic parasites have recently been sequenced, opening the way for rational design of targeted therapies. We analyzed genomes of pathogenic protozoan parasites as well as the genome of Schistosoma mansoni, and show the existence within them of genes encoding homologues of mammalian intracellular Ca2+ release channels: inositol 1,4,5-trisphosphate receptors (IP3Rs), ryanodine receptors (RyRs), two-pore Ca2+ channels (TPCs) and intracellular transient receptor potential (Trp) channels. The genomes of Trypanosoma, Leishmania and S. mansoni parasites encode IP3R/RyR and Trp channel homologues, and that of S. mansoni additionally encodes a TPC homologue. In contrast, apicomplexan parasites lack genes encoding IP3R/RyR homologues and possess only genes encoding TPC and Trp channel homologues (Toxoplasma gondii) or Trp channel homologues alone. The genomes of parasites also encode homologues of mammalian Ca2+ influx channels, including voltage-gated Ca2+ channels and plasma membrane Trp channels. The genome of S. mansoni also encodes Orai Ca2+ channel and STIM Ca2+ sensor homologues, suggesting that store-operated Ca2+ entry may occur in this parasite. Many anti-parasitic agents alter parasite Ca2+ homeostasis and some are known modulators of mammalian Ca2+ channels, suggesting that parasite Ca2+ channel homologues might be the targets of some current anti-parasitic drugs. Differences between human and parasite Ca2+ channels suggest that pathogen-specific targeting of these channels may be an attractive therapeutic prospect