Melatonin has antitumor activity via several mechanisms including its antiproliferative and pro‐apoptotic effects as well as its potent antioxidant actions, although recent evidence has indicated ...that melatonin may perform pro‐oxidant actions in tumor cells. Therefore, melatonin may be useful in the treatment of tumors in association with chemotherapy drugs. This study was intended to evaluate the in vitro effect of melatonin on the cytotoxic and pro‐apoptotic actions of various chemotherapeutic agents in cervical cancer HeLa cells. Herein, we found that both melatonin and three of the chemotherapeutic drugs tested, namely cisplatin (CIS), 5‐fluorouracil (5‐FU), and doxorubicin, induced a decrease in HeLa cell viability. Furthermore, melatonin significantly increased the cytotoxic effect of such chemotherapeutic agents. Consistently, costimulation of HeLa cells with any chemotherapeutic agent in the presence of melatonin further increased caspase‐3 activation, particularly in CIS‐ and 5‐FU‐challenged cells. Likewise, concomitant treatments with melatonin and CIS significantly enhanced the ratio of cells entering mitochondrial apoptosis due to reactive oxygen species (ROS) overproduction, substantially augmented the population of apoptotic cells, and markedly enlarged DNA fragmentation compared to the treatments with CIS alone. Nonetheless, melatonin only displayed moderate chemosensitizing effects in 5‐FU‐stimulated HeLa cells, as suggested by slight increments in the percentage of cells stimulated for ROS production and in the proportion of early apoptotic cells compared to the treatments with 5‐FU alone. In summary, our findings provided evidence that in vitro melatonin strongly enhances CIS‐induced cytotoxicity and apoptosis in HeLa cells and, hence, the indoleamine could be potentially applied to cervical cancer treatment as a powerful synergistic agent.
Currently, neuropathic pain is an underestimated socioeconomic health problem affecting millions of people worldwide, which incidence may increase in the next years due to chronification of several ...diseases, such as cancer and diabetes. Growing evidence links neuropathic pain present in several disorders i.e., spinal cord injury (SCI), cancer, diabetes and alcoholism to central sensitization, as a global result of mitochondrial dysfunction induced by oxidative and nitrosative stress. Additionally, inflammatory signals and the overload in intracellular calcium ion could be also implicated in this complex network that has not yet been elucidated. Recently, calcium channels namely transient receptor potential (TRP) superfamily, including members of the subfamilies A (TRAP1), M (TRPM2 and 7), and V (TRPV1 and 4), have demonstrated to play a role in the nociception mediated by sensory neurons. Therefore, as neuropathic pain could be a consequence of the imbalance between reactive oxygen species and endogen antioxidants, antioxidant supplementation may be a treatment option. This kind of therapy would exert its beneficial action through antioxidant and immunoregulatory functions, optimizing mitochondrial function and even increasing the biogenesis of this vital organelle; on balance, antioxidant supplementation would improve the patient's quality of life. This review seeks to deepen on current knowledge about neuropathic pain, summarizing clinical conditions and probable causes, the relationship existing between oxidative stress, mitochondrial dysfunction and TRP channels activation, and scientific evidence related to antioxidant supplementation.
Background
Melatonin has antitumor activity via several mechanisms including its antiproliferative and proapoptotic effects in addition to its potent antioxidant actions. Therefore, melatonin may be ...useful in the treatment of tumors in association with chemotherapy drugs.
Purpose and methods
This study was performed to study the role of melatonin receptors on the cytotoxicity and apoptosis induced by the chemotherapeutic agents cisplatin and 5-fluorouracil in two tumor cell lines, such as human colorectal cancer HT-29 cells and cervical cancer HeLa cells.
Results
We found that both melatonin and the two chemotherapeutic agents tested induced a decrease in HT-29 and HeLa cell viability. Furthermore, melatonin significantly increased the cytotoxic effect of chemotherapeutic agents, particularly, in 5-fluorouracil-challenged cells. Stimulation of cells with either of the two chemotherapeutic agents in the presence of melatonin further increased caspase-3 activation. Concomitant treatments with melatonin and chemotherapeutic agents augmented the population of apoptotic cells compared to the treatments with chemotherapeutics alone. Blockade of MT1 and/or MT2 receptors with luzindole or 4-P-PDOT was unable to reverse the enhancing effects of melatonin on both cytotoxicity, caspase-3 activation and the amount of apoptotic cells evoked by the chemotherapeutic agents, whereas when MT3 receptors were blocked with prazosin, the synergistic effect of melatonin with chemotherapy on cytotoxicity and apoptosis was reversed.
Conclusion
Our findings provided evidence that in vitro melatonin strongly enhances chemotherapeutic-induced cytotoxicity and apoptosis in two tumor cell lines, namely HT-29 and HeLa cells and, this potentiating effect of melatonin is mediated by MT3 receptor stimulation.
: Melatonin has antitumor activity via several mechanisms including its antiproliferative and proapoptotic effects in addition to its potent antioxidant action. Thus, melatonin has proven useful in ...the treatment of tumors in association with chemotherapeutic drugs. This study was performed to evaluate the effect of melatonin on the cytotoxicity and apoptosis induced by three different chemotherapeutic agents, namely 5‐fluorouracil (5‐FU), cisplatin, and doxorubicin in the rat pancreatic tumor cell line AR42J. We found that both melatonin and the three chemotherapeutic drugs induce a time‐dependent decrease in AR42J cell viability, reaching the highest cytotoxic effect after 48 hr of incubation. Furthermore, melatonin significantly augmented the cytotoxicity of the chemotherapeutic agents. Consistently, cotreatment of AR42J cells with each of the chemotherapeutic agents in the presence of melatonin increased the population of apoptotic cells, elevated mitochondrial membrane depolarization, and augmented intracellular reactive oxygen species (ROS) production compared to treatment with each chemotherapeutic agent alone. These results provide evidence that in vitro melatonin enhances chemotherapy‐induced cytotoxicity and apoptosis in rat pancreatic tumor AR42J cells and, therefore, melatonin may be potentially applied to pancreatic tumor treatment as a powerful synergistic agent in combination with chemotherapeutic drugs.
Sodium-glucose co-transporter-2 inhibitors (SGLT2-Is) have consistently demonstrated a clinically significant reduction of cardiovascular mortality. However, their safety in clinical practice is ...still incompletely characterized, and post-marketing monitoring is required considering the expected increase in clinical use. Different analyses of international spontaneous reporting systems, known as disproportionality analyses (DAs), have highlighted the occurrence of ketoacidosis, amputations, acute renal failure and skin toxicity.
In this viewpoint, we critically appraise these pharmacovigilance data on SGLT2-Is, with the aim of supporting clinicians in proper interpretation of these studies, and discussing their risk-benefit profile. To this aim, we offer a broad perspective on basic technical aspects subtending DAs of spontaneous reporting databases (describing peculiarities of the Food and Drug Administration Adverse Event Reporting System), their common and evolving uses, key pitfalls in presenting study results (in terms of “risk” or “association”) and relevant strategies to account for major confounders. This will also facilitate reviewers and editors in proper evaluation of DAs, and prompt pharmacovigilance experts in converging towards a set of minimum requirements in standardization of design, performance and reporting of DAs. A consensus on quality assessment of DAs will finally establish their transferability to clinical practice. It is anticipated that DAs cannot be used per se as a standalone approach to assess a drug-related risk and cannot replace clinical judgment in the individual patient.
Gene silencing therapies have successfully suppressed the translation of target proteins, a strategy that holds great promise for the treatment of central nervous system (CNS) disorders. Advances in ...the current knowledge on multimolecular delivery vehicles are concentrated on overcoming the difficulties in delivery of small interfering (si)RNA to target tissues, which include anatomical accessibility, slow diffusion, safety concerns, and the requirement for specific cell uptake within the unique environment of the CNS. The present work addressed these challenges through the implementation of polyornithine derivatives in the construction of polyplexes used as non-viral siRNA delivery vectors. Physicochemical and biological characterization revealed biodegradability and biocompatibility of our polyornithine-based system and the ability to silence gene expression in primary oligodendrocyte progenitor cells (OPCs) effectively. In summary, the well-defined properties and neurological compatibility of this polypeptide-based platform highlight its potential utility in the treatment of CNS disorders.
Summary
Background
The outcome of cholangiopathy developing in intensive care unit (ICU) is not known in patients surviving their ICU stay.
Aim
To perform a survey in liver units, in order to clarify ...the course of cholangiopathy after surviving ICU stay.
Methods
The files of the liver units affiliated to the French network for vascular liver disease were screened for cases of ICU cholangiopathy developing in patients with normal liver function tests on ICU admission, and no prior history of liver disease.
Results
Between 2005 and 2015, 16 cases were retrieved. Extensive burns were the cause for admission to ICU in 11 patients. Serum alkaline phosphatase levels increased from day 11 (2‐46) to a peak of 15 (4‐32) × ULN on day 81 (12‐511). Magnetic resonance cholangiography showed irregularities or frank stenosis of the intrahepatic ducts, and proximal extrahepatic ducts contrasting with a normal aspect of the distal common bile duct. Follow‐up duration was 20.6 (4.7‐71.8) months. Three patients were lost to follow‐up; 2 patients died from liver failure and no patient was transplanted. One patient had worsening strictures of the intrahepatic bile ducts with jaundice. Nine patients had persistent but minor strictures of the intrahepatic bile ducts on MR cholangiography, and persistent cholestasis without jaundice. One patient had normal liver function tests.
Conclusions
In patients surviving their ICU stay, ICU cholangiopathy is not uniformly fatal in the short term or clinically symptomatic in the medium term. Preservation of the distal common bile duct appears to be a finding differentiating ICU cholangiopathy from other diffuse cholangiopathies.
Linked ContentThis article is linked to MacGilchrist paper. To view this article visit https://doi.org/10.1111/apt.14441.
The pro‐apoptotic signalling cascades induced by tumour necrosis factor‐alpha (TNF‐α) have been intensively studied in multiple cellular systems. So far, it is known that TNF‐α can simultaneously ...activate survival and apoptotic cell death responses. The balance between these signals determines the ultimate response of the cell to TNF‐α. Moreover, emerging evidence suggests that melatonin may be involved in the protection of different cell types against apoptosis. Thus, the objective of this study was to evaluate the effect of melatonin on TNF‐α‐induced apoptosis in human leucocytes. Cells were treated with TNF‐α alone or in the presence of cycloheximide (CHX), which promotes caspase‐8 activation by eliminating the endogenous caspase‐8 inhibitor, c‐FLIP. Treatment with TNF‐α/CHX led to apoptotic cell death, as ascertained by annexin V/propidium iodide (PI) staining. Likewise, in the presence of CHX, TNF‐α stimulation produced cFLIP down‐regulation and subsequent caspase‐8 activation, thus directly triggering caspase‐3 activation and causing Bid truncation and subsequent caspase‐9 activation. Conversely, pre‐incubation of cells with melatonin inhibited TNF‐α‐/CHX‐evoked leucocyte apoptosis. Similarly, pretreatment of leucocytes with melatonin increased cFLIP protein levels, thereby preventing TNF‐α‐/CHX‐mediated caspase processing. Blockade of melatonin membrane receptor MT1/MT2 or extracellular signal‐regulated kinase (ERK) pathway with luzindole or PD98059, respectively, abolished the inhibitory effects of melatonin on leucocyte apoptosis evoked by TNF‐α/CHX. In conclusion, the model proposed by these findings is that the MT1/MT2 receptors, which are under the positive control of melatonin, trigger an ERK‐dependent signalling cascade that interferes with the anti‐apoptotic protein cFLIP modulating the cell life/death balance of human leucocytes.
To estimate the risk of sudden cardiac death (SCD) or sudden unexpected death (SUD) related to individual antipsychotics, a meta‐analysis of observational studies was performed. Adjusted odds ratio ...(OR) of SCD/SUD with 95% confidence intervals (CI) were extracted and pooled; heterogeneity was studied using Q statistic and I2 index, and its potential causes (e.g., hERG blockade potency) explored using meta‐regression. Two cohort (740,306 person‐years) and four case–control (2,557 cases; 17,670 controls) studies, investigating nine antipsychotics, were included. Compared with nonusers, the risk was increased for quetiapine (OR = 1.72, 95% CI: 1.33–2.23), olanzapine (OR = 2.04, 1.52–2.74), risperidone (OR = 3.04, 2.39–3.86), haloperidol (OR = 2.97, 1.59–5.54), clozapine (OR = 3.67, 1.94–6.94), and thioridazine (OR = 4.58, 2.09–10.05). Heterogeneity was found (Q = 20.0, P = 0.01; I2 = 60.0%), and the increasing mean hERG blockade potency (P = 0.01) accounted for 43% of this. The SCD/SUD risk differed between individual antipsychotics, and mean hERG blockade potency could be an explanatory factor. This should be considered when initiating antipsychotic treatment.
: Apoptosis or programmed cell death plays a critical role in both inflammatory and immune responses. Recent evidence demonstrates that control of leukocyte apoptosis is one of the most striking ...immune system‐related roles of melatonin. For this reason, this study evaluated the protective effects of melatonin on human leukocyte apoptosis induced by sustained cytosolic calcium increases. Such protective effects are likely mediated by melatonin’s free‐radical scavenging actions. Treatments with the specific inhibitor of cytosolic calcium re‐uptake, thapsigargin (TG), and/or the calcium‐mobilizing agonist, N‐formyl‐methionyl‐leucyl‐phenylalanine (FMLP), induced intracellular reactive oxygen species (ROS) production, caspase activation as well as DNA fragmentation in human leukocytes. Also, TG‐ and/or FMLP‐induced apoptosis was dependent on both cytosolic calcium increases and calcium uptake into mitochondria, because when cells were preincubated with the cytosolic calcium chelator, dimethyl BAPTA, and the inhibitor of mitochondrial calcium uptake, Ru360, TG‐ and FMLP‐induced apoptosis was largely inhibited. Importantly, melatonin treatment substantially prevented intracellular ROS production, reversed caspase activation, and forestalled DNA fragmentation induced by TG and FMLP. Similar results were obtained by preincubating the cells with another well‐known antioxidant, i.e., N‐acetyl‐l‐cysteine. To sum up, depletion of intracellular calcium stores induced by TG and/or FMLP triggers different apoptotic events in human leukocytes that are dependent on calcium signaling. The protective effects resulting from melatonin administration on leukocyte apoptosis likely depend on melatonin’s antioxidant action because we proved that this protection is melatonin receptor independent. These findings help to understand how melatonin controls apoptosis in cells of immune/inflammatory relevance.
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