Insights into the intracellular localization, protein associations and artemisinin resistance properties of Plasmodium falciparum K13.

The emergence of artemisinin (ART) resistance in Plasmodium falciparum intra-erythrocytic parasites has led to increasing treatment failure rates with first-line ART-based combination therapies in Southeast Asia. Decreased parasite susceptibility is caused by K13 mutations, which are associated clinically with delayed parasite clearance in patients and in vitro with an enhanced ability of ring-stage parasites to survive brief exposure to the active ART metabolite dihydroartemisinin. Herein, we describe a panel of K13-specific monoclonal antibodies and gene-edited parasite lines co-expressing epitope-tagged versions of K13 in trans. By applying an analytical quantitative imaging pipeline, we localize K13 to the parasite endoplasmic reticulum, Rab-positive vesicles, and sites adjacent to cytostomes. These latter structures form at the parasite plasma membrane and traffic hemoglobin to the digestive vacuole wherein artemisinin-activating heme moieties are released. We also provide evidence of K13 partially localizing near the parasite mitochondria upon treatment with dihydroartemisinin. Immunoprecipitation data generated with K13-specific monoclonal antibodies identify multiple putative K13-associated proteins, including endoplasmic reticulum-resident molecules, mitochondrial proteins, and Rab GTPases, in both K13 mutant and wild-type isogenic lines. We also find that mutant K13-mediated resistance is reversed upon co-expression of wild-type or mutant K13. These data help define the biological properties of K13 and its role in mediating P. falciparum resistance to ART treatment.

Discovery of New Classes of Compounds that Reactivate Acetylcholinesterase Inhibited by Organophosphates.

Acetylcholinesterase (AChE) that has been covalently inhibited by organophosphate compounds (OPCs), such as nerve agents and pesticides, has traditionally been reactivated by using nucleophilic oximes. There is, however, a clearly recognized need for new classes of compounds with the ability to reactivate inhibited AChE with improved in vivo efficacy. Here we describe our discovery of new functional groups--Mannich phenols and general bases--that are capable of reactivating OPC--inhibited AChE more efficiently than standard oximes and we describe the cooperative mechanism by which these functionalities are delivered to the active site. These discoveries, supported by preliminary in vivo results and crystallographic data, significantly broaden the available approaches for reactivation of AChE.

Rapid isolation of anti-idiotype aptamers for quantification of human monoclonal antibodies against SARS-CoV-2 spike protein.

Therapeutic antibodies that block viral entry have already proven to be important, first line drugs for treatments of viral infections. In the case of SARS-CoV-2, combinations of multiple therapeutic antibodies may need to be rapidly identified and formulated in a way that blocks each new, predominant variant of the virus. For efficient introduction of any new antibody combination into patients, it is important to be able to monitor patient-specific pharmacokinetics of individual antibodies, which would include the time course of their specific capacity to block the viral spike proteins. Here, we present three examples of microfluidic-based rapid isolation of companion reagents useful for establishing combination antibody therapies. These reagents are specific three-dimensional imprints of variable regions of individual human monoclonal antibodies against the -spike protein of SARS-CoV-2 virus in the form of oligonucleotide-based ligands (aptamers). We implement these anti-idiotypic aptamers as bioreceptors in graphene-based field-effect transistor sensors to accomplish label free, rapid, and sensitive detection of matching antibodies within minutes. Through this work we have demonstrated the general applicability of anti-idiotype aptamers as capture reagents in quantification of active forms of monoclonal antibodies in complex biological mixtures.

Neuropsychiatric Consequences of COVID-19 Pandemic: A Synthetic Review from a Global Perspective.

Some research suggests that distress, secondary to isolation and fear following COVID-19 infection, can negatively affect the long-term more than the COVID-19 infection itself. This narrative review aims to provide a global view on the neuropsychiatric consequences of COVID-19 that can be ascribed to several factors, ranging from the direct effect of infection, to the body's responses against the infection, or to the psychological sequelae of social isolation, unemployment, and fear for one's health and livelihood. Current findings show that the more severe the respiratory infection, the more likely are central nervous system (CNS) complications regarding the infection itself. The immune reactions to the infection may result in symptoms similar to chronic fatigue as well as neurocognitive deficits, which last long after the infection is gone. An increase in symptoms of depression, anxiety, and trauma-related stress may also follow upon economic fears and isolation from friends and family. The consequences of the pandemic are not limited to adults; children learning remotely and away from classmates and routine activities may develop adjustment disorders, acute stress disorder, and a variety of manifestations of grief. A summary of case reports suggests that COVID-19-related stress, economic recession, and political unrest increase the risk of suicidal behaviors and acts of violence. However, it is unknown whether manifestations of mental disorders result from social causes or whether CNS complications may be responsible.

The Plasmodium falciparum ABC transporter ABCI3 confers parasite strain-dependent pleiotropic antimalarial drug resistance.

Widespread Plasmodium falciparum resistance to first-line antimalarials underscores the vital need to develop compounds with novel modes of action and identify new druggable targets. Here, we profile five compounds that potently inhibit P. falciparum asexual blood stages. Resistance selection studies with three carboxamide-containing compounds, confirmed by gene editing and conditional knockdowns, identify point mutations in the parasite transporter ABCI3 as the primary mediator of resistance. Selection studies with imidazopyridine or quinoline-carboxamide compounds also yield changes in ABCI3, this time through gene amplification. Imidazopyridine mode of action is attributed to inhibition of heme detoxification, as evidenced by cellular accumulation and heme fractionation assays. For the copy-number variation-selecting imidazopyridine and quinoline-carboxamide compounds, we find that resistance, manifesting as a biphasic concentration-response curve, can independently be mediated by mutations in the chloroquine resistance transporter PfCRT. These studies reveal the interconnectedness of P. falciparum transporters in overcoming drug pressure in different parasite strains.

Strategy for COVID-19 vaccination in India: the country with the second highest population and number of cases.

Free vaccination against COVID-19 commenced in India on January 16, 2021, and the government is urging all of its citizens to be immunized, in what is expected to be the largest vaccination program in the world. Out of the eight COVID-19 vaccines that are currently under various stages of clinical trials in India, four were developed in the country. India's drug regulator has approved restricted emergency use of Covishield (the name employed in India for the Oxford-AstraZeneca vaccine) and Covaxin, the home-grown vaccine produced by Bharat Biotech. Indian manufacturers have stated that they have the capacity to meet the country's future needs for COVID-19 vaccines. The manpower and cold-chain infrastructure established before the pandemic are sufficient for the initial vaccination of 30 million healthcare workers. The Indian government has taken urgent measures to expand the country's vaccine manufacturing capacity and has also developed an efficient digital system to address and monitor all the aspects of vaccine administration.

Epitope mapping of novel monoclonal antibodies to human angiotensin I-converting enzyme.

Angiotensin I-converting enzyme (ACE, CD143) plays a crucial role in blood pressure regulation, vascular remodeling, and immunity. A wide spectrum of mAbs to different epitopes on the N and C domains of human ACE have been generated and used to study different aspects of ACE biology, including establishing a novel approach-conformational fingerprinting. Here we characterized a novel set of 14 mAbs, developed against human seminal fluid ACE. The epitopes for these novel mAbs were defined using recombinant ACE constructs with truncated N and C domains, species cross-reactivity, ACE mutagenesis, and competition with the previously mapped anti-ACE mAbs. Nine mAbs recognized regions on the N domain, and 5 mAbs-on the C domain of ACE. The epitopes for most of these novel mAbs partially overlap with epitopes mapped onto ACE by the previously generated mAbs, whereas mAb 8H1 recognized yet unmapped region on the C domain where three ACE mutations associated with Alzheimer's disease are localized and is a marker for ACE mutation T877M. mAb 2H4 could be considered as a specific marker for ACE in dendritic cells. This novel set of mAbs can identify even subtle changes in human ACE conformation caused by tissue-specific glycosylation of ACE or mutations, and can detect human somatic and testicular ACE in biological fluids and tissues. Furthermore, the high reactivity of these novel mAbs provides an opportunity to study changes in the pattern of ACE expression or glycosylation in different tissues, cells, and diseases, such as sarcoidosis and Alzheimer's disease.

Rapid and Flexible Platform To Assess Anti-SARS-CoV-2 Antibody Neutralization and Spike Protein-Specific Antivirals.

The COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) is ongoing and has shown the community that flexible methods for rapidly identifying and screening candidate antivirals are needed. Assessing virus-neutralizing activity of human serum to monitor population immunity and response to infection and vaccination is key to pandemic control. We developed a virus neutralization platform strategy that relies only on bioinformatic and genetic information of the virus of interest. The platform uses viral envelope glycoprotein cDNAs to set up an assay that mimics multicycle infection but is safe and, therefore, amenable to biosafety level 2 (BSL2) conditions for viruses that require BSL3 facilities (e.g., SARS-CoV-1 and SARS-CoV-2). As a complement to this platform, we present a new cell-based immunofluorescent (CBI) assay that uses SARS-CoV-2 spike protein (S)-expressing cells to accurately measure the neutralization potential of human sera and is readily adaptable to variants of concern. These methods should be useful additions to the tools for assessing antiviral immunity, whether acquired via natural infection or vaccines. IMPORTANCE Assays for rapid biosafety level 2 (BSL2) evaluation of neutralizing properties of antibodies acquired via natural infection or through vaccination is urgently needed. Here, we propose a combinatorial approach in which sera are screened for SARS-CoV-2 spike protein (S) binding using a cell-based immunofluorescent (CBI) assay, and positive samples are further evaluated in a pseudotyped viral multicycle infection-mimicking protocol under BSL2 conditions.

'Distant socializing,' not 'social distancing' as a public health strategy for COVID-19.

Social distancing, also referred to as physical distancing, means creating a safe distance of at least two meters (six feet) between yourself and others. This is a term popularized during the COVID-19 pandemic, as it is one of the most important measures to prevent the spread of this virus. However, the term 'social distancing' can be misleading, as it may imply that individuals should stop socializing. However, socializing in a safe context (i.e. over the phone, video-chat, etc.) is especially important during this time of crisis. Therefore, in this narrative review, we suggest the term 'distant socializing' as more apt expression, to promote physical distancing measures while also highlighting the importance of maintaining social bonds. Further, articles discussing the practice, implementation, measurement, and mental health effects of physical distancing are reviewed. Physical distancing is associated with psychiatric symptoms (such as anxiety and depression), suicidal ideation, and domestic violence. Further, unemployment and job insecurity have significantly increased during COVID-19, which may exacerbate these negative mental health effects. Governments, medical institutions, and public health bodies should therefore consider increasing mental health resources both during and after the pandemic, with a specific focus on frontline workers, COVID-19 survivors, and marginalized communities.

Conformational fingerprinting of the angiotensin I-converting enzyme (ACE). 1. Application in sarcoidosis.

Fine epitope mapping of monoclonal antibodies (mAbs) to 16 epitopes on human angiotensin I-converting enzyme (ACE) revealed that the epitopes of all mAbs contained putative glycosylation sites. ACE glycosylation is both cell- and tissue-specific and, therefore, the local conformation of ACE produced by different cells could be also unique. The pattern of ACE binding by a set of mAbs to 16 epitopes of human ACE - "conformational fingerprint of ACE" - is the most sensitive marker of ACE conformation and could be cell- and tissue-specific. The recognition of ACEs by mAbs to ACE was estimated using an immune-capture enzymatic plate precipitation assay. Precipitation patterns of soluble recombinant ACE released from Chinese hamster ovary (CHO)-ACE cells was influenced by conditions that alter ACE glycosylation. This pattern was also strongly cell type specific. Patients with sarcoidosis exhibited conformational fingerprints of tissue ACE (lungs and lymph nodes), as well as blood ACE, which were distinct from controls. Conformational fingerprinting of ACE may detect ACE originated from the cells other than endothelial cells in the blood and when combined with elevated blood ACE levels in patients with sarcoidosis may potentially reflect extrapulmonary sarcoidosis involvement (bone marrow, spleen, liver). If proven true, this would serve as a biomarker of enormous potential clinical significance.

Malaria: therapeutic implications of melatonin.

Malaria, which infects more than 300 million people annually, is a serious disease. Epidemiological surveys indicate that of those who are affected, malaria will claim the lives of more than one million individuals, mostly children. There is evidence that the synchronous maturation of Plasmodium falciparum, the parasite that causes a severe form of malaria in humans and Plasmodium chabaudi, responsible for rodent malaria, could be linked to circadian changes in melatonin concentration. In vitro melatonin stimulates the growth and development of P. falciparum through the activation of specific melatonin receptors coupled to phospholipase-C activation and the concomitant increase of intracellular Ca2+. The Ca2+ signaling pathway is important to stimulate parasite transition from the trophozoite to the schizont stage, the final stage of intraerythrocytic cycle, thus promoting the rise of parasitemia. Either pinealectomy or the administration of the melatonin receptor blocking agent luzindole desynchronizes the parasitic cell cycle. Therefore, the use of melatonin antagonists could be a novel therapeutic approach for controlling the disease. On the other hand, the complexity of melatonin's action in malaria is underscored by the demonstration that treatment with high doses of melatonin is actually beneficial for inhibiting apoptosis and liver damage resulting from the oxidative stress in malaria. The possibility that the coordinated administration of melatonin antagonists (to impair the melatonin signal that synchronizes P. falciparum) and of melatonin in doses high enough to decrease oxidative damage could be a novel approach in malaria treatment is discussed.

Physiological effects of melatonin: role of melatonin receptors and signal transduction pathways.

Melatonin, an endogenous signal of darkness, is an important component of the body's internal time-keeping system. As such it regulates major physiological processes including the sleep wake cycle, pubertal development and seasonal adaptation. In addition to its relevant antioxidant activity, melatonin exerts many of its physiological actions by interacting with membrane MT1 and MT2 receptors and intracellular proteins such as quinone reductase 2, calmodulin, calreticulin and tubulin. Here we review the current knowledge about the properties and signaling of melatonin receptors as well as their potential role in health and some diseases. Melatonin MT1 and MT2 receptors are G protein coupled receptors which are expressed in various parts of the CNS (suprachiasmatic nuclei, hippocampus, cerebellar cortex, prefrontal cortex, basal ganglia, substantia nigra, ventral tegmental area, nucleus accumbens and retinal horizontal, amacrine and ganglion cells) and in peripheral organs (blood vessels, mammary gland, gastrointestinal tract, liver, kidney and bladder, ovary, testis, prostate, skin and the immune system). Melatonin receptors mediate a plethora of intracellular effects depending on the cellular milieu. These effects comprise changes in intracellular cyclic nucleotides (cAMP, cGMP) and calcium levels, activation of certain protein kinase C subtypes, intracellular localization of steroid hormone receptors and regulation of G protein signaling proteins. There are circadian variations in melatonin receptors and responses. Alterations in melatonin receptor expression as well as changes in endogenous melatonin production have been shown in circadian rhythm sleep disorders, Alzheimer's and Parkinson's diseases, glaucoma, depressive disorder, breast and prostate cancer, hepatoma and melanoma. This paper reviews the evidence concerning melatonin receptors and signal transduction pathways in various organs. It further considers their relevance to circadian physiology and pathogenesis of certain human diseases, with a focus on the brain, the cardiovascular and immune systems, and cancer.

Pathophysiology of depression: role of sleep and the melatonergic system.

Profound disturbances in sleep architecture occur in major depressive disorders (MDD) and in bipolar affective disorders. Reduction in slow wave sleep, decreased latency of rapid eye movement (REM) sleep and abnormalities in the timing of REM/non-REM sleep cycles have all been documented in patients with MDD. It is thus evident that an understanding of the basic mechanisms of sleep regulation is essential for an analysis of the pathophysiology of depressive disorders. The suprachiasmatic nucleus (SCN), which functions as the body's master circadian clock, plays a major role in the regulation of the sleep/wakefulness rhythm and interacts actively with the homeostatic processes that regulate sleep. The control of melatonin secretion by the SCN, the occurrence of high concentrations of melatonin receptors in the SCN, and the suppression of electrical activity in the SCN by melatonin all underscore the major influence which this neurohormone has in regulating the sleep/wake cycle. The transition from wakefulness to high sleep propensity is associated with the nocturnal rise of endogenous melatonin secretion. Various lines of evidence show that depressed patients exhibit disturbances in both the amplitude and shape of the melatonin secretion rhythm and that melatonin can improve the quality of sleep in these patients. The choice of a suitable antidepressant that improves sleep quality is thus important while treating a depressive disorder. The novel antidepressant agomelatine, which combines the properties of a 5-HT(2C) antagonist and a melatonergic MT(1)/MT(2) receptor agonist, has been found very effective for resetting the disturbed sleep/wake cycle and in improving the clinical status of MDD. Agomelatine has also been found useful in treating sleep problems and improving the clinical status of patients suffering from seasonal affective disorder.

Melatonin and its relevance to jet lag.

Jet lag is a disorder in which body rhythms are out of phase with the environment because of rapid travel across time zones. Although it often produces minor symptoms it can cause serious problems in those who need to make rapid critical decisions including airline pilots and business travelers. In this article the authors review basic knowledge underlying the body clock, the suprachiasmatic nucleus (SCN) of the hypothalamus, and the manner in which it regulates the sleep/wake cycle. The regulation of melatonin by the SCN is described together with the role of the melatonin receptors which are integral to its function as the major hormonal output of the body clock. Several factors are known that help prevent and treat jet lag, including ensuring adequate sleep, appropriate timing of exposure to bright light and treatment with melatonin. Because travel can cross a variable number of time zones and in two different directions, recommendations for treatment are given that correspond with these different types of travel. In addition to use of bright light and melatonin, other factors including timed exercise, timed and selective diets and social stimuli deserve study as potential treatments. Moreover, new melatonin agonists are currently under investigation for treatment of jet lag.

Tissue ACE phenotyping in lung cancer.

BACKGROUND: Pulmonary vascular endothelium is the main metabolic site for Angiotensin I-Converting Enzyme (ACE)-mediated degradation of several biologically-active peptides (angiotensin I, bradykinin, hemo-regulatory peptide Ac-SDKP). Primary lung cancer growth and lung cancer metastases decrease lung vascularity reflected by dramatic decreases in both lung and serum ACE activity. We performed precise ACE phenotyping in tissues from subjects with lung cancer. METHODOLOGY: ACE phenotyping included: 1) ACE immunohistochemistry with specific and well-characterized monoclonal antibodies (mAbs) to ACE; 2) ACE activity measurement with two ACE substrates (HHL, ZPHL); 3) calculation of ACE substrates hydrolysis ratio (ZPHL/HHL ratio); 4) the pattern of mAbs binding to 17 different ACE epitopes to detect changes in ACE conformation induced by tumor growth (conformational ACE fingerprint). RESULTS: ACE immunostaining was dramatically decreased in lung cancer tissues confirmed by a 3-fold decrease in ACE activity. The conformational fingerprint of ACE from tumor lung tissues differed from normal lung (6/17 mAbs) and reflected primarily higher ACE sialylation. The increase in ZPHL/HHL ratio in lung cancer tissues was consistent with greater conformational changes of ACE. Limited analysis of the conformational ACE fingerprint in normal lung tissue and lung cancer tissue form the same patient suggested a remote effect of tumor tissue on ACE conformation and/or on "field cancerization" in a morphologically-normal lung tissues. CONCLUSIONS/SIGNIFICANCE: Local conformation of ACE is significantly altered in tumor lung tissues and may be detected by conformational fingerprinting of human ACE.

Native human autoantibodies targeting GIPC1 identify differential expression in malignant tumors of the breast and ovary.

BACKGROUND: We have been studying the native humoral immune response to cancer and have isolated a library of fully human autoantibodies to a variety of malignancies. We previously described the isolation and characterization of two fully human monoclonal antibodies, 27.F7 and 27.B1, from breast cancer patients that target the protein known as GIPC1, an accessory PDZ-domain binding protein involved in regulation of G-protein signaling. Human monoclonal antibodies, 27.F7 and 27.B1, to GIPC1 demonstrate specific binding to malignant breast cancer tissue with no reactivity with normal breast tissue. METHODS: The current study employs cELISA, flow cytometry, Western blot analysis as well as immunocytochemistry, and immunohistochemistry. Data is analyzed statistically with the Fisher one-tail and two-tail tests for two independent samples. RESULTS: By screening several other cancer cell lines with 27.F7 and 27.B1 we found consistently strong staining of other human cancer cell lines including SKOV-3 (an ovarian cancer cell line). To further clarify the association of GIPC1 with breast and ovarian cancer we carefully studied 27.F7 and 27.B1 using immunocytochemical and immunohistochemical techniques. An immunohistochemical study of normal ovarian tissue, benign, borderline and malignant ovarian serous tumors, and different types of breast cancer revealed high expression of GIPC1 protein in neoplastic cells. Interestingly, antibodies 27.F7 and 27.B1 demonstrate differential staining of borderline ovarian tumors. Examination of different types of breast cancer demonstrates that the level of GIPC1 expression depends on tumor invasiveness and displays a higher expression than in benign tumors. CONCLUSION: The present pilot study demonstrates that the GIPC1 protein is overexpressed in ovarian and breast cancer, which may provide an important diagnostic and prognostic marker and will constitute the basis for further study of the role that this protein plays in malignant diseases. In addition, this study suggests that human monoclonal antibodies 27.F7 and 27.B1 should be further evaluated as potential diagnostic tools.

A human monoclonal autoantibody to breast cancer identifies the PDZ domain containing protein GIPC1 as a novel breast cancer-associated antigen.

BACKGROUND: We have been studying the native autoimmune response to cancer through the isolation of human monoclonal antibodies that are cancer specific from cancer patients. To facilitate this work we previously developed a fusion partner cell line for human lymphocytes, MFP-2, that fuses efficiently with both human lymph node lymphocytes and peripheral blood lymphocytes. Using this unique trioma fusion partner cell line we isolated a panel of autologous human monoclonal antibodies, from both peripheral blood and lymph node lymphocytes, which are representative of the native repertoire of anti-cancer specific antibodies from breast cancer patients. METHODS: The current study employs immunocytochemistry, immunohistochemistry, Western blot analysis as well as Northern blots, Scatchard binding studies and finally SEREX analysis for target antigen identification. RESULTS: By application of an expression cloning technique known as SEREX, we determined that the target antigen for two monoclonal antibodies, 27.B1 and 27.F7, derived from lymph node B-cells of a breast cancer patient, is the PDZ domain-containing protein known as GIPC1. This protein is highly expressed not only in cultured human breast cancer cells, but also in primary and metastatic tumor tissues and its overexpression appears to be cancer cell specific. Confocal microscopy revealed cell membrane and cytoplasmic localization of the target protein, which is consistent with previous studies of this protein. CONCLUSION: We have determined that GIPC1 is a novel breast cancer-associated immunogenic antigen that is overexpressed in breast cancer. Its role, however, in the initiation and/or progression of breast cancer remains unclear and needs further clarification.

Immunomodulation by melatonin: its significance for seasonally occurring diseases.

Melatonin is not only synthesized by the pineal gland but also in many other organs and tissues of the body, particularly by lymphoid organs such as the bone marrow, thymus and lymphocytes. Melatonin participates in various functions of the body, among which its immunomodulatory role has assumed considerable significance in recent years. Melatonin has been shown to be involved in the regulation of both cellular and humoral immunity. Melatonin not only stimulates the production of natural killer cells, monocytes and leukocytes, but also alters the balance of T helper (Th)-1 and Th-2 cells mainly towards Th-1 responses and increases the production of relevant cytokines such as interleukin (IL)-2, IL-6, IL-12 and interferon-gamma. The regulatory function of melatonin on immune mechanisms is seasonally dependent. This fact may in part account for the cyclic pattern of symptom expression shown by certain infectious diseases, which become more pronounced at particular times of the year. Moreover, melatonin-induced seasonal changes in immune function have also been implicated in the pathogenesis of seasonal affective disorder and rheumatoid arthritis. The clinical significance of the seasonally changing immunomodulatory role of melatonin is discussed in this review.

Therapeutic actions of melatonin in cancer: possible mechanisms.

Melatonin is a phylogenetically well-preserved molecule with diverse physiological functions. In addition to its well-known regulatory control of the sleep/wake cycle, as well as circadian rhythms generally, melatonin is involved in immunomodulation, hematopoiesis, and antioxidative processes. Recent human and animal studies have now shown that melatonin also has important oncostatic properties. Both at physiological and pharmacological doses melatonin exerts growth inhibitory effects on breast cancer cell lines. In hepatomas, through its activation of MT1 and MT2 receptors, melatonin inhibits linoleic acid uptake, thereby preventing the formation of the mitogenic metabolite 1,3-hydroxyoctadecadienoic acid. In animal model studies, melatonin has been shown to have preventative action against nitrosodiethylamine (NDEA)-induced liver cancer. Melatonin also inhibits the growth of prostate tumors via activation of MT1 receptors thereby inducing translocation of the androgen receptor to the cytoplasm and inhibition of the effect of endogenous androgens. There is abundant evidence indicating that melatonin is involved in preventing tumor initiation, promotion, and progression. The anticarcinogenic effect of melatonin on neoplastic cells relies on its antioxidant, immunostimulating, and apoptotic properties. Melatonin's oncostatic actions include the direct augmentation of natural killer (NK) cell activity, which increases immunosurveillance, as well as the stimulation of cytokine production, for example, of interleukin (IL)-2, IL-6, IL-12, and interferon (IFN)-gamma. In addition to its direct oncostatic action, melatonin protects hematopoietic precursors from the toxic effect of anticancer chemotherapeutic drugs. Melatonin secretion is impaired in patients suffering from breast cancer, endometrial cancer, or colorectal cancer. The increased incidence of breast cancer and colorectal cancer seen in nurses and other night shift workers suggests a possible link between diminished secretion of melatonin and increased exposure to light during nighttime. The physiological surge of melatonin at night is thus considered a "natural restraint" on tumor initiation, promotion, and progression.

The roles of melatonin and light in the pathophysiology and treatment of circadian rhythm sleep disorders.

Normal circadian rhythms are synchronized to a regular 24 h environmental light-dark cycle, and the suprachiasmatic nucleus and the hormone melatonin have important roles in this process. Desynchronization of circadian rhythms, as occurs in chronobiological disorders, can produce severe disturbances in sleep patterns. According to the International Classification of Sleep Disorders, circadian rhythm sleep disorders (CRSDs) include delayed sleep phase syndrome, advanced sleep phase syndrome, non-24 h sleep-wake disorder, jet lag and shift-work sleep disorder. Disturbances in the circadian phase position of plasma melatonin levels have been documented in all of these disorders. There is compelling evidence to implicate endogenous melatonin as an important mediator in CRSD pathophysiology, although further research involving large numbers of patients will be required to clarify whether the disruption of melatonin secretion is a causal factor in CRSDs. In this Review, we focus on the use of exogenous melatonin and light therapy to treat the disturbed sleep-wake rhythms seen in CRSDs.