Exposure of human glioblastoma cells to thimerosal inhibits the thioredoxin system and decreases tumor growth-related factors.

Glioblastoma multiforme (GBM) is the most common, aggressive, and fatal primary malignant brain tumor in adults. The therapeutic efficacy of temozolomide (TMZ) is limited owing to frequent treatment resistance. The latter is in part related to the overexpression of redox systems such as the thioredoxin system. This system is fundamental for cell survival and proliferation, regulating hypoxia inducible factor-1alpha (HIF-1α) activity, in turn controlling vascular endothelial growth factor (VEGF), which is indispensable for tumor invasiveness, angiogenesis and microenvironment maintenance. HIF-1α can also be regulated by the signal transducer and activator of transcription 3 (STAT3), an oncogene stimulated by pro-inflammatory cytokines and growth factors. The thioredoxin system has several known inhibitors including mercury compounds such as Thimerosal (TmHg) which readily crosses the blood-brain barrier (BBB) and accumulates in the brain. Though previously used in various applications epidemiological evidence on TmHg's neurotoxicity is lacking. The objective of this study was to verify whether thimerosal is a suitable candidate for hard repurposing to control glioblastoma; therefore, the effects of this molecule were evaluated in human GBM (U87) cells. Our novel results show that TmHg decreased cellular viability (>50%) and migration (up to 90% decrease in wound closure), reduced thioredoxin reductase (TrxR/TXNRD1) and thioredoxin (Trx) activity, and increased reactive oxygen species (ROS) generation. Moreover, TmHg reduced HIF-1α expression (35%) as observed by immunofluorescence. Co-exposure of U87 cells to TmHg and TMZ reduced HIF-1α, VEGF, and phosphorylated STAT3. Consequently, TmHg alone or combined with chemotherapeutic drugs can reduce neoangiogenesis and ameliorate glioblastoma progression and treatment.

The emerging role of α7nAChRs/caspase-3/Nrf-2 signaling pathway in citicoline improved autistic behavior induced by thimerosal in mice.

AIMS: Autism spectrum disorder (ASD) is a global concern,affecting around 75 million individuals.Various factors contribute to ASD,including mercury-containing preservatives like thimerosal (Thim) found in some vaccines.This study explored whether citicoline could be a therapeutic option for Thim-induced neuronal damage in a mouse model of ASD.Additionally,the study investigated the effects of citicoline on the α7nAChRs/Akt/Nrf2/caspase-3 pathway,which may be involved in the development of ASD. MATERIALS AND METHODS: The study separated newborn mice into four groups.The control group received saline injections,while the Thim group received intramuscular injections of 3000 µg Hg/kg Thim on days 7,9,11,and 15 after birth.The two citicoline groups were administered Thim followed by intraperitoneal injections of 250 mg/kg or 500 mg/kg citicoline for three weeks.Afterward,various parameters were assessed, including growth,behavior,brain histopathology,oxidative stress,apoptotic,and inflammatory markers. KEY FINDINGS: Untreated Thim-exposed mice exhibited significant brain damage,which was substantially alleviated by citicoline treatment.This beneficial effect was associated with increased expressions and concentrations of brain α7nAChRs and Akt, increased brain content of Nrf2, and the hippocampus contents of acetylcholine. Citicoline treatment decreased the brain levels of oxidative stress markers (MDA and NO),the apoptotic marker caspase-3,and pro-inflammatory markers (NF-κB,TNF-α,and IL-1ß). The drug also increased the brain GPx activity. SIGNIFICANCE: Based on the results of this study,the α7nAChRs pathway appears to be essential for the therapeutic effectiveness of citicoline in treating Thim-induced ASD in mice.

Low-dose Oral Thimerosal for the Treatment of Oral Herpes: Clinical Trial Results and Improved Outcome After Post-hoc Analysis.

BACKGROUND: Thimerosal (TML) is an organomercury antimicrobial. Low doses (1/250th of the amount in a typical vaccine dose) may promote an antiviral immune response. Low-dose TML (BTL-TML) was evaluated for safety and efficacy against herpes labialis in two FDA-approved, randomized, double blind, placebo-controlled clinical trials. METHODS: BTL-TML was evaluated in a Phase IIa trial for its ability to block progression to lesion in subjects with recurrent oral herpes caused by dental trauma. Subjects were administered BTL-TML or a saline control over a 7-day period. In a Phase IIb trial, BTL-TML was evaluated for its ability to block progression to lesion over a 7-day period in subjects with herpes lip infections induced by exposure to ultraviolet (UV) radiation. RESULTS: Progression to lesion post-dental procedure was prevented in 54.5% (12/22) TML subjects versus 22.2% (2/9) control subjects (p = 0.106). Progression to lesion post-UV irradiation was blocked in 47.8% (11/23) BTL-TML treatment subjects and 42.8% (6/14) control subjects. A post-hoc analysis yielded 52.2% (12/23) BTL-TML subjects with no progression to lesion versus 28.6% (6/21) control subjects with no progression (p = 0.099). There were no significant differences in adverse effects between treatment and control groups in either trial. CONCLUSIONS: Neither clinical trial showed a statistically significant effect of BTL-TML on progression to lesion. However, the post-hoc analysis suggested there is a 48-hour period following UV radiation exposure during which the anti-herpes activity of antivirals such as BTL-TML is reduced. Accordingly, BTL-TML may have promise in subsequent, properly designed and powered clinical trials.

Can Unconventional Immunomodulatory Agents Help Alleviate COVID-19 Symptoms and Severity?

Severe acute respiratory syndrome coronavirus 2 (SARS coronavirus 2, or SARS-CoV-2) is the cause of the respiratory infection known as COVID-19. From an immunopathological standpoint, coronaviruses such as SARS-CoV-2 induce increased levels of a variety of T-helper 1 (Th1) and inflammatory cytokines and chemokines, including interleukin-1 (IL-1), IL-6, CCL2 protein, and CXCL10 protein. In the absence of proven antiviral agents or an effective vaccine, substances with immunomodulatory activity may be able to inhibit inflammatory and Th1 cytokines and/or yield an anti-inflammatory and/or Th2 immune response to counteract COVID-19 symptoms and severity. This report briefly describes the following four unconventional but commercially accessible immunomodulatory agents that can be employed in clinical trials to evaluate their effectiveness at alleviating disease symptoms and severity: low-dose oral interferon alpha, microdose DNA, low-dose thimerosal, and phytocannabinoids.

[THE CORRECTION OF THE LOCAL IMMUNE RESPONSE AT THE PATIENTS WITH HELICOBACTER PYLORI INFECTION].

INTRODUCTION: Helicobacter pylori infection is due to the high prevalence in population attracts the clinical interest of researchers in the whole World. It is well known that this microorganism not only resides in the mucosa of the gastrointestinal tract, but is also defined in the periodontal pocket of the oral cavity. THE AIM OF INVESTIGATION: to evaluate Helicobacter pylori diagnostics in the mouth and prove a method of relief of the inflammatory process by applying immunomodulator Imudon. RESULTS. On the basis of obtained results it was found that the inclusion of topical immunomodulator Imudon in the complex therapy of Helicobacter pylori-associated diseases leads to reduction of inflammatory potential through the decrease of the TNFα, IL-6 activity in saliva and to increase the protective properties of saliva as a result of increased levels of mucin, significantly reduces the frequency of relapses in the one year after therapy. CONCLUSION: It is practically important to determine the effectiveness of eradication therapy by the study of the contents of the tooth-gingival pocket for the detection of genetic material of Helicobacter pylori, as well as to include in the complex therapy of Helicobacter pylori-associated diseases of the immune modulator Imudon.

A longitudinal cohort study of the relationship between Thimerosal-containing hepatitis B vaccination and specific delays in development in the United States: Assessment of attributable risk and lifetime care costs.

Epidemiological evidence suggests a link between mercury (Hg) exposure from Thimerosal-containing vaccines and specific delays in development. A hypothesis-testing longitudinal cohort study (n=49,835) using medical records in the Vaccine Safety Datalink (VSD) was undertaken to evaluate the relationship between exposure to Hg from Thimerosal-containing hepatitis B vaccines (T-HBVs) administered at specific intervals in the first 6months of life and specific delays in development [International Classification of Disease, 9th revision (ICD-9): 315.xx] among children born between 1991 and 1994 and continuously enrolled from birth for at least 5.81years. Infants receiving increased Hg doses from T-HBVs administered within the first month, the first 2months, and the first 6months of life were significantly more likely to be diagnosed with specific delays in development than infants receiving no Hg doses from T-HBVs. During the decade in which T-HBVs were routinely recommended and administered to US infants (1991-2001), an estimated 0.5-1million additional US children were diagnosed with specific delays in development as a consequence of 25µg or 37.5µg organic Hg from T-HBVs administered within the first 6months of life. The resulting lifetime costs to the United States may exceed $1 trillion.

Cutaneous leishmaniasis "chiclero's ulcer" in subtropical Ecuador.

An 18-year-old female presented with a severe ulcerative lesion on her right ear of 6 weeks duration. Her right ear was edematous and erythematous with a large, painless ulcerative lesion covering a third of the pinna and satellite papular lesions on the posterior. She was diagnosed with chiclero's ulcer. A skin smear stained with Diff-quik showed abundant Leishmania parasites. Chiclero's ulcer is a rare clinical presentation and is typically severe and difficult to treat. Physicians in Ecuador recommend administering prolonged intramuscular Glucantime. Side effects are common and can be severe resulting in low patient compliance. Because of preferences of the patient and the large volume needed for her weight, we recommended topical treatment with a lotion of Glucantime mixed half and half with white Merthiolate. After applying this lotion to the lesion 3 to 4 times a day for 6 weeks, the lesion healed.

[Local immunomodulating agents in complex treatment of oral lichen planus].

The paper presents the results of local immunity status assessment in patients with erosive-ulcerous form of oral lichen planus by etiopatogenetic treatment including imudone and derinate. The positive dynamics of immunological parameters under imudone and derinate is demonstrated.

[Immune reactions of palatine tonsils in the patients with chronic tonsillitis and the possibilities for their immunological rehabilitation with the use of imudon].

The objective of the present study was to develop a rationale for the application of imudon (a bacterial lysate preparation)in the treatment of the patients presenting with chronic tonsillitis based on the elucidation of characteristics of local immunity in the oropharynx (determined from the results of cytograms, immunoenzyme assays for the quantitation of IgG, sIgA, IgA, and IgM antibodies, and calculation of the relative secretion coefficients). A total of 74 patients with chronic tonsillar pathology (24 children and 50 adults) were available for the observation along with 42 subjects having no tonsillar pathology with concomitant chronic bacterial rhinosinusitis. The control group was constituted by 25 practically healthy subjects. It was shown that the local application of imudon in the patients with the preserved function of palatine tonsils (in the absence of symptoms of chronic inflammation) produces the adequate response of the humoral and cellular immunity systems. In the patients with the simple form of chronic tonsillitis imudon therapy ensured statistically significant activation of congenital immunity including the phagocyte function and a tendency toward normalization of antibody formation. It is concluded that alteration of the function of palatine tonsils in the patients presenting with the toxico-allergic form (ТАФ-2) of chronic tonsillitis implies the necessity of surgical treatment (tonsillectomy).

[Experience in immunomodulators application for comprehensive dental caries prevention in children and teenagers].

Prophylaxis and treatment procedures in children with different dental status was done during 9 years. Children and teenagers of 6-12 and 15-years were given teeth treatment and professional hygiene. One group of patients was additionally treated by immunomodulators imudon. It was demonstrated that improving of oral cavity hygiene and local immunity factor balance was achieved. Positive result was better in the group with imudon.

Safety of influenza vaccination during pregnancy.

The Centers for Disease Control and Prevention Advisory Committee on Immunization Practices recommends routine influenza vaccination for all women who are or will be pregnant during the influenza season. During seasonal influenza epidemics, during previous pandemics, and with the current influenza A (H1N1) pandemic, pregnancy places otherwise healthy women at increased risk for serious complications from influenza, including death. Inactivated influenza vaccine can be safely and effectively administered during any trimester of pregnancy. No study to date has demonstrated an increased risk of either maternal complications or adverse fetal outcomes associated with inactivated influenza vaccination. Moreover, no scientific evidence exists that thimerosal-containing vaccines are a cause of adverse events among children born to women who received influenza vaccine during pregnancy. In this article, we review the evidentiary basis for the recommendation of vaccination of all women who will be pregnant during the influenza season and safety data of influenza vaccination during pregnancy.

Thimerosal-induced limbal stem cell failure: report of a case and review of the literature.

PURPOSE: To report a case of unilateral total limbal stem cell (LSC) failure and corneal opacification secondary to thimerosal- and contact lens-induced ocular surface toxicity. METHODS: Interventional case report and review of the literature on thimerosal-induced ocular surface changes. RESULTS: A 49-year-old woman with a 2-year history of long-term soft contact lens wear developed unilateral total LSC failure and corneal opacification secondary to presumed thimerosal-induced toxicity and contact lens wear. At presentation, best-corrected visual acuities were 20/120 in the right eye and 20/15 in the left eye. The patient underwent a keratolimbal allograft and amniotic membrane graft followed by a penetrating keratoplasty. At the last follow-up, the right eye showed a clear corneal graft with a best-corrected visual acuity of 20/30. CONCLUSIONS: Thimerosal toxicity can lead to total LSC failure with secondary corneal vascularization and opacification. Keratolimbal allograft followed by penetrating keratoplasty can be successful in reconstructing the ocular surface in such cases.

[Principles of the immune modulation therapy against papilloma virus infections].

The aim of the study was to investigate the effect of Immudone on local immune responses of cervical mucous in patients with papilloma virus cervicitis. 80 women of reproductive age with chronic cervicitis, 60 women with no signs of infection and 70 bioptates obtained from the base of vaginal section of the cervix. Colposcopic, bacterioscopic, patho-histological and immunohistochemical investigations have been performed. After using of Immudone healing of ectopia was observed in the most of cases. As a result of local application of Immudone in patients with PVI in the tissue of cervix the rate of CD4+ cells was increased, expression of receptors of interleukin-2 was increased, CD4/CD8 ratio also increased, quantity of macrophages and natural killers was increased. Local sIgA synthesis was restored.

El timerosal y las enfermedades del neurodesarrollo infantil / Thimerosal and children's neurodevelopmental disorders

Se evalúa la relación causal entre el timerosal (etilmercurio), como preservante en las vacunas pediátricas, y el incremento de casos de enfermedades del neurodesarrollo infantil, como consecuencia de la ampliación de los esquemas de inmunización. Se revisó la información científica, relacionando el timerosal y las evidencias que permitan evaluar una posible asociación causal, con estudios epidemiológicos, ecológicos, biomoleculares y toxicológicos, de bioseguridad, toxicológicos fetales y sobre salud reproductiva. Se encontró múltiples asociaciones entre la exposición a timerosal y las enfermedades del neurodesarrollo infantil. Tal neurotoxicidad ocurre en los infantes y fetos de gestantes vacunadas por dosis acumulativa de mercurio. Las diversas evidencias implican al timerosal como el agente causante, agravante o disparador de las enfermedades del neurodesarrollo infantil. La toxicidad del mercurio obligó al retiro progresivo del timerosal de los medicamentos. Lamentablemente, en las vacunas, ha habido una sustancial demora en la demostración de su impacto negativo. Actualmente, existen vacunas sin timerosal, cuyo uso está ocasionando la disminución de la incidencia de las enfermedades del neurodesarrollo infantil.

The causal relation of thimerosal (ethylmercury), preservative in pediatric vaccines, and the increase of childrenÆs neurodevelopmental disorders as a result of the increase in immunization schemes is determined. The scientific information on thimerosal and its influence on the childÆs neurodevelopmental disorders is reviewed. Evidences found in epidemiological, ecological, biomolecular, toxicology, biosecurity, fetal toxicology and reproductive health studies signal the possible causal association of thimerosal exposition and neurodevelopmental disorders of the child. Such neurotoxicity occurs in infants and fetuses of vaccinated pregnant women, due to mercury cumulative doses. The various evidences imply thimerosal as the causal agent, aggravating or triggering neurodevelopmental disorders of the child. The mercury toxicity forced progressive thimerosal withdrawal. Unfortunately, there was a delay in demonstrating thimerosal negative impact Currently vaccines without thimerosal are causing less incidence of childrenÆs neurodevelopmental disorders.

Thimerosal induces apoptosis and G2/M phase arrest in human leukemia cells.

Thimerosal is an organomercury compound with sulfhydryl-reactive properties. The ability of thimerosal to act as a sulfhydryl group is related to the presence of mercury. Due to its antibacterial effect, thimerosal is widely used as preservatives and has been reported to cause chemically mediated side effects. In the present study, we showed that the molecular mechanism of thimerosal induced apoptosis in U937 cells. Thimerosal was shown to be responsible for the inhibition of U937 cells growth by inducing apoptosis. Treatment with 2.5-5 microM thimerosal but not thiosalicylic acid (structural analog of thimerosal devoid of mercury) for 12 h produced apoptosis, G(2)/M phase arrest, and DNA fragmentation in a dose-dependent manner. Treatment with caspase inhibitor significantly reduced thimerosal-induced caspase 3 activation. In addition, thimerosal-induced apoptosis was attenuated by antioxidant Mn (III) meso-tetrakis (4-benzoic acid) porphyrin (Mn-TBAP). These data indicate that the cytotoxic effect of thimerosal on U937 cells is attributable to the induced apoptosis and that thimerosal-induced apoptosis is mediated by reactive oxygen species generation and caspase-3 activation.

Detection of antinuclear and antilaminin antibodies in autistic children who received thimerosal-containing vaccines.

Autism, a neurodevelopmental disorder, may involve autoimmune pathogenesis. Since mercury is potentially a risk factor for autoimmunity, we conducted a study of mercury-induced antinuclear and antilaminin antibodies in autistic and normal children who had been pre-administered with thimerosal-containing vaccines. Laboratory analysis by different immunoassays showed that the serum level of these two autoimmune markers did not significantly differ between autistic and normal children. This finding suggests that the mercury as in thimerosal-containing vaccines is likely not related to autoimmune phenomenon in autism.