From structure to clinic: Design of a muscarinic M1 receptor agonist with potential to treatment of Alzheimer's disease.

Current therapies for Alzheimer's disease seek to correct for defective cholinergic transmission by preventing the breakdown of acetylcholine through inhibition of acetylcholinesterase, these however have limited clinical efficacy. An alternative approach is to directly activate cholinergic receptors responsible for learning and memory. The M1-muscarinic acetylcholine (M1) receptor is the target of choice but has been hampered by adverse effects. Here we aimed to design the drug properties needed for a well-tolerated M1-agonist with the potential to alleviate cognitive loss by taking a stepwise translational approach from atomic structure, cell/tissue-based assays, evaluation in preclinical species, clinical safety testing, and finally establishing activity in memory centers in humans. Through this approach, we rationally designed the optimal properties, including selectivity and partial agonism, into HTL9936-a potential candidate for the treatment of memory loss in Alzheimer's disease. More broadly, this demonstrates a strategy for targeting difficult GPCR targets from structure to clinic.

The Electrostatic Model of Homeopathy: The Mechanism of Physicochemical Activities of Homeopathic Medicines.

This paper attempts to propose a model, called the electrostatic model of homeopathy, to explain a mechanism for the physicochemical activities of highly diluted homeopathic medicines (HMs). According to this proposed model, the source of HMs' action is dipole orientations as electrostatic imprints of the original molecules carried by diluent molecules (such as sugar molecules) or potentization-induced aqueous nanostructures. The nanoscale domains' contact charging and dielectric hysteresis play critical roles in the aqueous nanostructures' or sugar molecules' acquisition of the original molecules' dipole orientations. The mechanical stress induced by dynamization (vigorous agitation or trituration) is a crucial factor that facilitates these phenomena. After dynamization is completed, the transferred charges revert to their previous positions but, due to dielectric hysteresis, they leave a remnant polarization on the aqueous nanostructures or sugar molecules' nanoscale domains. This causes some nanoscale domains of the aqueous nanostructures or sugar molecules to obtain the original substance molecules' dipole orientations. A highly diluted HM may have no molecule of the original substance, but the aqueous nanostructures or sugar molecules may contain the original substance's dipole orientations. Therefore, HMs can precisely aim at the biological targets of the original substance molecules and electrostatically interact with them as mild stimuli.

Evaluation of the efficacy of isopathic immunotherapy in the treatment of allergic asthma in BALB/C mice.

Introduction: Homeopathy is a therapeutic method based on the fundamental principle of "like cures like." Homeopathic remedies are extremely dilute but involve vigorous shaking at each dilution. Isopathy is one approach of homeopathy, in which the causative agents or products of a disease are used to treat the same disease. Allergen immunotherapy is the only potential disease-modifying treatment for allergic patients. Subcutaneous immunotherapy is more effective than sublingual immunotherapy. However, subcutaneous immunotherapy is ineffective at a low dose, whereas at high doses it can result in an unacceptably high frequency of systemic reactions. In the current study, we evaluated the efficacy of isopathic immunotherapy with highly diluted ovalbumin (HD OVA) in the treatment of OVA-induced allergic asthma in BALB/c mice.Methods: BALB/c mice were sensitized with OVA and alum. Two weeks later, the mice received HD OVA on days 21, 22, 32 and 41 (8 h after the last challenge) of the treatment. The mice were challenged with OVA (5%) aerosols on days 35, 38 and 41 for 20 minutes using an ultrasonic nebulizer and sacrificed the next day.Results: Isopathic immunotherapy significantly reduced lung tissue inflammation, the number of eosinophils in bronchoalveolar fluid, allergen-specific IgE and interleukin-4 production. It also insignificantly increased the production of transforming growth factor-beta and proliferation of regulatory T cells against the allergen.Conclusion: Isopathic immunotherapy may be a good candidate treatment for allergic asthma.

Correction to: Blocking of opioid receptors in experimental formaline-inactivated respiratory syncytial virus (FI-RSV) immunopathogenesis: from beneficial to harmful impacts.

In the original publication, seventh author's name was incorrectly published as 'Maryam Golaram'.

Blocking of opioid receptors in experimental formaline-inactivated respiratory syncytial virus (FI-RSV) immunopathogenesis: from beneficial to harmful impacts.

Opioid system plays a significant role in pathophysiological processes, such as immune response and impacts on disease severity. Here, we investigated the effect of opioid system on the immunopathogenesis of respiratory syncytial virus (RSV) vaccine (FI-RSV)-mediated illness in a widely used mouse model. Female Balb/c mice were immunized at days 0 and 21 with FI-RSV (2 × 106 pfu, i.m.) and challenged with RSV-A2 (3 × 106 pfu, i.n.) at day 42. Nalmefene as a universal opioid receptors blocker administered at a dose of 1 mg/kg in combination with FI-RSV (FI-RSV + NL), and daily after live virus challenge (RSV + NL). Mice were sacrificed at day 5 after challenge and bronchoalveolar lavage (BAL) fluid and lungs were harvested to measure airway immune cells influx, T lymphocyte subtypes, cytokines/chemokines secretion, lung histopathology, and viral load. Administration of nalmefene in combination with FI-RSV (FI-RSV + NL-RSV) resulted in the reduction of the immune cells infiltration to the BAL fluid, the ratio of CD4/CD8 T lymphocyte, the level of IL-5, IL-10, MIP-1α, lung pathology, and restored weight loss after RSV infection. Blocking of opioid receptors during RSV infection in vaccinated mice (FI-RSV-RSV + NL) had no significant effects on RSV immunopathogenesis. Moreover, administration of nalmefene in combination with FI-RSV and blocking opioid receptors during RSV infection (FI-RSV + NL-RSV + NL) resulted in an increased influx of the immune cells to the BAL fluid, increases the level of IFN-γ, lung pathology, and weight loss in compared to control condition. Although nalmefene administration within FI-RSV vaccine decreases vaccine-enhanced infection during subsequent exposure to the virus, opioid receptor blocking during RSV infection aggravates the host inflammatory response to RSV infection. Thus, caution is required due to beneficial/harmful functions of opioid systems while targeting as potentially therapies.

Propranolol efficacy as a novel adjuvant for immunization against Toxoplasma gondii tachyzoites.

Severe or lethal damages, caused by Toxoplasma gondii infection in congenital cases and immunocompromised patients implies the necessity for development of a vaccine and an appropriate adjuvant would be needed to elicit a protective Th1 biased-immune response. The adjuvant activity of propranolol was surveyed and compared with alum by immunization of BALB/c mice with protein components of T. gondii tachyzoites. Five groups of BALB/c mice were immunized with phosphate buffered saline (negative control), Toxoplasma lysate antigen (TLA), alum plus TLA, Propranolol plus TLA, and alum, propranolol and TLA. Immunization efficacy was evaluated by lymphocyte proliferation and DTH tests, challenge with live tachyzoites, IFN-γ production by spleen cells, serum TNF-α concentration and anti- Toxoplasma total IgG, IgG1 and IgG2a measurements. Mice of the PRP-TLA group induced significantly more IFN-γ and TNF-α production and lymphocyte proliferation than other groups. This group of mice also showed more anti-T. gondii IgG2a and DTH responses and showed a significantly increased survival time after challenge. These findings indicate that propranolol as an adjuvant in combination with TLA, may enhance cellular immunity against T. gondii.

Association of altered gut microbiota composition with chronic urticaria.

BACKGROUND: An altered gut microbiota composition has recently been linked to some types of allergies. OBJECTIVE: To compare the relative amounts of Akkermansia muciniphila, Clostridium leptum, Faecalibacterium prausnitzii, and Enterobacteriaceae as members of gut microbiota among patients with chronic urticaria (CU) and healthy controls. METHODS: A total of 20 patients with CU and 20 healthy individuals matched by age and sex participated in the study. Fresh fecal samples were collected, and DNA extracted from stool samples was analyzed by real-time polymerase chain reaction for the qualitative and quantitative assays of the so-called bacteria. RESULTS: The frequencies of A muciniphila, C leptum, and F prausnitzii in healthy controls' stool samples were significantly more than those of patients with CU (P < .001, P < .01, and P < .05, respectively), whereas the Enterobacteriaceae family was detected in all patients and healthy controls' stool samples. The relative amounts of A muciniphila in healthy control positive samples were significantly higher than those of samples from patients with CU (P < .001). Furthermore, there was a corresponding increase of relative amounts of C leptum and F prausnitzii in healthy control positive samples compared with those of patients with CU (P = .09 and P = .08, respectively). The mean of the relative amounts of Enterobacteriaceae family in the stool samples from patients with CU was more than that of healthy controls; however, the difference was nearly significant (P = .12). CONCLUSION: The results reveal a change of frequency and relative amounts of A muciniphila, C leptum, and F prausnitzii in patients with CU compared with healthy controls. This is the first study, to our knowledge, to show the change of microbiota composition in patients with CU.

Polymorphisms in Beta-2 Adrenergic Receptor Gene and Association with Tuberculosis.

PURPOSE: Genetic susceptibility for tuberculosis in human has been previously demonstrated. Polymorphisms in genes involved in immune responses may alter the susceptibility of individuals to tuberculosis. Polymorphisms of beta-2 adrenergic receptor (ADRB2) gene can be possibly an important risk factor in tuberculosis. In this study, the association between rs1042713 (Arg16Gly +46A>G) and rs1042714 (Gln27Glu +79C>G) polymorphisms in ADRB2 gene and tuberculosis was evaluated. METHODS: Genotype distributions of the rs1042713 (Arg16Gly +46A>G) and rs1042714 (Gln27Glu +79C>G) polymorphisms in ADRB2 gene in 106 patients with pulmonary tuberculosis and 88 healthy subjects were studied by PCR-RFLP method in an Iranian population. RESULTS: The frequency of rs1042713*G and rs1042714*G alleles in ADRB2 gene in tuberculosis patients was significantly different from healthy controls [odds ratio (OR) 0.176, 95% confidence interval (CI) 0.065-0.48, P value <0.001 and OR 0.45, 95% CI 0.247-0.825, P value = 0.009, respectively]. There were no significant differences in haplotype analysis between the patients and control subjects. CONCLUSION: The association was reported between rs1042713 and rs1042714 polymorphisms in ADRB2 gene and tuberculosis for the first time. rs1042713*G and rs1042714*G polymorphisms in ADRB2 gene makes people more susceptible to develop the disease.

Mixture of Alum--Naloxone and Alum--Naltrexone as a novel adjuvant elicits immune responses for Toxoplasma gondii lysate antigen in BALB /c mice.

Toxoplasma gondii (T. gondii) is an obligate intracellular parasite. Treatment of the infection induced by this parasite is not straightforward due to the toxic side effects of the available drugs. Vaccine development could be a solution to this problem. In the present study, T.gondii Lysate Antigen (TLA), as a model vaccine, in combination with the Alum-NLT (Aluminum phosphate-Naltrexone) and Alum-NLX (Aluminum phosphate-Naloxone) were evaluated for immunization BALB/c. 147 female BALB/c mice which were divided into seven groups of 21, were allocated to immunization experiments. The first group was selected as the negative control group, followed by the second, third, fourth, fifth, sixth and seventh groups which were immunized with Vac, Vac-Alum, Vac-NLX, Vac-NLT, Vac-Alum-NLX, Vac-Alum-NLT, respectively. Ten days after the final immunization, mice in all groups were divided into three groups for evaluating cellular immune responses, measuring the delayed-type hypersensitivity responses (DTHs) and evaluating survival. The DTH and cellular immune responses showed that in mice immunized with the TLA vaccine combined with the Alum-NLT mixture, the efficacy improved by increasing the production of Interleukin-5(IL-5) and Interferon gamma. This consequently shifted the immune responses toward a Th1 profile by increasing the IFN-γ/IL-5 ratios. In challenge experiments, immunized mice with the Alum-NLT-Vac mixture survived for a longer period of time which indicated an improvement in protective immunity against T. gondii. Administration of the Alum-NLT mixture adjuvant in combination with TLA vaccine enhanced the cellular immunity by shifting the immune response to a Th1 pattern. This shift to the Th1 pattern plays an important role in the induction of cellular.

A novel adjuvant, the mixture of alum and naltrexone, augments vaccine-induced immunity against Plasmodium berghei.

We previously showed that the mixture of naltrexone (NLT), a general opioid antagonist, and alum, acts as an effective adjuvant in enhancing vaccine-induced T helper 1 (TH1) humoral immune responses against Toxoplasma gondii. Here, we tested the efficacy of the mixture of NLT and alum in the induction of immunity in response to blood stages of Plasmodium berghei (BSPb) as a model vaccine. BALB/c mice were divided into five vaccination groups. Mice in the experimental groups received the BSPb vaccine alone or in combination with the adjuvant alum, NLT or the alum-NLT mixture. Mice in the control group received PBS. All mice were immunized on days 0, 7 and 14. Two weeks after the last immunization, immune responses to Plasmodium berghei were assessed. Our results indicated that including the alum-NLT mixture as an adjuvant during vaccination increased the ability of the BSPb vaccine to enhance lymphocyte proliferation, shifted the immune response towards a TH1 profile and increased Plasmodium berghei-specific IgG2a. This resulted in improved protective immunity against Plasmodium berghei. In conclusion, administering alum-NLT mixture in combination with the BSPb vaccine enhanced the vaccine-induced immunity, and shifted the immune response toward TH1 pattern.

Like cures like: a neuroimmunological model based on electromagnetic resonance.

OBJECTIVES: Recent investigations have pointed to the production of characteristic electromagnetic (EM) waves in highly diluted sterile filtrates of different microorganisms and their associated DNA molecules. Analysis of these diluted solutions that are prepared using methods almost identical to the way that homeopathic medicines are prepared has pointed to the existence of nanostructures capable of emitting EM waves. Combining these results with findings that point to the interaction of EM waves with sensory nerves with subsequent activation of homeostatic efferent pathways, we propose a model to describe mechanisms underlying the effects of homeopathic remedies. THE MODEL: Living cells and tissues are capable of generating EM waves in their physiological conditions. When a cell deviates from its physiological state, in addition to normal EM emissions, it starts to produce EM waves with altered characteristics. According to our model, the main cause of the therapeutic effects of homeopathic remedies is the occurrence of resonance between the non-physiological EM waves of the patient and extremely low-frequency EM waves produced by nanostructures present in the homeopathic remedy. Resonance occurs if the frequency and amplitude characteristics of the patient's non-physiological EM waves and those produced by nanostructures of the applied homeopathic remedy are similar. Once resonance occurs, stimulation of the patient's sensory neurons, which are sensitized due to inflammation of any origin, leads to triggering of different regulatory mechanisms, including the activation of descending antinociceptive and/or cholinergic anti-inflammatory pathways, which leads to the restoration of homeostasis.

TRPA1 Antagonist LY3526318 Inhibits the Cinnamaldehyde-Evoked Dermal Blood Flow Increase: Translational Proof of Pharmacology.

Transient receptor potential Ankyrin 1 (TRPA1) is an ion channel expressed by sensory neurons, where it mediates pain signaling. Consequently, it has emerged as a promising target for novel analgesics, yet, to date, no TRPA1 antagonists have been approved for clinical use. In the present translational study, we utilized dermal blood flow changes evoked by TRPA1 agonist cinnamaldehyde as a target engagement biomarker to investigate the in vivo pharmacology of LY3526318, a novel TRPA1 antagonist. In rats, LY3526318 (1, 3, and 10 mg/kg, p.o.) dose-dependently reduced the cutaneous vasodilation typically observed following topical application of 10% v/v cinnamaldehyde. The inhibition was significant at the site of cinnamaldehyde application and also when including an adjacent area of skin. Similarly, in a cohort of 16 healthy human volunteers, LY3526318 administration (10, 30, and 100 mg, p.o.) dose-dependently reduced the elevated blood flow surrounding the site of 10% v/v cinnamaldehyde application, with a trend toward inhibition at the site of application. Comparisons between both species reveal that the effects of LY3526318 on the cinnamaldehyde-induced dermal blood flow are greater in rats relative to humans, even when adjusting for cross-species differences in potency of the compound at TRPA1. Exposure-response relationships suggest that a greater magnitude response may be observed in humans if higher antagonist concentrations could be achieved. Taken together, these results demonstrate that cinnamaldehyde-evoked changes in dermal blood flow can be utilized as a target engagement biomarker for TRPA1 activity and that LY3526318 antagonizes the ion channel both in rats and humans.

Modeling COVID-19 Mortality Across 44 Countries: Face Covering May Reduce Deaths.

INTRODUCTION: Despite ongoing efforts to vaccinate communities against COVID-19, the necessity of face mask use in controlling the pandemic remains subject to debate. Several studies have investigated face masks and COVID-19, covering smaller and less diverse populations than this study's sample. This study examines a hypothesized association of face-covering mandates with COVID-19 mortality decline across 44 countries in 2 continents. METHODS: In a retrospective cohort study, changes in COVID-19‒related daily mortality rate per million population from February 15 to May 31, 2020 were compared between 27 countries with and 17 countries without face mask mandates in nearly 1 billion (911,446,220 total) people. Longitudinal mixed effect modeling was applied and adjusted for over 10 relevant demographic, social, clinical, and time-dependent confounders. RESULTS: Average COVID-19 mortality per million was 288.54 in countries without face mask policies and 48.40 in countries with face mask policies. In no mask countries, adjusted average daily increase was 0.1553 - 0.0017 X (days since the first case) log deaths per million, compared with 0.0900 - 0.0009 X (days since the first case) log deaths per million in the countries with a mandate. A total of 60 days into the pandemic, countries without face mask mandates had an average daily increase of 0.0533 deaths per million, compared with the average daily increase of 0.0360 deaths per million for countries with face mask mandates. CONCLUSIONS: This study's significant results show that face mask mandates were associated with lower COVID-19 deaths rates than the rates in countries without mandates. These findings support the use of face masks to prevent excess COVID-19 deaths and should be advised during airborne disease epidemics.

A novel adjuvant, the general opioid antagonist naloxone, elicits a robust cellular immune response for a DNA vaccine.

While many adjuvants have been discovered and used in research, only a few adjuvants have been permitted for use with human vaccination. We have previously shown that the administration of naloxone (NLX), a general opioid antagonist, during infection with a non-virulent strain of herpes simplex virus type 1 (HSV-1) could enhance protection against HSV-1 challenge. Here, the adjuvant activity of NLX has been evaluated using a DNA vaccine for HSV-1 as a model. BALB/c mice were divided into four groups; for experimental groups, mice received the glycoprotein D1 (gD1) DNA vaccine alone or in combination with the adjuvant NLX. A positive control group received the KOS strain of HSV-1, and a negative control group received PBS. All mice were immunized three times on days 0, 21 and 42. Three weeks after the last immunization, immune responses against HSV-1 were assessed. Our results indicate that the administration of NLX as an adjuvant increased the ability of the gD1 DNA vaccine to enhance cytolytic T lymphocyte activity, lymphocyte proliferation, delayed-type hypersensitivity and shifting the immune response toward a T helper (Th)1 pattern and improved protective immunity against HSV-1. NLX also increased the IgG2a/IgG1 ratio, though it did not affect the production of HSV-1 antiserum. In conclusion, administration of NLX as an adjuvant in combination with the gD1 DNA vaccine can enhance cell-mediated immunity and shift the immune responses to Th1.

Sitagliptin Repositioning in SARS-CoV-2: Effects on ACE-2, CD-26, and Inflammatory Cytokine Storms in the Lung.

No Abstract.

Nicotine, as a novel tolerogenic adjuvant, enhances the efficacy of immunotherapy in a mouse model of allergic asthma.

An increasing trend in the incidence of allergic diseases including asthma and related morbidity and mortality is observed worldwide during the last decades. Allergen-specific immunotherapy is suggested for the treatment of some allergic diseases; nevertheless, there is always a menace of uncommon, but life-treating reactions due to increasing the administration of allergen extract doses. Hence, improving its efficacy may reduce the required doses as well as the risk of such reactions. The current study aimed at examining the effects of nicotine (NIC), as a tolerogenic adjuvant, on the improvement of immunotherapy efficacy in a mouse model of allergic asthma. BALB/c mice were sensitized using alum and ovalbumin (OVA) on the days 0 and 7. Mice received OVA either alone or together with NIC (1 or 10 mg/kg) on the days 21, 23, and 25. Then, the mice were challenged with OVA 5% using a nebulizer on the days 35, 38, and 41 and sacrificed the next day. Co-administration of OVA and NIC decreased the inflammation of the lung tissue, eosinophils count in the bronchoalveolar lavage (BAL) fluid, the serum level of OVA-specific immunoglobulin E, as well as interleukin (IL)-4 production, while increasing the population of antigen-specific regulatory T-cells (Treg cells) and transforming growth factor-ß/IL-4 (TGF-ß/IL-4) ratio compared to the OVA and control groups in a dose-dependent manner. Collectively, the findings suggest that administration of NIC plus the allergen increased immunotherapy efficacy through decreasing allergic inflammation and allergic responses intensity, and increasing Treg cells population.

Regulatory effects of hemp seed/evening primrose oil supplement in comparison with rapamycin on the expression of the mammalian target of rapamycin-complex 2 and interleukin-10 genes in experimental autoimmune encephalomyelitis.

The mammalian target of rapamycin (mTOR) signaling plays a critical role in lipid synthesis and immune responses. The T regulatory cells (Treg) as suppressor of T cells, are a subset of T cells that modulate the immune system, maintain tolerance, and prevent autoimmune diseases.. The interleukin (IL) -10 derived from the Treg and T helper (Th) 2 is an anti-inflammatory cytokine in multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE). Due to the exclusive roles of rapamycin (RAPA) in mTOR inhibition, we evaluated the regulatory effect of the hemp seed oil/evening primrose oil (HSO/EPO) supplement in comparison with RAPA in EAE. EAE was induced by using myelin oligodendrocyte glycoprotein peptide and complete freund's adjuvant (CFA) in C57BL/6 mice, total mRNA was extracted from local lymph nodes and real-time polymerase chain reaction was used to evaluate the expression level of the rapamycin-insensitive companion of mTOR complex 2 (RICTOR) and IL-10 genes. The expression of IL-10 and RICTOR genes were significantly increased in HSO/EPO group. In contrast with RAPA groups, histological findings have shown that the HSO/EPO treated group remarkably reduced cell infiltration and promoted remyelination. The EPO/HSO has beneficial effects on the repair of myelin, which was confirmed by immunological and histological findings.

Evaluation of Immunogenic Effect of Toxoplasma gondii Recombinant SAG-1 Antigen with Propranolol as Adjuvant in BALB/c Mice.

Purpose: Propranolol as a novel adjuvant, was used to evaluate the immunogenic effect of three doses of recombinant SAG-1 (rSAG-1) antigen of Toxoplasma gondii in BALB/c mice for finding the optimal dose, and was compared with efficacy of tachyzoite lysate antigen (TLA). Methods: Eight different groups of 15 BALB/c mice received different volumes of the immunogenic material (three doses of r SAG-1 and one dose of TLA antigens), with or without propranolol adjuvant, subcutaneously. The control group mice received only PBS. Three weeks after the last immunization, the serum levels of IgG2a, IgG1 and IgG total antibodies against TLA, splenic interleukin-5 (IL-5) and Interferon-gamma (IFN-γ) (produced against TLA) and the splenic lymphocyte proliferation after adding TLA were measured to evaluate humoral and cellular immune responses. Challenge test was performed by subcutaneously injection of 1000 alive and active tachyzoites in to five mice per each group and survival days for each group of mice were recorded. Results: The mice group that received propranolol adjuvant and 20 µg of r SAG-1 antigen per dose of injection showed significantly more IFN-γ production, more proliferation of splenic lymphocytes and higher anti-TLA-specific IgG2a production (three main indexes for cell mediated immunity) in comparison with other groups. Moreover, in the challenge test, this group of mice had a significantly increased survival time, indicating the positive effect of propranolol in the more stimulating of cellular immunity that is necessary for toxoplasmosis prevention or suppress. Conclusion: Our results showed that T. gondii rSAG-1 antigen in combination with propranolol as adjuvant (which can induce Th1 related responses) are good candidates for further study to a vaccine design.

Hot and Cold natures and some parameters of neuroendocrine and immune systems in traditional Iranian medicine: a preliminary study.

AIM: The purpose of this study was to assess differences in persons of a Hot or Cold nature (according to traditional Iranian medicine), in terms of changes in their neuroendocrine and immune systems. MATERIALS AND METHODS: Thirty-seven (37) male volunteers (20-40 years old) were divided into two groups, by whether they had a Hot or Cold nature. In addition, the Warmth/Coldness ratio of all the volunteers was assessed. Plasma concentrations of epinephrine, norepinephrine and cortisol, and also the concentrations of interferon (IFN)-gamma and interleukin (IL)-4 produced by peripheral blood mononuclear cells stimulated by mitogen were measured. RESULTS: The results showed that norepinephrine/epinephrine and norepinephrine/cortisol ratios were significantly higher, and that there was a borderline significantly increased IL-4/IFN-gamma ratio in the Hot nature group compared with those in the Cold nature group. In addition, there was a significant linear positive correlation between the norepinephrine/epinephrine and Warmth/Coldness ratios and a significant nonlinear association between the IL-4/IFN-gamma and Warmth/Coldness ratios. CONCLUSIONS: It can be deduced that the persons of a Hot nature had more sympathetic nervous system activity, less adrenal sympathetic, adrenal corticosteroid, and parasympathetic nervous system activities and more deviation of the immune system toward T-helper (Th)2 responses than the persons of a Cold nature. Moreover, the activity of the sympathetic nervous system was increased and adrenal sympathetic was decreased with an increasing Warmth/Coldness ratio. Furthermore, when the person's nature veered toward extreme Warmth or extreme Coldness, the deviation of the immune system toward Th2-like responses was greater, but this increased deviation was much more marked when veering toward extreme Warmth than toward extreme Coldness.

Evaluation of the efficacy of nicotine in treatment of allergic asthma in BALB/c mice.

Nicotine, an nAChR agonist, shows prominent anti-inflammatory properties, and some studies have illustrated its suppressive effects on inflammation. Here, we have examined whether nicotine as a medicine may have beneficial effects on the treatment of asthma in a mouse model of allergic asthma. BALB/c mice were sensitized with OVA and alum. Two weeks later, the mice received nicotine with concentrations of 1 and 10 mg/kg three times every other day. After 10 days, the mice were challenged with OVA (5%) using an ultrasonic nebulizer and died the next day. Our results showed that the administration of nicotine reduced lung-tissue inflammation, the number of eosinophils in bronchoalveolar fluid, allergen-specific IgE and IL-4 production, while it increased the TGF-ß/IL-4 ratio and the number of Treg cells. Our results showed that nicotine applies its suppressive effects in a dose-dependent manner: administration of 10 mg/kg of nicotine showed more suppressive effects than 1 mg/kg. Such data suggested that nicotine might be a good candidate to be used as a medicine in the treatment of allergic asthma by decreasing allergic inflammation severity and potentiating Treg cells proliferation against the allergen.