Long-term prevention of bladder cancer progression by alpha1-oleate alone or in combination with chemotherapy.

Bladder cancer is common and one of the most costly cancer forms, due to a lack of curative therapies. Recently, clinical safety and efficacy of the alpha1-oleate complex was demonstrated in a placebo-controlled study of nonmuscle invasive bladder cancer. Our study investigated if long-term therapeutic efficacy is improved by repeated treatment cycles and by combining alpha1-oleate with low-dose chemotherapy. Rapidly growing bladder tumors were treated by intravesical instillation of alpha1-oleate, Epirubicin or Mitomycin C alone or in combination. One treatment cycle arrested tumor growth, with a protective effect lasting at least 4 weeks in mice receiving 8.5 mM of alpha1-oleate alone or 1.7 mM of alpha-oleate combined with Epirubicin or Mitomycin C. Repeated treatment cycles extended protection, defined by a lack of bladder pathology and a virtual absence of bladder cancer-specific gene expression. Synergy with Epirubicin was detected at the lower alpha1-oleate concentration and in vitro, alpha1-oleate was shown to enhance the uptake and nuclear translocation of Epirubicin, by tumor cells. Effects at the chromatin level affecting cell proliferation were further suggested by reduced BrdU incorporation. In addition, alpha1-oleate triggered DNA fragmentation, defined by the TUNEL assay. The results suggest that bladder cancer development may be prevented long-term in the murine model, by alpha1-oleate alone or in combination with low-dose Epirubicin. In addition, the combination of alpha1-oleate and Epirubicin reduced the size of established tumors. Exploring these potent preventive and therapeutic effects will be of immediate interest in patients with bladder cancer.

Revisiting the environmental Kuznetz curve and pollution haven hypothesis in N-11 economies: Fresh evidence from panel quantile regression.

Human activities in recent decades have severely affected environmental quality, and CO2 emissions have irreparable consequences on human health and the survival of the earth. Moreover, achieving sustainable development goals requires the expansion of environmental literature to accelerate the performing of critical actions. With this in mind, this study evaluates the impact of foreign direct investment, economic complexity, and the utilization of renewable energy on CO2 emission in N-11 countries from 1995 to 2019 by Panel Quantile Regression. As a novelty, the interaction between economic complexity and foreign direct investment is considered to get a better comprehension. Given the results, Environmental Kuznetz Curve is validated in N-11 countries through economic complexity. Notably, the impact of economic complexity is more substantial and robust in the incipient stages of industrialization. Furthermore, foreign direct investment is a destructive factor for environmental quality, and Pollution Haven Hypothesis is not rejected. Interestingly, the interaction of economic complexity and foreign direct investment mitigates the trend of CO2 emissions. Eventually, the utilization of renewable energy reduces CO2 emissions. Thereby, applying more strict environmental regulations and standards, developing green energy infrastructure and technologies, improving institutional quality, and supporting knowledge-based and technology-intensive exports are the main policy recommendations of this study.

Tropheryma whipplei in the stool samples of children with acute diarrhea: a study from Tehran, Iran.

BACKGROUND: Recently, Tropheryma whipplei has been suggested as one of the causative agents of diarrhea among children worldwide. Limited data is available on the prevalence of T. whipplei among children with diarrhea in most countries such as Iran. This study was conducted to evaluate the prevalence of T. whipplei in children with acute diarrhea in Iran. METHODS: In this study, the stool samples were collected from 130 children under 10 years old with acute diarrhea from children's hospitals in Tehran city. Genomic DNA was extracted from stool samples and was tested for the presence of DNA of T. whipplei using the SYBR Green Real-time PCR method. Positive T. whipplei samples were finally confirmed by PCR Product sequencing. RESULTS: The mean age of participants was 32.5 months, and 54.6% of children were female. Using the SYBR Green Real-time PCR, 9.23% (12/130) of samples were positive for T. whipplei, which were confirmed by sequencing. 66.67% of positive cases were males. The duration of diarrhea in infected children with T. whipplei (83.3%) was significantly longer (OR: 5.93, 95% CI 1.24-28.22) compared to children with negative results (45.8%). Other demographic factors and clinical signs had not a statistically significant relationship with T. whipplei infection. CONCLUSIONS: In this study, T. whipplei was detected in stool samples of children with acute diarrhea. The results indicated that T. whipplei could be associated with childhood diarrhea in Iran. The health care system and physicians should be aware of the presence of T. whipplei infection in Iran, especially in childhood diarrhea.

BAMLET administration via drinking water inhibits intestinal tumor development and promotes long-term health.

Though new targeted therapies for colorectal cancer, which progresses from local intestinal tumors to metastatic disease, are being developed, tumor specificity remains an important problem, and side effects a major concern. Here, we show that the protein-fatty acid complex BAMLET (bovine alpha-lactalbumin made lethal to tumor cells) can act as a peroral treatment for colorectal cancer. ApcMin/+ mice, which carry mutations relevant to hereditary and sporadic human colorectal cancer, that received BAMLET in the drinking water showed long-term protection against tumor development and decreased expression of tumor growth-, migration-, metastasis- and angiogenesis-related genes. BAMLET treatment via drinking water inhibited the Wnt/ß-catenin and PD-1 signaling pathways and prolonged survival without evidence of toxicity. Systemic disease in the lungs, livers, spleens, and kidneys, which accompanied tumor progression, was inhibited by BAMLET treatment. The metabolic response to BAMLET included carbohydrate and lipid metabolism, which were inhibited in tumor prone ApcMin/+ mice and weakly regulated in C57BL/6 mice, suggesting potential health benefits of peroral BAMLET administration in addition to the potent antitumor effects. Together, these findings suggest that BAMLET administration in the drinking water maintains antitumor pressure by removing emergent cancer cells and reprogramming gene expression in intestinal and extra-intestinal tissues.

The role of economic policy uncertainty and social welfare in the view of ecological footprint: evidence from the traditional and novel platform in panel ARDL approaches.

In the contemporary world, environmental degradation has become a concern for human beings. Accordingly, the impact of social welfare, economic policy uncertainty, natural resource rents, life expectancy, and trade openness are examined on ecological footprint (the most comprehensive proxy of environmental degradation) in 19 energy-intensive countries from 1997 to 2018. With this in mind, this study used the traditional panel ARDL and CS-ARDL approaches to evaluate how the study's variables influence ecological footprint. Notably, the results of the CS-ARDL approach are more robust due to cross-sectional dependence and slope heterogeneity problems. The outcomes revealed that economic policy uncertainty and trade openness affect the ecological footprint negatively in the short run and positively in the long run. Moreover, social welfare degrades the environment in the long run, and natural resource rents improve environmental quality by mitigating the ecological footprint in the short run and harming the environment in the long run. Besides, life expectancy does not significantly affect ecological footprint in the long or short run. Meanwhile, the results confirmed the bi-directional causal relationship between the study's variable and ecological footprint. Based on the outcomes, the way to adopt effective policies to improve the quality of the environment has been paved. Furthermore, a comprehensive policy framework for stricter environmental regulation is expected to be developed using the outcomes derived from this study.

The benefits of Vitamin D in the COVID-19 pandemic: biochemical and immunological mechanisms.

In December 2019, a new infectious complication called CoronaVirus Infectious Disease-19, briefly COVID-19, caused by SARS-COV-2, is identified in Wuhan, China. It spread all over the world and became a pandemic. In many individuals who had suffered SARS-COV-2 infection, cytokine storm starts through cytokine overproduction and leads to Acute Respiratory Syndrome (ARS), organ failure, and death. According to the obtained evidence, Vitamin D (VitD) enhances the ACE2/Ang(1-7)/MasR pathway activity, and it also reduces cytokine storms and the ARS risk. Therefore, VitD intake may be beneficial for patients with SARS-COV-2 infection exposed to cytokine storm but do not suffer hypotension. In the present review, we have explained the effects of VitD on the renin-angiotensin system (RAS) function and angiotensin-converting enzyme2 (ACE2) expression. Furthermore, we have reviewed the biochemical and immunological effects of VitD on immune function in the underlying diseases and its role in the COVID-19 pandemic.

Serological evidence of Yersinia pestis infection in rodents and carnivores in Northwestern Iran.

BACKGROUND: Plague may recur after several decades in its endemic regions; therefore, the continuous monitoring of wildlife is essential, even when no human cases are reported in the old foci. The present study was conducted to monitor rodents and their ectoparasites as well as carnivores to learn about the epidemiology of plague infection in an old focus of Iran. METHODOLOGY: The present study was conducted from 2019 to 2020 in Takestan county of Qazvin Province in northwestern Iran. Rodents were caught using live traps, and their fleas were separated. Blood and spleen specimens were taken from the captured rodents. Serum samples were also collected from sheepdogs and wild carnivores. The collected samples were tested by culture, serology (ELISA), and molecular methods to detect Yersinia pestis infection. FINDINGS: A total of 399 small mammals were caught, of which 68.6% were Meriones persicus. A total of 2438 fleas were collected from the rodents, 95.3% of which were Xenopsylla buxtoni. Overall, 23 out of 377 tested rodents (5.7%, CI 95%, 3.9-9.0) had IgG antibodies against the F1 antigen of Y. pestis, and all the positive samples belonged to M. persicus. Nine (4.8%) out of 186 collected sera from the sheepdogs' serum and one serum from the Canis aureus had specific IgG antibodies against the F1 antigen of Y. pestis. There were no positive cases of Y. pestis in the rodents and fleas based on the culture and real-time PCR. CONCLUSION: Serological evidence of Y. pestis circulation was observed in rodents and carnivores (sheepdogs and C. aureus). The presence of potential plague vectors and serological evidence of Y. pestis infection in the surveyed animals could probably raise the risk of infection and clinical cases of plague in the studied region. Training health personnel is therefore essential to encourage their detection of possible human cases of the disease.

The surveillance of plague among rodents and dogs in Western Iran.

BACKGROUND: The causative agent of plague, Yersinia pestis, is maintained in nature via a flea-rodent cycle. Western Iran is an old focus for plague, and recent data indicate that rodents and dogs in this region have serological evidence of Y. pestis infection. The purpose of this study was to conduct a large-scale investigation of Y. pestis infection in shepherd dogs, rodents, and their fleas in old foci for plague in Western Iran. MATERIALS AND METHODS: This study was conducted in Hamadan province from 2014 to 2020. Rodents and fleas were collected from various locations throughout this region. Y. pestis was investigated in rodent spleen samples and fleas using culture, serology, and real-time PCR methods. Additionally, sera samples were collected from carnivores and hares in this region, and the IgG antibody against the Y. pestis F1 antigen was assessed using an ELISA. RESULTS: In this study, 927 rodents were captured, with Meriones spp. (91.8%) and Microtus qazvinensis (2.6%) being the most prevalent. A total of 6051 fleas were collected from rodents and carnivores, most of which were isolated from Meriones persicus. None of the rodents or fleas examined tested positive for Y. pestis using real-time PCR and culture methods. Meanwhile, IgG antibodies were detected in 0.32% of rodents. All serologically positive rodents belonged to M. persicus. Furthermore, none of the sera from the 138 carnivores (129 sheepdogs, five Vulpes vulpes, four Canis aureus), and nine hares tested positive in the ELISA test. CONCLUSION: This primary survey of rodent reservoirs shows serological evidence of Y. pestis infection. Western Iran is an endemic plague focus, and as such, it requires ongoing surveillance.

Energy intensity determinants based on structure-oriented cointegration by embedding a knowledge box in a time series model: evidence from Iran.

Energy intensity reduction is an exigent issue for Iran, where energy consumption is so high. Therefore, finding effective policies to reduce energy intensity is essential. With this in mind, the impact of financial development, government investment, oil revenues, and trade openness on energy intensity is assessed in this study. We combined structural vector error correction model (SVECM) and directed acyclic graphs (DAG) technique to examine the relationships between study variables. The results of DAG prove that financial development, government investment, oil revenues, and trade openness influence the intensity of energy. Besides, the significant and long-run relationships among variables allowed us to apply SVECM. Impulse response functions and variance decomposition analysis indicate that government investment, oil revenues, and trade openness are negatively associated with the intensity of energy. Also, financial development positively influences energy intensity. Meanwhile, the impact of government investment is more significant than oil revenues, trade openness, and financial development impacts. So, government investment is the most effective policy regarding optimizing the consumption of energy and reducing energy intensity. We also advise policymakers to use oil revenues to increase government investment, enhance trade openness, and tax the private sector to improve the level of energy intensity.

A case report of ulceroglandular tularemia caused by Francisella tularensis subsp. Holarctica in Iran.

BACKGROUND: Tularemia is a zoonotic disease that has been reported in many countries of the Northern Hemisphere. However, in some countries, such as Iran, this disease has been neglected by the health care system, and it is under-reported. CASE PRESENTATION: Here we report an unusual case of ulceroglandular tularemia occurring in a 35-year-old woman who presented with a skin lesion of the left flank, inguinal lymphadenopathy, and an abdominal abscess. The serological and real-time PCR tests for tularemia were positive for this patient, and infection by Francisella tularensis subsp. holarctica was confirmed. CONCLUSIONS: It is necessary to implement various educational programs to increase the awareness of physicians with tularemia.

Lipid bilayer composition as a determinant of cancer cell sensitivity to tumoricidal protein-lipid complexes.

Complexes formed by the alpha1 N-terminal peptide of alpha-lactalbumin and oleic acid (alpha1-oleate) interact with lipid bilayers. Plasma membrane perturbations trigger tumor cell death but normal differentiated cells are more resistant, and their plasma membranes are less strongly affected. This study examined membrane lipid composition as a determinant of tumor cell reactivity. Bladder cancer tissue showed a higher abundance of unsaturated lipids enriched in phosphatidylcholine, PC (36:4) and PC (38:4), and sphingomyelin, SM (36:1) than healthy bladder tissue, where saturated lipids predominated and the lipid extracts from bladder cancer tissue inhibited the tumoricidal effect of the complex more effectively than healthy tissue extracts. Furthermore, unsaturated PC in solution inhibited tumor cell death, and the complex interacted with giant unilamellar vesicles formed by PC, confirming the affinity of alpha1-oleate for fluid membranes enriched in PC. Quartz Crystal Microbalance with dissipation monitoring (QCM-D) detected a preference of the complex for the liquid-disordered phase, suggesting that the insertion into PC-based membranes and the resulting membrane perturbations are influenced by membrane lipid saturation. The results suggest that the membrane lipid composition is functionally important and that specific unsaturated membrane lipids may serve as "recognition motifs" for broad-spectrum tumoricidal molecules such as alpha1-oleate.

Effects of Gliadin on Autoimmune Responses of Central Nervous System of C57BL/6 Mice.

Gluten sensitivity contributes to various degrees of neurological manifestations and neurodegenerative immunological changes. We investigated the experimental features of anti-gliadin immune responses in the central nervous system (CNS) of mice. Female C57BL6 mice were divided into three groups. Mice immunized with complete Freund's adjuvant (CFA) or gliadin emulsified in CFA, and the control group received phosphate-buffered saline (PBS). Immunohistochemistry, hematoxylin-eosin, and Luxol fast blue staining were performed on the sections. The serum levels of interleukin (IL)-17 and interferon-gamma (IFN-γ) were measured using enzyme-linked immunosorbent assay (ELISA). Reverse transcriptase-polymerase chain reaction (RT-PCR) was used to assess the mRNA levels of chemokine (C-X-C motif) ligand-2 (CXCL-2), C-C motif chemokine ligand-2 (CCL-2), and CXCL-10.  In gliadin+CFA immunized mice, the microscopic lesions included perivascular edema, focal-microgliosis, and acute neuronal necrosis in the cortex, subcortical, Purkinje cell layer, and ventral horn of the spinal cord. While extravasation of anti-IgG antibodies and selective targeting of Purkinje cells were observed in gliadin+CFA immunized mice. A significant increase in serum IL-17 and IFN-g levels (p<0.05), as well as expression of CXCL-2, CCL-2, and CXCL-10 in mice immunized with gliadin+CFA, were monitored versus controls. Our findings indicated that the immune responses directed against gliadin peptides might contribute to blood-brain barrier breakdown, extravasation of serum anti-IgG, gliosis, and acute neuronal necrosis in the cortex and cerebellar Purkinje cells. Anti-IgG antibodies may cause extravasation of blood-born anti-gliadin antibodies and selective targeting of Purkinje cells observed in mice immunized with peptide tryptic (pt) -gliadin in CFA.

Active bacterial modification of the host environment through RNA polymerase II inhibition.

Unlike pathogens, which attack the host, commensal bacteria create a state of friendly coexistence. Here, we identified a mechanism of bacterial adaptation to the host niche, where they reside. Asymptomatic carrier strains were shown to inhibit RNA polymerase II (Pol II) in host cells by targeting Ser2 phosphorylation, a step required for productive mRNA elongation. Assisted by a rare, spontaneous loss-of-function mutant from a human carrier, the bacterial NlpD protein was identified as a Pol II inhibitor. After internalization by host cells, NlpD was shown to target constituents of the Pol II phosphorylation complex (RPB1 and PAF1C), attenuating host gene expression. Therapeutic efficacy of a recombinant NlpD protein was demonstrated in a urinary tract infection model, by reduced tissue pathology, accelerated bacterial clearance, and attenuated Pol II-dependent gene expression. The findings suggest an intriguing, evolutionarily conserved mechanism for bacterial modulation of host gene expression, with a remarkable therapeutic potential.

Bladder cancer therapy using a conformationally fluid tumoricidal peptide complex.

Partially unfolded alpha-lactalbumin forms the oleic acid complex HAMLET, with potent tumoricidal activity. Here we define a peptide-based molecular approach for targeting and killing tumor cells, and evidence of its clinical potential (ClinicalTrials.gov NCT03560479). A 39-residue alpha-helical peptide from alpha-lactalbumin is shown to gain lethality for tumor cells by forming oleic acid complexes (alpha1-oleate). Nuclear magnetic resonance measurements and computational simulations reveal a lipid core surrounded by conformationally fluid, alpha-helical peptide motifs. In a single center, placebo controlled, double blinded Phase I/II interventional clinical trial of non-muscle invasive bladder cancer, all primary end points of safety and efficacy of alpha1-oleate treatment are reached, as evaluated in an interim analysis. Intra-vesical instillations of alpha1-oleate triggers massive shedding of tumor cells and the tumor size is reduced but no drug-related side effects are detected (primary endpoints). Shed cells contain alpha1-oleate, treated tumors show evidence of apoptosis and the expression of cancer-related genes is inhibited (secondary endpoints). The results are especially encouraging for bladder cancer, where therapeutic failures and high recurrence rates create a great, unmet medical need.

Anti-inflammatory activity of emu oil-based nanofibrous scaffold through downregulation of IL-1, IL-6, and TNF-α pro-inflammatory cytokines.

Background Inflammation is one of the most important responses of the body against infection or disease, and it protects tissues from injury; however, it causes redness, swelling, pain, fever and loss of function. The aim of this present study was to evaluate the anti-inflammatory activity of emu oil (Eu) formulated nanofibrous scaffold in HFFF2 fibroblast cells. Materials and methods Eu was formulated successfully in nanofibers through the electrospinning method. Besides, the morphological and structural properties of Eu nanofibres were evaluated using Fourier transform infrared spectroscopy (FTIR) and scanning electron microscopy (SEM). The MTT assay (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide) was performed to evaluate the HFFF2 fibroblast cells' viability. Also, real-time polymerase chain reaction (PCR) was used to evaluate the anti-inflammatory signaling pathway in treated HFFF2 cells with Eu nanofiber. Results Our study showed that the Eu nanofiber increased the viability of fibroblast HFFF2 cells (p < 0.05). Also, the expression of interleukin1 (IL1), IL6 and tumor necrosis factor- alpha (TNF-α) pro-inflammatory cytokines genes were significantly decreased in treated HFFF2 cells with Eu nanofiber (p < 0.05). Conclusions In conclusion, Eu nanofiber scaffold potentially can reduce the inflammation process through downregulation of IL-1, IL-6 and TNF-α cytokines.

Altered helper T cell-mediated immune responses in male mice conceived through in vitro fertilization.

A study using a mouse IVF model was conducted to examine the hypothesis that in vitro fertilization (IVF) treatment may lead to immune system alteration in the offspring. Phagocytic activity and lymphocyte proliferative responses to mitogen, alloantigen, and purified protein derivative (PPD) of Mycobacterium bovis were investigated in the splenocytes of BCG-treated male mice conceived by IVF or natural conception. Intracellular expression of T-bet and GATA3 in helper T-cell population were examined in both groups. Moreover, the serum levels of IFN-γ and IL-4 along with BCG-specific levels of IgG1 and IgG2a were assessed by ELISA. In comparison with naturally-conceived mice, PPD-specific proliferative response and T-bet/GATA3 ratio were significantly decreased in IVF-conceived mice. Moreover, IVF-conceived mice exhibited marked decreases in IFN-γ/IL-4 and IgG2a/IgG1 ratios. Results indicate that in comparison with male mice conceived by natural conception, IVF counterparts exhibit less efficient immune responses against BCG through further promotion of Th2 responses.

Cannabinoid receptor agonism suppresses tremor, cognition disturbances and anxiety-like behaviors in a rat model of essential tremor.

Cognitive and motor disturbances are serious consequences of tremor induced by motor disorders. Despite a lack of effective clinical treatment, some potential therapeutic agents have been used to alleviate the cognitive symptoms in the animal models of tremor. In the current study, the effects of WIN55, 212-2 (WIN), a cannabinoid receptor (CBR) agonist, on harmaline-induced motor and cognitive impairments were studied. Adult rats were treated with WIN (0.5mg/kg; i.p.) 15min before harmaline administration (10mg/kg; ip) after which exploratory and anxiety related behaviors, and cognitive function were assessed using open-field behavior and shuttle box tests. Rats that received harmaline only exhibited a markedly reduced number of central square entries when compared to harmaline vehicle-treated controls, whereas those treated with WIN and harmaline showed a significant increase in central square entries, compared to harmaline only treated. The passive avoidance memory impairments observed in harmaline treated rats, was reversed somewhat by administration of WIN. The neuroprotective and anxiolytic effects of WIN demonstrated in the current study can be offered cannabinoid receptor (CBR) agonism as a potential neuroprotective agent in the treatment of patients with tremor that manifest mental dysfunctions.