The onset of inflammation is associated with reactive oxygen species and oxidative damage to macromolecules like 7,8-dihydro-8-oxoguanine (8-oxoG) in DNA. Because 8-oxoguanine DNA glycosylase 1 (OGG1) binds 8-oxoG and because Ogg1-deficient mice are resistant to acute and systemic inflammation, we hypothesized that OGG1 inhibition may represent a strategy for the prevention and treatment of inflammation. We developed TH5487, a selective active-site inhibitor of OGG1, which hampers OGG1 binding to and repair of 8-oxoG and which is well tolerated by mice.TH5487 prevents tumor necrosis factor-α-induced OGG1-DNA interactions at guanine-rich promoters of proinflammatory genes. This, in turn, decreases DNA occupancy of nuclear factor κB and proinflammatory gene expression, resulting in decreased immune cell recruitment to mouse lungs. Thus, we present a proof of concept that targeting oxidative DNA repair can alleviate inflammatory conditions in vivo.
The folate metabolism enzyme MTHFD2 (methylenetetrahydrofolate dehydrogenase/cyclohydrolase) is consistently overexpressed in cancer but its roles are not fully characterized, and current candidate inhibitors have limited potency for clinical development. In the present study, we demonstrate a role for MTHFD2 in DNA replication and genomic stability in cancer cells, and perform a drug screen to identify potent and selective nanomolar MTHFD2 inhibitors; protein cocrystal structures demonstrated binding to the active site of MTHFD2 and target engagement. MTHFD2 inhibitors reduced replication fork speed and induced replication stress followed by S-phase arrest and apoptosis of acute myeloid leukemia cells in vitro and in vivo, with a therapeutic window spanning four orders of magnitude compared with nontumorigenic cells. Mechanistically, MTHFD2 inhibitors prevented thymidine production leading to misincorporation of uracil into DNA and replication stress. Overall, these results demonstrate a functional link between MTHFD2-dependent cancer metabolism and replication stress that can be exploited therapeutically with this new class of inhibitors.
A case of co-infection due to Demodex cati and feline immunodeficiency virus in a cat is described. A 5 year-old neutered male cat was presented to the Small Animal Clinic at the Faculty of Veterinary Medicine, Trakia University with lethargy, diarrhoea, pyrexia, anorexia, adipsia, skin lesions, intense itching and alopecia. Parasitological, mycological and serological examinations were carried out. Adult D. cati mites and antibodies against FIV were detected. A proper therapy with an endectocide, antibiotic and antihistamine drug was prescribed. The improvement of the general condition was observed after a month of treatment. Later, the disease recurred twice and the animal was humanely euthanased for medical reasons and at the owner’s request.
Acute phase proteins (APPs) are a large group of proteins synthesised mainly by the liver. Their production is stimulated in response to disturbances in the systemic homeostasis. It is known that each species has a specific set of APPs. Serum amyloid A and haptoglobin are the main APPs in small ruminants and their plasma concentration is changed most significantly in comparison with minor APPs such as ceruloplasmin. In general, APPs could provide valuable information on the general condition of the organism but cannot point at the exact disease. Therefore, APPs should be included as an additional indicator in clinical diagnosis. Knowledge of APPs behaviour in disease states has a remarkable potential for detecting animals with subclinical infections, determining the prognosis of clinical infection, differentiation between viral and bacterial disease, treatment monitoring, vaccine effectiveness and stress conditions. The aim of this review is to present data on APPs behaviour during some parasitic and infectious diseases as well as pathological conditions leading to aseptic inflammation and stress in sheep and goats.
SummaryKalkanov, I., I. Dinev, K. Dimitrov & P. Iliev, 2016. Clinical and morphological investigations in a spontaneous Cryptosporidium enteritis outbreak in calves. Bulg. J. Vet. Med., 19, No 4,[334][335][336][337][338][339] The purpose of this report was to present the results of histopathological examination during the course of a natural Cryptosporidium parvum outbreak, as well as the morphology of cells infiltrating affected gastrointestinal tract areas in newborn calves. The study included 18 calves exhibiting a marked diarrhoeic syndrome, between 1 and 8 days of age. Sporulated C. parvum oocysts were demonstrated in faecal smears stained by the method of Henriksen. Coproantigens of C. parvum were detected by the rapid Rainbow calf scour 5 BIO K 306 test. Gross lesions were mainly present in the gastrointestinal tract, together with inflammation in regional mesenteric lymph nodes. Microscopic histopathological lesions consisted mainly in desquamative catarrh of intestinal mucosa and intestinal villous atrophy. The affected intestinal epithelium contained multiple Cryptosporidium spp. forms at different stage of the life cycle. The results from histopathological studies of the outbreak allowed confirming some main morphogenetic features of the disease caused by C. parvum in newborn and growing calves.
SummaryThe present work was designed to evaluate the prevalence of gastrointestinal parasites and some vector-borne pathogens in dogs in Bulgaria. A total of 172 owned dogs, keeping outside, were included in the study. Fecal samples were examined using standard flotation and sedimentation methods. Blood samples were processed by Knott’s technique, SNAP™ 4Dx Plus Test (IDEXX) and Angio Detect™ Test (IDEXX). The overall prevalence of gastrointestinal parasites was 64.5%. Eggs of hookworms (Ancylostoma sp. and Uncinaria sp.) were the most frequently detected (54.1%), followed by Trichuris vulpis (15.1%), Capillaria sp. (11.0%), Toxocara canis (6.4%), Cystoisospora sp. (4.1%), Sarcocystis sp. (2.3%), Toxascaris leonina (1.7%), Taenia sp. (1.2%) and Linguatula serrata (0.6%). In addition, hookworms were the most commonly involved in the cases of single infection (20.3%). Combinations between Capillaria sp./hookworms and T. vulpis/hookworms were the most common co-infections (4.1% and 2.9%, respectively). Blood samples revealed the presence of antibodies against Ehrlichia sp. (13.4%), Anaplasma sp. (13.4%) and Borrelia burgdorferi (1.7%). Antigens of Dirofilaria immitis and Angiostrongylus vasorum were detected in 10.5% and 0.6% of the samples tested, respectively. Microfilariae of Dirofilaria repens were found in 5.8% of the blood samples. Additionally, the prevalence of D. immitis and Ehrlichia sp. was significantly higher in adult than in young dogs (p<0.05). In contrast, the gender was not considered as a risk factor contributing to the occurrence of infections.
Dihydrofolate reductase (DHFR) is an established anti-cancer drug target whose inhibition disrupts folate metabolism and STAT3-dependent gene expression. Cycloguanil was proposed as a DHFR inhibitor in the 1950s and is the active metabolite of clinically approved plasmodium DHFR inhibitor Proguanil. The Cycloguanil scaffold was explored to generate potential cancer therapies in the 1970s. Herein, current computational and chemical biology techniques were employed to re-investigate the anti-cancer activity of Cycloguanil and related compounds. In silico modeling was employed to identify promising Cycloguanil analogues from NCI databases, which were cross-referenced with NCI-60 Human Tumor Cell Line Screening data. Using target engagement assays, it was found that these compounds engage DHFR in cells at sub-nanomolar concentrations; however, growth impairments were not observed until higher concentrations. Folinic acid treatment rescues the viability impairments induced by some, but not all, Cycloguanil analogues, suggesting these compounds may have additional targets. Cycloguanil and its most promising analogue, NSC127159, induced similar metabolite profiles compared to established DHFR inhibitors Methotrexate and Pyrimethamine while also blocking downstream signaling, including STAT3 transcriptional activity. These data confirm that Cycloguanil and its analogues are potent inhibitors of human DHFR, and their anti-cancer activity may be worth further investigation.
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