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Unveiling the 4-aminoquinoline derivatives as potent agents against pancreatic ductal adenocarcinoma (PDAC) cell lines
No full textCommon antimalarials such as artemisinins, chloroquine and their derivatives also possess potent anti-inflamantory, antiviral and anticancer properties. In the search for new therapeutics to combat difficult-to-treat pancreatic carcinomas, we unveiled that 4-aminoquinoline derivatives, with significant antiplasmodial properties and a great safety profile in vivo, have remarkable anticancer activity against pancreatic ductal adenocarcinoma (PDAC) and considerable efficacy in the xenograft model in vivo. The aim of the present study was to further investigate anticancer properties of these compounds in a drug-repurposing manner. The compounds showed profound cytotoxic effects at nanomolar to low micromolar concentration in 2D cultured cells (in vitro) and in the zebrafish PDAC xenograft model (in vivo). A deeper insight into their mechanisms of cytotoxic action showed these compounds induce apoptosis while increasing reactive oxygen species levels along with autophagy inhibition. Additional investigation of the autophagy modulation proved that tested quinoline derivatives cause P62 and LC3-II accumulation in PDAC cells alongside lysosomal alkalinization. Further, in vivo toxicity studies in the zebrafish model showed low toxicity without developmental side effects of the investigated 4-aminoquinolines, while the applied compounds effectively inhibited tumor growth and prevented the metastasis of xenografted pancreatic cells. Taken together, these results highlight the 4-aminoquinolines as privileged structures that ought to be investigated further for potential application in pancreatic carcinoma treatment
Pain, dietary habits and physical activity of children with developmental disabilities in Croatia, North Macedonia and Serbia: a cross-sectional study
No full textBackground Multiple studies have shown that children with developmental disabilities (CDD) often live with unrecognized and untreated pain, consume inadequate diet and have inadequate levels of physical activity. This study
aimed to analyze pain, dietary habits and physical activity of CDD in Croatia, North Macedonia and Serbia.
Methods A cross-sectional study was conducted in Croatia, North Macedonia and Serbia in March–April 2023
within the Erasmus+ SynergyEd project. The study included parents and caregivers of CDD. Data were collected
via online survey.
Results We included 954 participants from Croatia (N=543; 57%), North Macedonia (N=205; 21%) and Serbia (N=206;
22%). Participants reported that 16% of children sufered from chronic pain related to their condition.
The main fndings of our study are that chronic pain is prevalent in CDD (16%). Almost half (48%) of participants avoid
certain foods for their children. The majority of children (86%) were not on a special diet. Among those that were
on a special diet, they were most commonly (60%) on a gluten-free diet. Most (54%) participants stated that their
children used nutritional supplements. Less than half participants (45%) stated that the child is involved in some kind
of physical activity. Only 17% of CDD engaged in physical activities 5 h or more per week.
Conclusion Our fndings indicate that chronic pain, inadequate dietary patterns and insufcient physical activity
are common in CDD from Croatia, Macedonia and Serbia. Education of parents and caregivers can mitigate their use
of interventions that have not been proven efective, such as for example the use of gluten-free diets in CDD
First Clinical Evidence with One-Year Monitoring of Babesia Gibsoni Mono-Infection in Two Dogs from Serbia
No full textIn Serbia, Babesia gibsoni in dogs is less common than Babesia canis. Although two clinical cases were reported a decade ago, no additional clinical reports have since been published. Recently, a co-infection of B. gibsoni and B. canis was documented in Austria following a dog’s trip to Serbia. The objectives of this study were to present comprehensive clinicopathological results of two clinical cases of B. gibsoni mono-infection in dogs in Serbia. Two male dogs: an 11-year-old Shih Tzu, and a 2-year-old Pit Bull Terrier, presented with clinical signs related to babesiosis with a history of biting by another dog. Both dogs had regenerative anemia, thrombocytopenia, and monocytosis while Shih Tzu had immune-mediated hemolytic anemia (IMHA). B. gibsoni mono-infection was confirmed by PCR testing. Both dogs were treated with a single dose of imidocarb-dipropionate, and a combination of metronidazole, clindamycin, and doxycycline (MCD protocol). The Shih Tzu also received prednisolone for three weeks. Following the MCD protocol, the Pitt Bull recovered, although thrombocytopenia persisted for nine months. In contrast, Shih Tzu's clinical condition worsened. The prednisolone treatment was discontinued, and azithromycin and atovaquone were introduced, leading to recovery after another three weeks of treatment. Long-term clinical and PCR monitoring revealed that the Pit Bull Terrier exhibited a more favorable response and a lower frequency of relapses compared to Shih Tzu. The findings suggest that B. gibsoni has become a clinically significant pathogen in Serbia. The MCD protocol appears effective for treating acute B. gibsoni infection in dogs, but further investigation is required to evaluate its efficacy in eliminating the parasite
Structural Characterization of Toxoplasma gondii Brain Cysts in a Model of Reactivated Toxoplasmosis Using Computational Image Analysis
Get PDFToxoplasma gondii is an obligate intracellular parasite existing in three infectious life stages—tachyzoites, bradyzoites, and sporozoites. Rupture of tissue cysts and re-conversion of bradyzoites to tachyzoites leads to reactivated toxoplasmosis (RT) in an immunocompromised host. The aim of this study was to apply ImageJ software for analysis of T. gondii brain cysts obtained from a newly established in vivo model of RT. Mice chronically infected with T. gondii (BGD1 and BGD26 strains) were treated with cyclophosphamide and hydrocortisone (experimental group—EG) or left untreated as infection controls (ICs). RT in mice was confirmed by qPCR (PCR+); mice remaining chronically infected were PCR−. A total of 90 images of cysts were analyzed for fractal dimension (FD), lacunarity (L), diameter (D), circularity (C), and packing density (PD). Circularity was significantly higher in PCR+ compared to IC mice (p < 0.05 for BGD1, p < 0.001 for the BGD26 strain). A significant negative correlation between D and PD was observed only in IC for the BGD1 strain (ρ = −0.384, p = 0.048), while fractal parameters were stable. Significantly higher D, C, and PD and lower lacunarity, L, were noticed in the BGD1 compared to the more aggressive BGD26 strain. In conclusion, these results demonstrate the complexity of structural alterations of T. gondii cysts in an immunocompromised host and emphasize the application potential of ImageJ in the experimental models of toxoplasmosis
Polyphenol-rich black currant and cornelian cherry juices ameliorate metabolic syndrome induced by a high-fat high-fructose diet in Wistar rats
Get PDFDiets high in fat and sugar lead to metabolic syndrome (MetS) and related chronic diseases. We investigated the effects of commercially available, cold-pressed polyphenol-rich black currant (BC) and cornelian cherry (CC) juices on the prevention of MetS in Wistar rats induced by a 10-weeks high-fat high-fructose (HFF) diet. Juice consumption, either BC or CC, with a HFF diet resulted in lower serum triglycerides compared to only the HFF consumption. Both juices also mitigated the effects of HFF on the liver, pancreas, and adipose tissue, by preserving liver and pancreas histomorphology and reducing visceral fat and adipocyte size. Furthermore, supplementation with both juices reduced glucagon and up-regulated insulin expression in the pancreas of the rats on the HFF diet, whereas the BC also showed improved glucose regulation. BC juice also reduced the expression of IL-6 and hepatic inflammation compared to the group only on HFF diet. Both juices, especially BC, could be a convenient solution for the prevention of MetS in humans
Perspectives on the diagnosis and management of functional cognitive disorder: An international Delphi study
Get PDFBackground: Current proposed criteria for functional cognitive disorder (FCD) have not been externally validated. We sought to analyse the current perspectives of cognitive specialists in the diagnosis and management of FCD in comparison with neurodegenerative conditions. Methods: International experts in cognitive disorders were invited to assess seven illustrative clinical vignettes containing history and bedside characteristics alone. Participants assigned a probable diagnosis and selected the appropriate investigation and treatment. Qualitative, quantitative and inter-rater agreement analyses were undertaken. Results: Eighteen diagnostic terminologies were assigned by 45 cognitive experts from 12 countries with a median of 13 years of experience, across the seven scenarios. Accurate discrimination between FCD and neurodegeneration was observed, independently of background and years of experience: 100% of the neurodegenerative vignettes were correctly classified and 75%–88% of the FCD diagnoses were attributed to non-neurodegenerative causes. There was <50% agreement in the terminology used for FCD, in comparison with 87%–92% agreement for neurodegenerative syndromes. Blood tests and neuropsychological evaluation were the leading diagnostic modalities for FCD. Diagnostic communication, psychotherapy and psychiatry referral were the main suggested management strategies in FCD. Conclusions: Our study demonstrates the feasibility of distinguishing between FCD and neurodegeneration based on relevant patient characteristics and history details. These characteristics need further validation and operationalisation. Heterogeneous labelling and framing pose clinical and research challenges reflecting a lack of agreement in the field. Careful consideration of FCD diagnosis is advised, particularly in the presence of comorbidities. This study informs future research on diagnostic tools and evidence-based interventions
Isolation, genotyping and phenotype analysis of European Toxoplasma gondii strains - what have we discovered?
No full textOver the last two decades, a considerable effort has been undertaken
to isolate, genotype, classify and analyze the phenotype
of Toxoplasma gondii strains worldwide. Initiated by a desire for
scientific discovery, this effort is now fueled primarily through
the implementation of the One Health approach. Specifically, the
addition of the environment as a novel research frontier provided
the rationale, framework and purpose to ask new research
questions, develop surveillance strategies and methodologies. In
Europe, there has been a tremendous increase in knowledge of
the parasite’s genetic diversity - both at a low and high level of
resolution - as compared to data available a decade ago. Shifting
the focus from humans and farmed food animals to free range animals,
wildlife and even soil and water as reservoirs of infection,
has resulted in the discovery of a higher diversity than anticipated,
while experimental analyses of natural isolates revealed that
virulent genotypes circulate in the environment. Together, the
emerging data is gradually changing conventional epidemiological
knowledge of transmission and risk factors and providing
a new perspective on T. gondii i nfection a nd d isease m anagement.
Exciting future research targets include development of
diagnostic tools with source attribution capabilities, strategies for
environmental surveillance and novel solutions for transmission
prevention.Abstracts: 14th European Multicolloquium of Parasitology (EMOP), Wrocław, Poland, 26-30.08.2024
Perceptions on support, challenges and needs among parents and caregivers of children with developmental disabilities in Croatia, North Macedonia and Serbia: a cross-sectional study
No full textBackground: Parents/caregivers of children with developmental disabilities (CDD) have a wide range of support needs and there are various interventions available. Support, challenges, and needs among parents/caregivers of CDD likely vary in different geographical settings. This study aimed to analyze the perceptions of support, challenges, and needs among parents/caregivers of CDD in Croatia, North Macedonia, and Serbia. Methods: We conducted a cross-sectional study in March-April 2023 within the Erasmus + SynergyEd project. The eligible participants were parents and caregivers of CDD in Croatia, North Macedonia, and Serbia, who filled out a modified Caregiver Needs Survey online. Results: Among 953 participants, 542 (57%) were from Croatia, 205 (21%) were from North Macedonia and 206 (22%) were from Serbia. The most common diagnosis of participants’ children was autism spectrum disorder (26%). The child most often received the first diagnosis at the median of 2 years, diagnosed by a team of professionals. More than half (58%) of children attended preschool and public school, while 22% did not attend any schooling. Additional support from the state/city/county was received by 66% of CDD. Most participants declared not participating in association/organization for family support. Participants mostly (68%) used experts who work with the child as a source of information about their child’s condition, followed by the Internet (53%). In the last 12 months, 60% of participants had difficulties with the availability of services in their area or problems getting appointments. The biggest problem in getting support was ensuring the child’s basic rights were protected. Participants stated that ensuring greater rights for CDD was the greatest need for their families. Conclusion: Parents/caregivers of CDD in Croatia, North Macedonia, and Serbia faced multiple challenges, but most of them were satisfied with the services provided to their children. Future efforts to develop policies and services related to CDD should consider the opinions of their parents/caregivers and disparities in access to services
Early immune response to Toxoplasma gondii lineage III isolates of different virulence phenotype
No full textIntroductionToxoplasma gondii is an intracellular parasite of importance to human and veterinary health. The structure and diversity of the genotype population of T. gondii varies considerably with respect to geography, but three lineages, type I, II and III, are distributed globally. Lineage III genotypes are the least well characterized in terms of biology, host immunity and virulence. Once a host is infected with T.gondii, innate immune mechanisms are engaged to reduce the parasite burden in tissues and create a pro-inflammatory environment in which the TH1 response develops to ensure survival. This study investigated the early cellular immune response of Swiss-Webster mice post intraperitoneal infection with 10 tachyzoites of four distinct non-clonal genotypes of lineage III and a local isolate of ToxoDB#1. The virulence phenotype, cumulative mortality (CM) and allele profiles of ROP5, ROP16, ROP18 and GRA15 were published previously.MethodsParasite dissemination in different tissues was analyzed by real-time PCR and relative expression levels of IFNγ, IL12-p40, IL-10 and TBX21 in the cervical lymph nodes (CLN), brain and spleen were calculated using the ΔΔCt method. Stage conversion was determined by detection of the BAG1 transcript in the brain.ResultsTissue dissemination depends on the virulence phenotype but not CM, while the TBX21 and cytokine levels and kinetics correlate better with CM than virulence phenotype. The earliest detection of BAG1 was seven days post infection. Only infection with the genotype of high CM (69.4%) was associated with high T-bet levels in the CLN 24 h and high systemic IFNγ expression which was sustained over the first week, while infection with genotypes of lower CM (38.8%, 10.7% and 6.8%) is characterized by down-regulation and/or low systemic levels of IFNγ. The response intensity, as assessed by cytokine levels, to the genotype of high CM wanes over time, while it increases gradually to genotypes of lower CM.DiscussionThe results point to the conclusion that the immune response is not correlated with the virulence phenotype and/or allele profile, but an early onset, intense pro-inflammatory response is characteristic of genotypes with high CM. Additionally, high IFNγ level in the brain may hamper stage conversion
A substituent-modified new salicylaldehyde-diphenyl-azine based AIEgen: A promising skeleton for copper ion sensor
No full textIn this study, we have reported a novel 4-bromo-salicylaldehyde-diphenyl-azine (B-1), a new member of salicylaldehyde-diphenyl-azine (SDPA) family known for its excellent sensing properties. In contrast to the previously reported AIEgens, we found that the bromo-substitution at the 4th position of the salicylaldehyde moiety blue-shifted the emission by 10 and 15 nm as compared to the unsubstituted (Tong et.al 2017) and Bromo at the 5th position (Jain et.al 2023) respectively. Moreover, B-1 crystallizes instantly as the cooling process starts, which was not observed in the previously reported scaffolds. The sensing investigation again demonstrated the precise and ultrasensitive behavior of B-1 for copper ions. B-1 has a very low LOD value i.e. 29.2 x 10-8 M with a high association constant and binds with copper ion in 2:1 mode. This time we also analyzed the practical applicability in the solid phase using cotton swabs and performed the real-time estimation of copper ions in water and biological samples like urine and blood serum. The excellent percentage recovery and the RSD value suggest the precision of the experiments. Further, we also perform the sensing in living cancer HeLa cells. Altogether, we found that the SDPA skeleton is precise and ultrasensitive for copper ions and versatile which can be used variously to detect copper ions in the real world. This research will surely help in developing new specific skeleton-based AIEgens with desirable emission properties and precise applications in the future