Exosome-mediated PROTAC delivery for treatment of RNA viral infections and zoonosis.

The increase in diseases caused by RNA viruses, such as influenza, severe acute respiratory syndrome-coronavirus (SARS-CoV), Middle East respiratory syndrome (MERS), and Ebola, presents a growing global health challenge as well as the threat of zoonosis. Traditional antiviral treatments are often undermined by fast-mutating viruses, drug resistance, and newly emerging pathogens. Here, we explore proteolysis-targeting chimeras (PROTACs), a novel protein degradation machinery that has the potential to reshape the way in which RNA viral infections can be managed. PROTACs excel at specifically degrading pathogenic proteins, offering a targeted and efficient antiviral strategy. We also investigate the potential of exosome-based diagnostic technologies, which harness cell-derived nanovesicles for non-invasive sampling and early viral infection detection. Addressing the challenge of PROTAC delivery, we introduce a groundbreaking strategy utilizing exosomes to deliver PROTACs with improved precision and as a targeted delivery vehicle. Integrating these innovative strategies provides a novel approach to combat RNA zoonotic viral diseases, paving the way for a new era in antiviral therapy.

Curcumin as a natural potential drug candidate against important zoonotic viruses and prions: A narrative review.

Zoonotic diseases are major public health concerns and undeniable threats to human health. Among Zoonotic diseases, zoonotic viruses and prions are much more difficult to eradicate, as they result in higher infections and mortality rates. Several investigations have shown curcumin, the active ingredient of turmeric, to have wide spectrum properties such as anti-microbial, anti-vascular, anti-inflammatory, anti-tumor, anti-neoplastic, anti-oxidant, and immune system modulator properties. In the present study, we performed a comprehensive review of existing in silico, in vitro, and in vivo evidence on the antiviral (54 important zoonotic viruses) and anti-prion properties of curcumin and curcuminoids in PubMed, Google Scholar, Science Direct, Scopus, and Web of Science databases. Database searches yielded 13,380 results, out of which 216 studies were eligible according to inclusion criteria. Of 216 studies, 135 (62.5%), 24 (11.1%), and 19 (8.8%) were conducted on the effect of curcumin and curcuminoids against SARS-CoV-2, Influenza A virus, and dengue virus, respectively. This review suggests curcumin and curcuminoids as promising therapeutic agents against a wide range of viral zoonoses by targeting different proteins and signaling pathways.

Metalloenzyme Inhibitors against Zoonotic Infections: Focus on Leishmania and Schistosoma.

The term "zoonosis" denotes diseases transmissible among vertebrate animals and humans. These diseases constitute a significant public health challenge, comprising 61% of human pathogens and causing an estimated 2.7 million deaths annually. Zoonoses not only affect human health but also impact animal welfare and economic stability, particularly in low- and middle-income nations. Leishmaniasis and schistosomiasis are two important neglected tropical diseases with a high prevalence in tropical and subtropical areas, imposing significant burdens on affected regions. Schistosomiasis, particularly rampant in sub-Saharan Africa, lacks alternative treatments to praziquantel, prompting concerns regarding parasite resistance. Similarly, leishmaniasis poses challenges with unsatisfactory treatments, urging the development of novel therapeutic strategies. Effective prevention demands a One Health approach, integrating diverse disciplines to enhance diagnostics and develop safer drugs. Metalloenzymes, involved in parasite biology and critical in different biological pathways, emerged in the last few years as useful drug targets for the treatment of human diseases. Herein we have reviewed recent reports on the discovery of inhibitors of metalloenzymes associated with zoonotic diseases like histone deacetylases (HDACs), carbonic anhydrase (CA), arginase, and heme-dependent enzymes.

Identification of Francisella tularensis in ascites in the context of typhoidal tularaemia.

Tularaemia is a highly infectious, zoonotic disease caused by Francisella tularensis, which has become increasingly prevalent over the past decade. Depending on the route of infection, different clinical manifestations can be observed. We report a case of typhoidal tularaemia presenting as a febrile illness with gastrointestinal symptoms in a patient in her mid-80s. During the acute illness phase and in the context of alcohol-related liver cirrhosis, the patient developed progressive ascites. During paracentesis, spontaneous bacterial peritonitis was consistently reported. Blood culture revealed Gram-negative bacilli identified as F. tularensis upon microscopic examination. Immediate clinical improvement was observed after adaptation to a pathogen-specific antibiotic regime. Typhoidal tularaemia presents general, non-specific symptoms without the local manifestations seen in other forms of the disease, thus representing a diagnostic challenge. In the case of protracted fever and if the epidemiological context as well as possible exposure are compatible, tularaemia should be considered in the differential diagnosis.

Palliative Treatment for the Management of Advanced Pelvic Hydatid Bone Disease.

Hydatid bone disease is a zoonotic parasitic infection that is caused primarily by the tapeworm Echinococcus granulosus, and it continues to be a major public health concern in pastoral regions. The reconstruction of limb function after limb salvage surgery remains a challenge for clinicians. The purpose of this study was to determine the clinical efficacy of palliative treatment of the management of advanced pelvic hydatid bone disease. From March 2005 to December 2018, medical records and images of patients with advanced pelvic hydatid bone disease treated with surgery combined with antiparasitic chemotherapy were evaluated retrospectively. The Enneking classification was applied to determine the location of the lesion, and the Musculoskeletal Tumor Society score system was used for outcome evaluation. Fifteen patients who met the criteria were included in this study, with a mean follow-up of 4.40 ± 1.76 years. All patients received treatment with surgery combined with antiparasitic chemotherapy. The mean number of surgical interventions per patient for pelvic cystic echinococcosis was 5.3 (range, 2-9 interventions per patient). Recurrence of pelvic hydatid bone disease occurred in 5 patients and was managed successfully through repeated debridement procedures. Palliative treatment with limb salvage surgery was an effective and practical approach to the management of advanced pelvic hydatid bone disease. Standard antiparasitic chemotherapy, which included albendazole at a dose of 10 mg/kg/day administered in two daily doses for 3 to 6 months, was also considered an essential part of the overall treatment strategy.

Viruela del mono y hombres que tienen sexo con hombres: la necesidad de tratarla con una perspectiva desestigmatizante / Monkeypox and men who have sex with men: we need to treat it with a destigmatizing perspective

La viruela del mono es una zoonosis, que se transmite por contacto estrecho, y que ha producido recientemente un gran broteepidémico en zonas no endémicas, calificado como Emergencia de Salud Pública de importancia internacional por la OrganizaciónMundial de la Salud (OMS). La respuesta tibia y tardía a nivel global, y el enfoque estigmatizante sobre los hombres que tienen sexocon hombres (los principales afectados) promovido por la opinión pública, algunos científicos, agentes sociopolíticos y medios decomunicación, podrían ser algunos de los motivos por los que aún no se ha contenido la epidemia. El estigma asociado a la enfer-medad produce daños severos en sus víctimas y dificulta las acciones dirigidas al control de la enfermedad, como ya ocurrió conel VIH. Para limitar el estigma y contener el brote, los científicos deben dirigir la difusión de información científicamente validada,educar a la población sobre prevención, sobre sintomatología, sobre cómo actuar en caso de sospecha y sobre la importancia de noestigmatizar. También se debe actuar sobre las víctimas del estigma para eliminar sus consecuencias y fomentar su autoeficacia. Lasintervenciones de salud deben realizarse con los actores políticos y sociales para integrar la evidencia en la normativa y procedimientos, así como para facilitar la acción de la Salud Pública. Asimismo, los expertos deben colaborar con los medios de comunicaciónpara facilitar una comunicación en salud adecuada y amonestar las malas prácticas. De igual forma, se debe mejorar la relaciónentre organizaciones y profesionales sanitarios e individuos estigmatizados para optimizar su acceso y retención en los sistemassanitarios. El objetivo del presente estudio fue hacer una revisión sobre la respuesta estigmatizante de algunos agentes políticos, demedios de comunicación y de la opinión social ante la epidemia de viruela del mono, exponer las graves consecuencias del estigma...AU)

Monkeypox is a zoonosis, which is transmitted by direct and close contact, and has recently produced a large epidemic outbreak innonendemic areas, classified as a Public Health Emergency of international concern by the World Health Organization. The globaldoubting and delayed response, and the stigmatizing approach to men who have sex with men promoted by public opinion, somescientists, sociopolitical agents, and the media, could be some of the reasons why the epidemic has not yet been contained. Thestigma around the disease produces severe injuries to its victims and obstructs actions aimed at controlling the disease, as occurredwith HIV in the past. To limit stigma and contain the outbreak, scientists should lead the diffusion of scientifically validated information, educate the population about prevention, symptoms, how to react in case of suspicion and the importance of not contributingto others’ stigmatization. Interventions must also be conducted on victims of stigma to counter act its consequences and encouragetheir selfefficacy. Public health interventions should be carried out in collaboration with political and social actors to integrateevidence into regulations and procedures and facilitate public health interventions. Experts should also work together with the mediato facilitate proper health communication and warn about bad practices. Similarly, the relationship between organizations and healthprofessionals and stigmatized individuals must be improved to optimize their access and retention in health systems. The objective ofthis study was to review the stigmatizing response of some political agents, the media and social opinion to the Monkeypox epidemic,to highlight the consequences of stigma on the patients and the control of the disease. And to establish a series of recommendationsto treat this situation effectively through a non-stigmatizing approach.(AU)

The management of Babesia, amoeba and other zoonotic diseases provoked by protozoa.

INTRODUCTION: There are 12 protozoan genera that provoke zoonotic disease in humans and animals. We discuss the most common ones with a highlight on Babesia spp and Entamoeba histolytica, also mentioning Toxoplasma gondii, Trypanosoma cruzi, and Leishmania spp. AREAS COVERED: The complex life cycle of pathogenic protozoans is deeply understood but this did not contribute to the discovery of new drugs. The clinical armamentarium is poor and includes antiinfectives originally proposed as antibacterial (azithromycin, clindamycin, paromomycin, sulfadrugs), antifungals (amphotericin B), or they are outdated compounds with poor efficacy and many side effects (nitroazoles, antimonials, etc.). Few patents and innovative ideas are available. EXPERT OPINION: Protozoan diseases are not restricted to tropical countries and are difficult or impossible to treat with currently available drugs, which are limited and restricted to a low number of clinical classes. The antiprotozoal drug targets are also limited, and this had deleterious effects on translational studies for designing efficient antiprotozoal drugs. There is a stringent need for innovative approaches to tackle these problems.

Hepatitis E virus and Zoonosis: Recent Advances and Therapeutic Implications.

Hepatitis E is viral hepatitis caused by infection with the hepatitis E virus (HEV). This article aims to review HEV disease and recent advances in the management of hepatitis E. We used PubMed Clinical Queries and keywords of "hepatitis E", "hepatitis E virus" AND "zoonosis" as the search engine. "Therapy", "Clinical Prediction Guides", "Diagnosis", "Etiology" and "Prognosis" were used as filters, and "Narrow" scope was used. The search was conducted in April 2022. The information retrieved from the above search was used in the compilation of the present article. Hepatitis E is viral hepatitis caused by infection with the hepatitis E virus (HEV). Hepatitis E has mainly a fecal-oral transmission route. Hepatitis E infection usually follows an acute and self-limiting course of illness with low death rates in resource-rich areas; however, it can be more severe in pregnant women and immunocompromised people. The mortality rates in these groups are substantially higher. A vaccine for HEV is available but is not universally approved. Ribavirin remains the most efficacious medication for the treatment of HEV but is contraindicated in pregnancy. Sofosbuvir and pegylated interferon, with or without ribavirin, have not been shown in the latest literature reviews to provide reliable additional benefits to the treatment of hepatitis. Sofosbuvir should not be used as monotherapy for HEV. Food is an important source of infection in many countries while rats are the primary vector in developing nations. Management must include an understanding of the rat habitats for this zoonotic disease. Hepatitis E remains an important cause of hepatitis and a zoonotic disease globally. Public health policies are key to containing this viral infectious disease, including policy in the transfusion of blood products.

Subcutaneous infection mouse model could be applied into real time monitoring the efficacy of anti-cystic echinococcosis drug in vivo.

Cystic echinococcosis (CE) is a zoonotic parasitic disease with a cosmopolitan distribution, and it is urgent to develop novel anti-helminthic agents. The intraperitoneal (ip) infection mice model was widely used to evaluate the efficacy of potential anti-CE compounds. Still, it's time-consuming, and the inability to achieve real-time monitoring hinders the development of potential anti-CE compounds. In this study, a CE mouse model was established by subcutaneous (sc) injection of protoscoleces of Echinococcus granulosus sensu stricto (E.granulosus s.s.) and used to assess the efficiency and efficacy of prospective anti-CE drugs. Compared to the ip infection CE mice model, the lesion volume of sc infection protoscoleces of E.granulosus s.s. (EgPSCs) could be measured by vernier caliper at week 6 post-infection. In contrast, the lesion volume of ip infection CE mice model was detected by ultrasound-assisted diagnosis at week 16 post-infection. Oral administration of albendazole (ABZ) could reduce cystic weight by 32.17% and 17.61%, the cystic number by 12.24% and 25.19%, and damage the ultrastructure of the cysts of E. granulosus s.s. in the sc and ip infection group, respectively. Furthermore, we found that the sc infection mice model could real-time monitor the lesion volume of E. granulosus s.s. during the ABZ and everolimus treatment. Therefore, we consider that the sc infection CE mice model is an assistant tool for screening and developing potential anti-CE compounds.

Brucellosis with rare complications and review of diagnostic tests: a case report.

BACKGROUND: Brucellosis is one of the most common zoonotic diseases in the world. Osteoarticular complications, especially vertebral system involvement, are most commonly reported. However, reports and coreports of pulmonary complications and thoracal spondylodiscitis and epidural abscess are rare. CASE PRESENTATION: Spondylodiscitis was detected at the T11-12 vertebral level, followed by epidural and paravertebral abscess, and then empyema was detected in a 17-year-old Asian female patient without any additional disease. The patient had used various antibiotics and the disease could not be proven bacteriologically. Also, the Rose Bengal test was negative. However, serologically high titer Brucella positivity was detected in the blood and pleural fluid sample. Drainage was required for bilateral empyema. Disease duration prolonged due to multiple complications. The patient was cured with combined long-term treatment for brucellosis. CONCLUSIONS: Although some are rare, brucellosis is a zoonotic disease that can cause many complications. The gold standard for diagnosis is the growth of bacteria in blood culture or tissue culture. However, isolation of the microorganism can be very difficult. Clinical suspicion and serological tests are important guides.

Tongue worm (subclass: Pentastomida) infection and treatment in two domesticated reptiles - A case report.

Tongue worms (Subclass: Pentastomida) are endoparasites found in carnivorous reptiles, fish, amphibians, birds, and mammals. Several pentastomids cause pentastomiasis, a zoonotic disease. We encountered tongue worm infection in two reptiles imported into Japan: a Wahlberg's velvet gecko (Homopholis wahlbergii) bred in Germany and a wild-caught green tree python (Morelia viridis) from the Republic of Indonesia. The infecting tongue worms were identified as Raillietiella sp. and Armillifer sp. in the gecko and python, respectively, based on morphological and molecular analyses. Gecko is a newly recorded definitive host harboring Raillietiella tongue worm. Live tongue worms were first detected in domestic reptiles in Japan, and this indicates a risk that these tongue worms could be spread to other animals, as well as humans. Therefore, the diagnosis and treatment of infected pets are of importance. In the case of the two infected reptiles, the availability of fecal egg examination for diagnosis was shown. In addition, the effectiveness of treatment with 200 µg/kg/day ivermectin orally once weekly was demonstrated, without no side-effects and no re-detection of eggs after the cessation of treatment.

The spread of cat-transmitted sporotrichosis due to Sporothrix brasiliensis in Brazil towards the Northeast region.

BACKGROUND: Sporotrichosis is a worldwide subcutaneous mycosis caused by Sporothrix spp. In the past, this infection was associated with armadillo hunting, horticulturists, miners, and gardeners, being considered an implantation mycosis acquired by plant debris injury. Nevertheless, since the late nineties, it has been considered a zoonotic disease in Brazil. Here we report a case series of 121 patients with cat-transmitted sporotrichosis seen in Northeast Brazil. METHODOLOGY/PRINCIPAL FINDINGS: Patient's demographic, clinical data, and length of treatment were recorded. In addition, a mycological examination and further PCR confirmation of species identification were performed. One hundred and twenty two patients were diagnosed with subcutaneous sporotrichosis from October 2016 to December 2019, while PCR revealed that 71 of them were due to S. brasiliensis. The majority of the individuals were female (n = 86; 70.5%). Patient's age ranged from 5 to 87 years old. The clinical forms found were lymphocutaneous (58.2%) and fixed cutaneous (39.4%). Interestingly, 115 patients reported previous contact with cats diagnosed with sporotrichosis. Patients were successfully treated with itraconazole and potassium iodide. CONCLUSIONS/SIGNIFICANCE: Our study adds important contributions for the investigation of the spread of cat-transmitted subcutaneous sporotrichosis in Brazil, specifically towards the Northeast region of a continental-size country. It will also help clinicians to be aware of the existence and importance to accurately diagnose sporotrichosis and treat patients with this infectious disease in the lowest income region of Brazil.

The kinetic profile of clinical and laboratory findings and treatment outcome of patients with toxocariasis.

OBJECTIVES: Human toxocariasis is a widespread zoonosis for which a chemotherapy decision and therapy effectiveness are difficult to determine. We aimed to investigate the kinetic profile of clinical and laboratory findings and treatment outcome of patients with toxocariasis in Vietnam. METHODS: The prospective study was conducted between October 2017 and June 2019. The diagnosis of toxocariasis was established based on clinical, laboratory (eosinophilia, raised IgE concentration) and serological (positive Toxocara IgG ELISA) evaluation as well as the exclusion of another helminthic co-infection. The patients were followed up after seven days, then one, three and six months after chemotherapy by thiabendazole. RESULTS: The study involved 80 patients with a mean age of 41.6 ± 15.2 years of whom 58.8% were female. At three and six months after chemotherapy, most patients demonstrated resolution of clinical signs and symptoms, eosinophil count and IgE concentration but not in the proportion of IgG seropositivity. Skin lesions and eosinophilia resolved earlier than the other symptoms (one month after treatment). About four-fifths of the patients were "cured" after three and six months of follow-up; 33.8% showed side effects to thiabendazole therapy but no severe events were reported. The most common adverse reaction was neurologic symptoms followed by gastrointestinal or skin manifestations which lasted as long as 4 days. CONCLUSIONS: In toxocariasis patients, cutaneous manifestations and eosinophilia resolve more rapidly than other clinical and laboratory findings while IgG titre has a very slow kinetic after therapy. Thiabendazole seems to be a potential alternative for the treatment of human toxocariasis.

In vitro antifungal susceptibility patterns of Trichophyton benhamiae complex isolates from diverse origin.

BACKGROUND: Species from the Trichophyton benhamiae complex are mostly zoophilic dermatophytes which cause inflammatory dermatophytosis in animals and humans worldwide. OBJECTIVES: This study was purposed to (a) to identify 169 reference and clinical dermatophyte strains from the T benhamiae complex species by molecular method and adhering to the newest taxonomy in the complex (b) to evaluate the in vitro antifungal susceptibility profile of these strains against eight common and new antifungal agents that may be used for the treatment of dermatophytosis. METHODS: All isolates, mainly originated from Europe but also from Iran, Japan and USA, were subjected to ITS-rDNA sequencing. The in vitro antifungal susceptibility profiles of eight common and new antifungal drugs against the isolates were determined by CLSI M38-A2 protocol and according to microdilution method. RESULTS: Based on the ITS-rDNA sequencing, T benhamiae was the dominant species (n = 102), followed by T europaeum (n = 29), T erinacei (n = 23), T japonicum (n = 10), Trichophyton sp (n = 4) and T eriotrephon (n = 1). MIC ranges across all isolates were as follows: luliconazole: 0.0002-0.002 µg/ml, terbinafine: 0.008-0.125 µg/ml, efinaconazole: 0.008-0.125 µg/ml, ciclopirox olamine: 0.03-0.5 µg/ml, itraconazole: 0.06-2 µg/ml, griseofulvin: 0.25-4 µg/ml, amorolfine hydrochloride: 0.125-4 µg/ml and tavaborole: 1-16 µg/ml. CONCLUSION: Luliconazole, efinaconazole and terbinafine were the most potent antifungals against T benhamiae complex isolates, regardless of the geographic locations where strains were isolated. These data might help dermatologists to develop effective therapies for successful treatment of infections due to T benhamiae complex species.

Pathogenicity and drug resistance of animal streptococci responsible for human infections.

Bacteria of the genus Streptococcus, earlier considered typically animal, currently have also been causing infections in humans. It is necessary to make clinicians aware of the emergence of new species that may cause the development of human diseases. There is an increasing frequency of isolation of streptococci such as S. suis, S. dysgalactiae, S. iniae and S. equi from people. Isolation of Streptococcus bovis/Streptococcus equinus complex bacteria has also been reported. The streptococcal species described in this review are gaining new properties and virulence factors by which they can thrive in new environments. It shows the potential of these bacteria to changes in the genome and the settlement of new hosts. Information is presented on clinical cases that concern streptococcus species belonging to the groups Bovis, Pyogenic and Suis. We also present the antibiotic resistance profiles of these bacteria. The emerging resistance to ß-lactams has been reported. In this review, the classification, clinical characteristics and antibiotic resistance of groups and species of streptococci considered as animal pathogens are summarized.

Effectiveness of doxycycline for the treatment of zoonotic cutaneous leishmaniasis in vivo.

There are available data on in vivo studies of monotherapy of zoonotic cutaneous leishmaniasis with some antibacterial drugs (doxycycline) and their comparison with meglumine antimoniate (glucantime). We used golden Syrian hamsters as a laboratory model. Experimental groups were formed, each of which was treated with one of the tested drugs. Infection of animals was carried out with Leishmania major promastigotes. We selected highly virulent strains of L. major culture isolated from human ulcers or rodents. Meglumine antimoniate monotherapy and doxycycline monotherapy are quite effective and do not differ by the 30th day of their use in such indicators as the average degree of local damage and the average number of Leishmania in the lesions. The main differences were recorded in terms of average body weight gain and average clinical recovery in favour of doxycycline. Leishmania in the lesion on the 60th day were completely absent in treatment with doxycycline. The experiment proved the effectiveness of doxycycline monotherapy: Leishmania in the lesions were absolutely absent by the end of the treatment.

Diagnosis of Streptococcus suis Meningoencephalitis with metagenomic next-generation sequencing of the cerebrospinal fluid: a case report with literature review.

BACKGROUND: Streptococcus suis meningoencephalitis is a zoonotic disease that mostly infects slaughterhouse workers. Rapid diagnosis of Streptococcus suis meningoencephalitis is critical for effective clinical management of this condition. However, the current diagnostic techniques are not effective for early diagnosis of this condition. To the best of our knowledge, the use of cerebrospinal fluid metagenomic next generation sequencing in the diagnosis of Streptococcus suis meningoencephalitis has been rarely reported. CASE PRESENTATION: Here, we report a case of Streptococcus suis meningoencephalitis in a 51-year-old female patient. The patient had a history of long-term contact with pork and had a three-centimeter-long wound on her left leg prior to disease onset. Conventional tests, including blood culture, gram staining and cerebrospinal fluid culture, did not reveal bacterial infection. However, Streptococcus suis was detected in cerebrospinal fluid using metagenomic next generation sequencing. CONCLUSIONS: Metagenomic next generation sequencing is a promising approach for early diagnosis of central nervous system infections. This case report indicates that cases of clinical meningeal encephalitis of unknown cause can be diagnosed through this method.

Where are we with understanding of COVID-19?

Coronavirus disease 2019 caused by SARS-CoV-2 originated from China and spread across every corner of the world. The scientific interest on COVID-19 increased after WHO declared it a pandemic in the early February of 2020. In fact, this pandemic has had a worldwide impact on economy, health, and lifestyle like no other in the last 100 years. SARS-CoV-2 belongs to Coronaviridae family and causes the deadliest clinical manifestations when compared to other viruses in the family. COVID-19 is an emerging zoonotic disease that has resulted in over 383,000 deaths around the world. Scientists are scrambling for ideas to develop treatment and prevention strategies to thwart the disease condition. In this review, we have attempted to summarize the latest information on the virus, disease, prevention, and treatment strategies. The future looks promising.