Valence-Change MnO2-Coated Arsenene Nanosheets as a Pin1 Inhibitor for Hepatocellular Carcinoma Treatment.

The heterogeneity of hepatocellular carcinoma (HCC) can prevent effective treatment, emphasizing the need for more effective therapies. Herein, we employed arsenene nanosheets coated with manganese dioxide and polyethylene glycol (AMPNs) for the degradation of Pin1, which is universally overexpressed in HCC. By employing an "AND gate", AMPNs exhibited responsiveness toward excessive glutathione and hydrogen peroxide within the tumor microenvironment, thereby selectively releasing AsxOy to mitigate potential side effects of As2O3. Notably, AMPNs induced the suppressing Pin1 expression while simultaneously upregulation PD-L1, thereby eliciting a robust antitumor immune response and enhancing the efficacy of anti-PD-1/anti-PD-L1 therapy. The combination of AMPNs and anti-PD-1 synergistically enhanced tumor suppression and effectively induced long-lasting immune memory. This approach did not reveal As2O3-associated toxicity, indicating that arsenene-based nanotherapeutic could be employed to amplify the response rate of anti-PD-1/anti-PD-L1 therapy to improve the clinical outcomes of HCC patients and potentially other solid tumors (e.g., breast cancer) that are refractory to anti-PD-1/anti-PD-L1 therapy.

Function of PML-RARA in Acute Promyelocytic Leukemia.

The transformation of acute promyelocytic leukemia (APL) from the most fatal to the most curable subtype of acute myeloid leukemia (AML), with long-term survival exceeding 90%, has represented one of the most exciting successes in hematology and in oncology. APL is a paradigm for oncoprotein-targeted cure.APL is caused by a 15/17 chromosomal translocation which generates the PML-RARA fusion protein and can be cured by the chemotherapy-free approach based on the combination of two therapies targeting PML-RARA: retinoic acid (RA) and arsenic. PML-RARA is the key driver of APL and acts by deregulating transcriptional control, particularly RAR targets involved in self-renewal or myeloid differentiation, also disrupting PML nuclear bodies. PML-RARA mainly acts as a modulator of the expression of specific target genes: genes whose regulatory elements recruit PML-RARA are not uniformly repressed but also may be upregulated or remain unchanged. RA and arsenic trioxide directly target PML-RARA-mediated transcriptional deregulation and protein stability, removing the differentiation block at promyelocytic stage and inducing clinical remission of APL patients.

Research on different compound combinations of Realgar-Indigo naturalis formula to reverse acute promyelocytic leukemia arsenic resistance by regulating autophagy through mTOR pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: In China, the Chinese patent drug Realgar-Indigo naturalis Formula (RIF) is utilized for the therapy of acute promyelocytic leukemia (APL). Comprising four traditional Chinese herb-Realgar, Indigo naturalis, Salvia miltiorrhiza, and Pseudostellaria heterophylla-it notably includes tetra-arsenic tetra-sulfide, indirubin, tanshinone IIa, and total saponins of Radix Pseudostellariae as its primary active components. Due to its arsenic content, RIF distinctly contributes to the therapy for APL. However, the challenge of arsenic resistance in APL patients complicates the clinical use of arsenic agents. Interestingly, RIF demonstrates a high remission rate in APL patients, suggesting that its efficacy is not significantly compromised by arsenic resistance. Yet, the current state of research on RIF's ability to reverse arsenic resistance remains unclear. AIM OF THE STUDY: To investigate the mechanism of different combinations of the compound of RIF in reversing arsenic resistance in APL. MATERIALS AND METHODS: The present study utilized the arsenic-resistant HL60-PMLA216V-RARα cell line to investigate the effects of various RIF compounds, namely tetra-arsenic tetra-sulfide (A), indirubin (I), tanshinone IIa (T), and total saponins of Radix Pseudostellariae (S). The assessment of cell viability, observation of cell morphology, and evaluation of cell apoptosis were performed. Furthermore, the mitochondrial membrane potential, changes in the levels of PMLA216V-RARα, apoptosis-related factors, and the PI3K/AKT/mTOR pathway were examined, along with autophagy in all experimental groups. Meanwhile, we observed the changes about autophagy after blocking the PI3K or mTOR pathway. RESULTS: Tanshinone IIa, indirubin and total saponins of Radix Pseudostellariae could enhance the effect of tetra-arsenic tetra-sulfide down-regulating PMLA216V-RARα, and the mechanism was suggested to be related to inhibiting mTOR pathway to activate autophagy. CONCLUSIONS: We illustrated that the synergistic effect of different compound combinations of RIF can regulate autophagy through the mTOR pathway, enhance cell apoptosis, and degrade arsenic-resistant PMLA216V-RARα.

Reinvent Aliphatic Arsenicals as Reversible Covalent Warheads toward Targeted Kinase Inhibition and Non-acute Promyelocytic Leukemia Cancer Treatment.

The success of arsenic in acute promyelocytic leukemia (APL) treatment is hardly transferred to non-APL cancers, mainly due to the low selectivity and weak binding affinity of traditional arsenicals to oncoproteins critical for cancer survival. We present herein the reinvention of aliphatic trivalent arsenicals (As) as reversible covalent warheads of As-based targeting inhibitors toward Bruton's tyrosine kinase (BTK). The effects of As warheads' valency, thiol protection, methylation, spacer length, and size on inhibitors' activity were studied. We found that, in contrast to the bulky and rigid aromatic As warhead, the flexible aliphatic As warheads were well compatible with the well-optimized guiding group to achieve nanomolar inhibition against BTK. The optimized As inhibitors effectively blocked the BTK-mediated oncogenic signaling pathway, leading to elevated antiproliferative activities toward lymphoma cells and xenograft tumor. Our study provides a promising strategy enabling rational design of new aliphatic arsenic-based reversible covalent inhibitors toward non-APL cancer treatment.

Mutations at proximal cysteine residues in PML impair ATO binding by destabilizing the RBCC domain.

Acute promyelocytic leukemia (APL) is characterized by the fusion gene promyelocytic leukemia-retinoic acid receptor-alpha (PML-RARA) and is conventionally treated with arsenic trioxide (ATO). ATO binds directly to the RING finger, B-box, coiled-coil (RBCC) domain of PML and initiates degradation of the fusion oncoprotein PML-RARA. However, the mutational hotspot at C212-S220 disrupts ATO binding, leading to drug resistance in APL. Therefore, structural consequences of these point mutations in PML that remain uncertain require comprehensive analysis. In this study, we investigated the structure-based ensemble properties of the promyelocytic leukemia-RING-B-box-coiled-coil (PML-RBCC) domains and ATO-resistant mutations. Oligomeric studies reveal that PML-RBCC wild-type and mutants C212R, S214L, A216T, L217F, and S220G predominantly form tetramers, whereas mutants C213R, A216V, L218P, and D219H tend to form dimers. The stability of the dimeric mutants was lower, exhibiting a melting temperature (Tm) reduction of 30 °C compared with the tetrameric mutants and wild-type PML protein. Furthermore, the exposed surface of the C213R mutation rendered it more prone to protease digestion than that of the C212R mutation. The spectroscopic analysis highlighted ATO-induced structural alterations in S214L, A216V, and D219H mutants, in contrast to C213R, L217F, and L218P mutations. Moreover, the computational analysis revealed that the ATO-resistant mutations C213R, A216V, L217F, and L218P caused changes in the size, shape, and flexibility of the PML-RBCC wild-type protein. The mutations C213R, A216V, L217F, and L218P destabilize the wild-type protein structure due to the adaptation of distinct conformational changes. In addition, these mutations disrupt several hydrogen bonds, including interactions involving C212, C213, and C215, which are essential for ATO binding. The local and global structural features induced by these mutations provide mechanistic insight into ATO resistance and APL pathogenesis.

Parasitological, Serological and Molecular Prevalence of Trypanosoma evansi among Arabian Camels (Camelus dromedaries) with Evaluation of Antitrypanosomal Drugs.

PURPOSE: This study was carried out to assess the prevalence of Trypanosoma evansi infection in naturally diseased Dromedary camels in Dammam, Eastern region of Saudi Arabia. The detection of Trypanosoma evansi was performed using the parasitological, serological, and molecular diagnosis and a comparison between such methods were analyzed. In addition, evaluation of therapeutic efficacy of selected antitrypanosomal drugs, cymelarsan and quinapyrmine (aquin-1.5), was trialed for treatment of diagnosed infected cases. METHODS: A total 350 randomly selected camels were evaluated using thin blood smear (TBS), RoTat1.2 PCR and CATT/T. evansi techniques. RESULTS: The total prevalence was 6.9%, 7.7%, and 32.8% by TBS, RoTat1.2 PCR and CATT/T. evansi techniques, respectively. Although PCR detect T. evansi in more samples than TBS, the agreement was good (K = 0.9). Among the CATT/T. evansi results, PCR detect T. evansi in 12 and 15 CATT positive and negative camels, respectively, with low agreement (Kappa = 0.1). The use of cymelarsan and quinapyramine sulfate in the treatment of naturally infected cases demonstrated a very efficient therapeutic response. CONCLUSION: It was found that 1. Comparing the CATT/T. evansi and PCR results, the positivity of CATT was higher than PCR detection, while the agreement was poor (K = 0.1). 2. Cymelarsan and aquin-1.5 proved to be effective in the treatment of naturally infected camels, but cymelarsan presented with higher effectiveness (100%) than aquin-treated camels (83.3%). a 3. The use of cymelarsan and CATT is recommended for disease treatment and control.

Harness arsenic in medicine: current status of arsenicals and recent advances in drug delivery.

INTRODUCTION: Arsenicals have a special place in the history of human health, acting both as poison and medicine. Having been used to treat a variety of diseases in the past, the success of arsenic trioxide (ATO) in treating acute promyelocytic leukemia (APL) in the last century marked its use as a drug in modern medicine. To expand their role against cancer, there have been clinical uses of arsenicals worldwide and progress in the development of drug delivery for various malignancies, especially solid tumors. AREAS COVERED: In this review, conducted on Google Scholar [1977-2024], we start with various forms of arsenicals, highlighting the well-known ATO. The mechanism of action of arsenicals in cancer therapy is then overviewed. A summary of the research progress in developing new delivery approaches (e.g. polymers, inorganic frameworks, and biomacromolecules) in recent years is provided, addressing the challenges and opportunities in treating various malignant tumors. EXPERT OPINION: Reducing toxicity and enhancing therapeutic efficacy are guidelines for designing and developing new arsenicals and drug delivery systems. They have shown potential in the fight against cancer and emerging pathogens. New technologies and strategies can help us harness the potency of arsenicals and make better products.

Arsenic sulfide enhances radiosensitivity in rhabdomyosarcoma via activating NFATc3-RAG1 mediated DNA double strand break (DSB).

Rhabdomyosarcoma (RMS) represents one of the most lethal soft-tissue sarcomas in children. The toxic trace element arsenic has been reported to function as a radiosensitizer in sarcomas. To investigate the role of arsenic sulfide (As4S4) in enhancing radiation sensitization in RMS, this study was conducted to elucidate its underlying mechanism in radiotherapy. The combination of As4S4 and radiotherapy showed significant inhibition in RMS cells, as demonstrated by the cell counting kit-8 (CCK-8) assay and flow cytometry. Subsequently, we demonstrated for the first time that As4S4, as well as the knockdown of NFATc3 led to double-strand break (DSB) through increased expression of RAG1. In vivo experiment confirmed that co-treatment efficiently inhibited RMS growth. Furthermore, survival analysis of a clinical cohort consisting of 59 patients revealed a correlation between NFATc3 and RAG1 expression and overall survival (OS). Cox regression analysis also confirmed the independent prognostic significance of NFATc3 and RAG1.Taken together, As4S4 enhances radiosensitivity in RMS via activating NFATc3-RAG1 mediated DSB. NFATc3 and RAG1 are potential therapeutic targets. As4S4 will hopefully serve as a prospective radio-sensitizing agent for RMS.

Historia del tratamiento de la Sífilis / The history of Syphilis´ treatment

El nombre sífilis proviene del griego siph: cerdo y philus: amor. Recuerda al personaje de una obra, llamado Syphilo, que fue castigado por los dioses a sufrir una terrible enfermedad. Se analizan los datos sobre la sífilis en la antigüedad (que difieren según su fuente). Su mención en la Edad Media, su controversial origen, la ayuda de los paleopatólogos para encontrarlo. Luego de la Revolución Francesa y el inicio de la Edad Contemporánea, el porcentaje de enfermos fue creciendo y se acentuó la segregación de los mismos por la sociedad. Desde el año 1500 hasta principios del siglo XX el tratamiento de la sífilis dependía del mercurio. Tenía una gran variedad de formas de aplicación. La vía tópica: el ungüento gris, en calomelano o tabletas, en inyecciones, en fricciones y fumigaciones en donde el mercurio se introducía en el cuerpo por lo pulmones. Se adjudicó a la madera del guayaco pretendidas características curativas, que no poseía. Los ioduros se utilizaron para el terciarismo. Ehrlich en 1907, patentó el compuesto 606 o Salvarsan y en 1910, el Neo-Salvarsan o Arsfenamina (compuesto 914). Por estos descubrimientos recibió el Premio Nobel. En 1887, Julios Wagner Jauregg sugirió que la fiebre terapéuticamente inducida era útil en el tratamiento de enfermos psicóticos. En 1912 publicó sus satisfactorios resultados al tratar la paresias con una combinación de mercurio-iodo y tuberculina de Koch. En 1917 ingresó a su servicio un enfermo de malaria, con cuya sangre escarificaron la piel palúdica de tres paréticos, en lugar de darle inmediatamente quinina. Por ello fue galardona con el Premio Nobel. Se utilizó luego el bismuto, a partir de 1922, pero posteriormente fue sustituido por las sulfamidas, de aplicación dificultosa. El avance terapéutico más importante ocurrió en 1943, año en que se comenzó a utilizar la penicilina por Mahoney y colaboradores. Luego se confirmó la eficacia de la tetraciclina para los alérgicos a la penicilina. Últimamente se confirmó la eficacia de la azitromicina en dosis de 500mg cada día, durante los 10 días o el régimen de 500mg en días alternos.

The name Syphilis comes from greek language: Siph: Pig and Philus: Love, meaning, in honor of the Sheppard of a story where the Character, Named Syphilo, is punished by the gods to suffer a terrible disease. Data about Syphilis was analized in ancient times (which differ according to the source). Its mention in the middle age, its controversial origin, the help provided from paleopathologists to find it. When the French revolution and the beginning of the contemporary age began, the percentage of sick people grew. The segregation of these is proved by the society. From the year 1500 to the beginnings of the XX century, the treatment of Syphilis depended on mercury. There were a great variety of application methods: topical: the grey ointment, in «calomelanos or tabs¼, in injections, in frictions and fumigations where the mercury was introduced in the body by the lungs. Guayacos wood was named with curative features which it did not posses. The iodides were used for tertiary syphilis. In 1907, Ehrlich formulates the 606 compound or Salvarsan and in 1910 the Neo-Salvarsan or Arsfenamina or compound 914.Due to these discoveries he received the nobel prize. In 1887, Julius Wagner of Jauregg suggested that: the inducted therapeutic fiber was useful in the treatment of the psychosis. In 1912 he published his satisfactory results in treating the paresis with a combination of mercury and iodides and tuberculin of Koch. In 1917 he treated a patient who had malaria and instead of giving him immediately quinine, he made a scarification with his paludic blood the skin of 3 paretic patients. Because of this he was awarded with the nobel prize. Since 1922 bismuth was used, but then it was substituted by the sulphamidas of difficult application. The most important therapeutical advance happened in 1943, year in which penicillin was put in use by Mahoney and col. Later it was confirmed the efficiency of the tetracycline for the penicillin-allergic patients. Lately it has been confirmed the efficiency of the azithromizine in 500 mg dosis each day during 10 days or the regimen of 500 mg in alternate days.

Eosinofilia pulmonar tropical filariotica e o seu diagnostico diferencial / Tropical pulmonary eosinophilia its differential diagnosis

Os autores fazem uma ampla revisao sobre a eosinofilia pulmonar tropical (EPT) de origem filarial e o seu diagnostico diferencial com relacao a outras sindromes afins. Abordaram os aspectos epidemiologicos, clinicos, diagnosticos, terapeuticos e fisiopatogenicos, enfatizando os novos avancos ocorridos no conhecimento da doenca filarial e sua repercussao para um melhor entendimento da EPT. Tambem destacaram a ocorrencia de uma forma denominada EPT-LIKE, causada por helmintos intestinais, de dificil diagnostico diferencial com relacao a EPT e que pode ocorrer tambem em areas nao endemicas de filariose. No final do artigo, os autores sugerem um roteiro para a interpretacao dos dados epidemiologicos, clinicos, laboratoriais, radiologicos (e ultra-sonograficos) e terapeuticos na orientacao para a suspeicao diagnostica do paciente portador de EPT...