Mechanisms involved in the antidepressant-like action of orally administered 5-((4-methoxyphenyl)thio)benzo[c][1,2,5]thiadiazole (MTDZ) in male and female mice.

RATIONALE: The compound 5-((4-methoxyphenyl)thio)benzo[c][1,2,5]thiadiazole (MTDZ) has recently been shown to inhibit in vitro acetylcholinesterase activity, reduce cognitive damage, and improve neuropsychic behavior in mice, making it a promising molecule to treat depression. OBJECTIVES: This study investigated the antidepressant-like action of MTDZ in mice and its potential mechanisms of action. RESULTS: Molecular docking assays were performed and suggested a potential inhibition of monoamine oxidase A (MAO-A) by MTDZ. The toxicity study revealed that MTDZ displayed no signs of toxicity, changes in oxidative parameters, or alterations to biochemistry markers, even at a high dose of 300 mg/kg. In behavioral tests, MTDZ administration reduced immobility behavior during the forced swim test (FST) without adjusting the climbing parameter, suggesting it has an antidepressant effect. The antidepressant-like action of MTDZ was negated with the administration of 5-HT1A, 5-HT1A/1B, and 5-HT3 receptor antagonists, implying the involvement of serotonergic pathways. Moreover, the antidepressant-like action of MTDZ was linked to the NO system, as L-arginine pretreatment inhibited its activity. The ex vivo assays indicated that MTDZ normalized ATPase activity, potentially linking this behavior to its antidepressant-like action. MTDZ treatment restricted MAO-A activity in the cerebral cortices and hippocampi of mice, proposing a selective inhibition of MAO-A associated with the antidepressant-like effect of the compound. CONCLUSIONS: These findings suggest that MTDZ may serve as a promising antidepressant agent due to its selective inhibition of MAO-A and the involvement of serotonergic and NO pathways.

May-Thurner Syndrome: The Worst-Case Scenario.

May-Thurner syndrome (MTS) is caused by compression of the left common iliac vein by the right common iliac artery against the spinal column. It can range from asymptomatic or present with subtle and unspecific signs and symptoms and rarely exhibit severe complications such as pulmonary embolism (PE). The diagnosis is confirmed by typical imaging findings. Treatment may include conservative measures, anticoagulation, endovascular or even surgical options. We report the case of a 20-year-old female who presented with cardiac arrest caused by an acute massive PE. Further study showed partial thrombosis of the internal iliac veins resulting from MTS. She continued anticoagulation therapy with low-molecular-weight heparin and then switched to edoxaban with a good clinical outcome. She was also referred to Vascular Surgery to discuss the possibility of iliac vein stenting. Abdominopelvic vascular compression syndromes include a large spectrum of conditions, and they are rarely considered as an etiology for venous thromboembolism. The clinical presentation of PE varies with several triggering factors and atypical presentation is more common in nonmalignant causes. The combination of noninvasive and invasive imaging modalities might be beneficial to establish a definitive diagnosis. Nevertheless, invasive procedures are often restricted to doubtful cases or to guide endovascular procedures which is the current treatment of choice. There is little evidence using nonvitamin K oral anticoagulants, but there are some case reports detailing their successful use. This case aims to point out the need for a profound understanding of different causes of deep vein and pulmonary thromboembolism; common entities in our practice but with a variety of clinical presentations and potentially caused by rare underlying conditions. MTS can be the origin of serious and deadly complications, hence the importance of early recognition and treatment.

The Antinociceptive Responses of MTDZ to Paclitaxel-Induced Peripheral Neuropathy and Acute Nociception in Mice: Behavioral, Pharmacological, and Biochemical Approaches.

The efficacy of 5-((4-methoxyphenyl)thio)benzo[c][1,2,5] thiodiazole (MTDZ) in mitigating paclitaxel (PTX)-induced peripheral neuropathy was investigated in male and female Swiss mice. The study examined the effects of MTDZ on various pathways, including transient receptor potential cation channel subfamily V member 1 (TRPV1), glutamatergic, nitrergic, guanylate cyclase (cGMP), serotonergic, and opioidergic. Mice received intraperitoneal PTX (2 mg/kg) or vehicle on days 1, 2, and 3, followed by oral MTDZ (1 mg/kg) or vehicle from days 3 to 14. Mechanical and thermal sensitivities were assessed using Von Frey and hot plate tests on days 8, 11, and 14. The open field test evaluated locomotion and exploration on day 12. On day 15, nitrite and nitrate (NOx) levels and Ca2+-ATPase activity in the cerebral cortex and spinal cord were measured after euthanizing the animals. MTDZ administration reversed the heightened mechanical and thermal sensitivities induced by PTX in male and female mice without affecting locomotion or exploration. MTDZ also modulated multiple pathways, including glutamatergic, NO/L-arginine/cGMP, serotonergic (5-HT1A/1B), opioid, and TRPV1 pathways. Additionally, MTDZ reduced NOx levels and modulated Ca2+-ATPase activity. In conclusion, MTDZ effectively alleviated PTX-induced peripheral neuropathy and demonstrated multi-targeted modulation of pain-related pathways. Its ability to modulate multiple pathways, reduce NOx levels, and modulate Ca2+-ATPase activity makes it a potential pharmacological candidate for peripheral neuropathy, acute nociceptive, and inflammatory conditions. Further research is needed to explore its therapeutic potential in these areas.

Bioactivity of aqueous extract of Jacaranda spp. (Bignoniaceae) on Plutella xylostella L. 1758 (Lepidoptera: Plutellidae).

The high consumption rate of vegetables stimulates the cultivation and increases the demand regarding the adequacy of the production processes. The attack of the pest Plutella xylostella causes high losses by reducing product quality, typifying a phytosanitary problem. This study aimed to verify the bioactivity of aqueous extracts of leaves of Jacaranda decurrens and Jacaranda mimosifolia at concentrations of 5, 10, and 15% on the insect. The choice test was carried out at the laboratory to determine the food effect of plant extracts and evaluate changes in the life cycle of insects exposed to active compounds through the analysis of biological parameters. Plant extracts of J. decurrens and J. mimosifolia presented with phagodeterrent classification in the choice experiments. The three J. decurrens extract concentrations promoted a prolongation of larval and pupal duration, while the duration of individuals treated with J. mimosifolia at 10% was significantly reduced. Occurred reduction in larval survival of individuals treated with aqueous extracts of J. decurrens and J. mimosifolia. Eggs from treatments with aqueous extract of J. decurrens and J. mimosifolia had reduced survival. Pupal survival of individuals treated with extract at 15% showed a significant reduction compared to the treatments at 5% and 10%. Pupae from the treatment with aqueous extract of Jacaranda mimosifolia showed a reduction in biomass in the treatment at 15% differing from the control e 5%. Thus, the aqueous extracts of the species J. decurrens and J. mimosifolia show insecticidal potential in the tests performed on P. xylostella.

Gastric MALT Lymphoma: A 8-Year Experience.

Gastric mucosa-associated lymphoid tissue non-Hodgkin lymphoma (gMALT NHL) is the second most common gastrointestinal lymphoma (50% of all gastric lymphomas), being closely associated with Helicobacter pylori infection, justifying that antibiotic therapy is effective in over 75% of all cases. This is a retrospective study analyzing all adult gMALT NHL cases diagnosed and treated in a single center for 8 years, focusing on demographic features, treatment outcomes, and survival analysis. Sixty patients with a median age of 61 years (53.3% female gender) were analyzed. Most of the cases had localized disease (66.7% were Lugano stage I) and had low IPI scores (median: 1). There was a high prevalence of Helicobacter pylori infection (68.3%). Nearly 97% of the cases received treatment for the disease, a median of one line; 55% of the patients treated endured complete response after first-line therapy (mostly antibiotics). Median overall survival time and median progression-free survival time were not reached. The mean follow-up time was 81.8 months (95% CI: [73.3-90.3]). Thirty-six patients (60%) achieved a 3-year follow-up time; the mortality rate was 15% at the end of the study. Age superior to 65 years and transformation into DLBCL were statistically significant negative prognostic markers for survival in this study (p = 0.006 and p = 0.033, respectively). Our study confirms that gMALT NHL is an indolent disease with long-term survival. Many patients, however, are exposed to several treatment lines along their disease course.

Spondias purpurea L. Bark Extract Protects against Oxidative Stress and Reduces Hypercholesterolemia in Mice Fed High-Fat Diet.

Oxidative stress plays a key role in the initiation and progression of metabolic diseases, including obesity. Preventing the accumulation of reactive oxygen species and oxidative damage to macromolecules is a beneficial strategy for reducing comorbidities associated with obesity. Fruits from the Spondias genus are known for their antioxidant activity, but they are not available year-round due to their seasonality. In this context, we investigated the antioxidant activity and identified the chemical constituents of the aqueous extract of the stem bark of Spondias purpurea L. (EBSp). Additionally, we evaluated the effect of EBSp consumption on metabolic parameters in mice with obesity induced by a high-fat diet. Chemical analyses revealed 19 annotated compounds from EBSp, including flavan-3-ols, proanthocyanidins, methoxylated coumarin, and gallic and ellagic acids, besides other phenolic compounds. In vitro, EBSp showed antioxidant activity through the scavenging of the free radicals and the protection of macromolecules against oxidative damage. Cellular assays revealed that EBSp reduced the levels of malondialdehyde produced by erythrocytes exposed to the oxidizing agent AAPH. Flow cytometry studies showed that EBSp reduced reactive oxygen species levels in human peripheral blood mononuclear cells treated with hydrogen peroxide. Obese mice treated with EBSp (400 mg.kg-1) for 60 days showed reduced levels of malondialdehyde in the heart, liver, kidneys, and nervous system. The total cholesterol levels in mice treated with EBSp reached levels similar to those after treatment with the drug simvastatin. Together, the results show that the combination of the different phenolic compounds in S. purpurea L. bark promotes antioxidant effects in vitro and in vivo, resulting in cytoprotection in the context of oxidative stress associated with obesity and a reduction in hypercholesterolemia. From a clinical perspective, the reduction in oxidative stress in obese individuals contributes to the reduction in the emergence of comorbidities associated with this metabolic syndrome.

A new arylsulfanyl-benzo-2,1,3-thiadiazoles derivative produces an anti-amnesic effect in mice by modulating acetylcholinesterase activity.

The aim of the present study was investigate the binding affinity of 5-((4-methoxyphenyl)thio)benzo[c][1,2,5]thiadiazole (MTDZ) with acetylcholinesterase (AChE). We also evaluated the effect of MTDZ against scopolamine (SCO)-induced amnesia in mice and we looked at the toxicological potential of this compound in mice. The binding affinity of MTDZ with AChE was investigated by molecular docking analyses. For an experimental model, male Swiss mice were treated daily with MTDZ (10 mg/kg, intragastrically (i.g.)) or canola oil (10 ml/kg, i.g.), and induced, 30 min later, with injection of SCO (0.4 mg/kg, intraperitoneally (i.p.)) or saline (0.9%, 5 ml/kg, i.p.) daily. From day 1 to day 10, mice were submitted to the behavioral tasks (Barnes maze, open-field, object recognition and location, Y-maze and step-down inhibitory avoidance tasks), 30 min after induction with SCO. On the tenth day, the animals were euthanized and blood was collected for the analysis of biochemical markers (creatinine, aspartate (AST), and alanine (ALT) aminotransferase). MTDZ interacts with residues of the AChE active site. SCO caused amnesia in mice by changing behavioral tasks. MTDZ treatment attenuated the behavioral changes caused by SCO. In ex vivo assay, MTDZ also protected against the alteration of AChE activity, reactive species (RS) levels, thiobarbituric acid reative species (TBARS) levels, catalase (CAT) activity in tissues, as well as in transaminase activities of plasma caused by SCO in mice. In conclusion, MTDZ presented anti-amnesic action through modulation of the cholinergic system and provided protection from kidney and liver damage caused by SCO.

Target enzymes in oxaliplatin-induced peripheral neuropathy in Swiss mice: A new acetylcholinesterase inhibitor as therapeutic strategy.

In the present study it was hypothesized that 5-((4-methoxyphenyl)thio)benzo[c][1,2,5] thiodiazole (MTDZ), a new acetylcholinesterase inhibitor, exerts antinociceptive action and reduces the oxaliplatin (OXA)-induced peripheral neuropathy and its comorbidities (anxiety and cognitive deficits). Indeed, the acute antinociceptive activity of MTDZ (1 and 10 mg/kg; per oral route) was observed for the first time in male Swiss mice in formalin and hot plate tests and on mechanical withdrawal threshold induced by Complete Freund's Adjuvant (CFA). To evaluate the MTDZ effect on OXA-induced peripheral neuropathy and its comorbidities, male and female Swiss mice received OXA (10 mg/kg) or vehicle intraperitoneally, on days 0 and 2 of the experimental protocol. Oral administration of MTDZ (1 mg/kg) or vehicle was performed on days 2-14. OXA caused cognitive impairment, anxious-like behaviour, mechanical and thermal hypersensitivity in animals, with females more susceptible to thermal sensitivity. MTDZ reversed the hypersensitivity, cognitive impairment and anxious-like behaviour induced by OXA. Here, the negative correlation between the paw withdrawal threshold caused by OXA and acetylcholinesterase (AChE) activity was demonstrated in the cortex, hippocampus, and spinal cord. OXA inhibited the activity of total ATPase, Na+ K+ - ATPase, Ca2+ - ATPase and altered Mg2+ - ATPase in the cortex, hippocampus, and spinal cord. OXA exposure increased reactive species (RS) levels and superoxide dismutase (SOD) activity in the cortex, hippocampus, and spinal cord. MTDZ modulated ion pumps and reduced the oxidative stress induced by OXA. In conclusion, MTDZ is an antinociceptive molecule promising to treat OXA-induced neurotoxicity since it reduced nociceptive and anxious-like behaviours, and cognitive deficit in male and female mice.

Schiff bases complexed with iron and their relation with the life cycle and infection by Schistosoma mansoni.

Introduction: The trematode Schistosoma mansoni causes schistosomiasis, and this parasite's life cycle depends on the mollusk Biomphalaria glabrata. The most effective treatment for infected people is administering a single dose of Praziquantel. However, there are naturally resistant to treatment. This work has developed, considering this parasite's complex life cycle. Methods: The synthetics compound were evaluated: i) during the infection of B. glabrata, ii) during the infection of BALB/c mice, and iii) during the treatment of mice infected with S. mansoni. Results and Discussion: For the first objective, snails infected with miracidia treated with compounds C1 and C3 at concentrations of 25% IC50 and 50% IC50, after 80 days of infection, released fewer cercariae than the infected group without treatment. For the second objective, compounds C1 and C3 did not show significant results in the infected group without treatment. For the third objective, the mice treated with C3 and C1 reduced the global and differential cell count. The results suggest that although the evaluated compounds do not present schistosomicidal properties when placed in cercariae suspension, they can stimulate an immune reaction in snails and decrease mice's inflammatory response. In general, we can conclude that compound C1 and C3 has an anti-schistosomicidal effect both in the larval phase (miracidia) and in the adult form of the parasite.

IgA nephropathy in IgG kappa multiple myeloma.

Multiple myeloma (MM) frequently affects kidney function through multiple mechanisms. Nonetheless, some patients develop kidney injury due to other causes. A 54-year-old woman was diagnosed with IgG kappa MM developed IgA nephropathy without cast nephropathy. Further studies did not show criteria for MM progression or other causes. This case highlights the need for further investigation of kidney injury in MM patients (such as toxicity of previous drugs, infectious events, or immune-mediated disorders).

Stingless Bee Propolis: New Insights for Anticancer Drugs.

Natural products are important sources of biomolecules possessing antitumor activity and can be used as anticancer drug prototypes. The rich biodiversity of tropical and subtropical regions of the world provides considerable bioprospecting potential, including the potential of propolis produced by stingless bee species. Investigations of the potential of these products are extremely important, not only for providing a scientific basis for their use as adjuvants for existing drug therapies but also as a source of new and potent anticancer drugs. In this context, this article organizes the main studies describing the anticancer potential of propolis from different species of stingless bees with an emphasis on the chemical compounds, mechanisms of action, and cell death profiles. These mechanisms include apoptotic events; modulation of BAX, BAD, BCL2-L1 (BCL-2 like 1), and BCL-2; depolarization of the mitochondrial membrane; increased caspase-3 activity; poly (ADP-ribose) polymerase (PARP) cleavage; and cell death induction by necroptosis via receptor interacting protein kinase 1 (RIPK1) activation. Additionally, the correlation between compounds with antioxidant and anti-inflammatory potential is demonstrated that help in the prevention of cancer development. In summary, we highlight the important antitumor potential of propolis from stingless bees, but further preclinical and clinical trials are needed to explore the selectivity, efficacy, and safety of propolis.

Cerebral Venous Thrombosis and Its Clinical Diversity.

Cerebral venous thrombosis (CVT) is a serious medical condition which is difficult to diagnose because of its wide range of clinical presentations. The symptoms can vary from an isolated headache to coma. Here, we present the case of a 76-year-old female patient with a history of immune thrombocytopenic purpura, arterial hypertension, and pulmonary embolism. The diagnosis of CVT was challenging because the initial form of disease presentation mimicked a transient ischemic attack (transient aphasia and right hemiparesis). Therapeutical decisions were also a challenge because, at the time of the diagnosis, the patient was suffering from severe thrombocytopenia (29 × 109/L), which had to be taken into account. After multidisciplinary discussions, therapeutic subcutaneous enoxaparin was started, resulting in a progressive and significant neurological recovery. In presenting this case, our primary goal is to point out that CVT can be difficult to diagnose because of its wide range of clinical presentations. Headache (a symptom that was never present in this case) is the most frequent complaint, occurring in 90% of cases. Following diagnosis, an etiological study is required.

Disseminated Saprochaete capitata fungal infection in a patient with acute myeloid leukemia.

The case highlights the importance of actively obtaining informative samples at an early stage and of prompt initiation of combination therapy with antifungal drugs.

Gastric Diffuse Large B-Cell Lymphoma: A Single-Center 9-Year Experience.

Gastric diffuse large B cell lymphoma (DLBCL) represents the majority of all gastric lymphomas. We report a series of gastric DLBCL diagnosed and treated in a single center, between 2010 and 2018 (included). We retrospectively analyzed the population demographic features, treatment outcomes and survival. One-hundred-and-one patients were studied, 50.5% males and median age of 64 years [23-94]. Lugano staging was I in 16.8%, II1 in 20.8%, II2 in 10.9%, IIE in 13.9% and IV in 34.7% of cases. Twenty percent had Helicobacter pylori infection. R-CHOP-like therapy was used as first line in 96.9% of the patients. A complete response was achieved in 80% after first line therapy. At 3-years of follow-up (FU), 54% were in complete remission. The mean FU time was 73.6 months. Median overall survival and median progression free survival were not reached. We identified seven factors with negative impact in survival: age above 65 years-old (p < 0.01), ECOG 2-3 (p < 0.01), B symptoms (p = 0.001), bulky disease (p = 0.003), IPI 3-4 (p = 0.001), more than 3 treatment lines (p < 0.01), absence of response to first line treatment (p < 0.01). This study demonstrates that gastric DLBCL is a potentially curable disease with R-CHOP-like therapy, entailing long term survival and comparing well with other published series.

Case Report: Cryptococcal meningitis in Hodgkin's Lymphoma patient receiving brentuximab-vedotin therapy.

Cryptococcus neoformans infections occur mostly in immunodeficient individuals, being the most common opportunistic fungi central nervous system (CNS) infection in HIV seropositive patients. Moreover, other conditions affecting host immunity, such as hematologic malignancies, organ transplantation and immunosuppressive drugs are implicated as risk factors. The authors present a case of a 48-year-old male with Hodgkin Lymphoma for 26 years and submitted to several lines of treatment, diagnosed with cryptococcal meningitis while on therapy with brentuximab. The patient presented with positive cerebral spinal fluid (CSF) cryptococcal antigen plus positive blood cultures. He was put under induction antifungal treatment with liposomal amphotericin B and flucytosine, as well as corticotherapy with dexamethasone with headache improvement and a favorable clinical evolution. There are no reported cases of cryptococcal meningoencephalitis under CD30-directed monoclonal antibody. Furthermore, this case illustrates the risk of Cryptococcus neoformans infection in immunocompromising conditions other than HIV, underlining the need of considering this differential diagnosis when physicians face an opportunist neuroinfection.

Synthesis and biological activities of a nitro-shiff base compound as a potential anti-inflammatory agent.

In order to discover a new compound having anti-inflammatory activity, a nitro-Schiff base was evaluated. The compound was synthesized and characterized by 1H NMR and 13C NMR. The cytotoxic activity was evaluated in vitro by hemolysis and MTT cell viability assay. To evaluate genotoxicity, the micronucleus assay was performed in vivo. The anti-inflammatory effects of the compound were examined using in vivo models of inflammation such as neutrophil migration assay, paw edema, and exudation assay. The production of NO was also estimated in vivo and in vitro. The data showed that the compound did not induce hemolysis at all the tested concentrations. Similarly, the compound did not induce cytotoxicity and genotoxicity to the cells. The neutrophil migration assay showed that the compound reduced the number of neutrophils recruited to the peritoneal cavity by approximately 60% at all the tested concentrations. In the exudation assay, the compound showed a reduction in extravasation by 24%. The paw edema model demonstrated a significant reduction in the paw volume at all the evaluated time points. The production of NO was decreased both in vitro and in vivo. These results suggest that the nitro-Schiff base compound efficiently inhibited inflammation and might be a good candidate for the treatment of inflammatory-associated conditions.

Review of the Syntheses and Activities of Some Sulfur-Containing Drugs.

BACKGROUND: Sulfur-containing compounds represent an important class of chemical compounds due to their wide range of biological and pharmaceutical properties. Moreover, sulfur-containing compounds may be applied in other fields, such as biological, organic, and materials chemistry. Several studies on the activities of sulfur compounds have already proven their anti-inflammatory properties and use to treat diseases, such as Alzheimer's, Parkinson's, and HIV. Moreover, examples of sulfur-containing compounds include dapsone, quetiapine, penicillin, probucol, and nelfinavir, which are important drugs with known activities. OBJECTIVE: This review will focus on the synthesis and application of some sulfur-containing compounds used to treat several diseases, as well as promising new drug candidates. CONCLUSION: Due to the variety of compounds containing C-S bonds, we have reviewed the different synthetic routes used toward the synthesis of sulfur-containing drugs and other compounds.

Myeloid Disease with the CSF3R T618I Mutation after CLL.

Chronic lymphocytic leukemia (CLL) is frequently an indolent diagnosis, with most of the patients being under surveillance for long time. There is an increased risk of a second neoplasia in CLL, rarely hematological (in the myeloid lineage is even rarer). A 58-year-old male was diagnosed with CLL in 2012, remaining in regular surveillance until 2014. Then, the CLL progressed, and 6 cycles of rituximab, fludarabine, and cyclophosphamide were prescribed with partial response. He remained in surveillance and suffered 2 episodes of autoimmune hemolytic anemia until 2019. Then, the hemolytic anemia relapsed and a neutrophilia became evident (progressing slowly), as well as a thrombocytopenia and splenomegaly without adenopathy were found. The bone marrow aspirate showed a chronic myeloproliferative disease without dysplasia. A peripheral blood search for the CSF3R mutation (T618I) was positive, also suggesting Chronic Neutrophilic Leukemia (CNL). For a discrete monocytosis, a chronic myelomonocytic leukemia (CMML) was also considered. Hydroxyurea was then prescribed. The T618I CSF3R mutation is highly suggestive of CNL (being diagnostic criteria for CNL); however, this case may also suggest CMML as a possible diagnosis (there are other mutations in the CSF3R gene described for CMML, but not the T618I, which is highly exclusive of CNL according to the literature). To our knowledge, this is the first report of a possible CNL in a CLL patient (the opposite was already described in 1998).