Potential molecular patterns for tuberculosis susceptibility in diabetic patients with poor glycaemic control: a pilot study.

Type 2 diabetes (DM2) is an increasingly prevalent disease that challenges tuberculosis (TB) control strategies worldwide. It is significant that DM2 patients with poor glycemic control (PDM2) are prone to developing tuberculosis. Furthermore, elucidating the molecular mechanisms that govern this susceptibility is imperative to address this problem. Therefore, a pilot transcriptomic study was performed. Human blood samples from healthy controls (CTRL, HbA1c < 6.5%), tuberculosis (TB), comorbidity TB-DM2, DM2 (HbA1c 6.5-8.9%), and PDM2 (HbA1c > 10%) groups (n = 4 each) were analyzed by differential expression using microarrays. We use a network strategy to identify potential molecular patterns linking the differentially expressed genes (DEGs) specific for TB-DM2 and PDM2 (p-value < 0.05, fold change > 2). We define OSM, PRKCD, and SOCS3 as key regulatory genes (KRGs) that modulate the immune system and related pathways. RT-qPCR assays confirmed upregulation of OSM, PRKCD, and SOCS3 genes (p < 0.05) in TB-DM2 patients (n = 18) compared to CTRL, DM2, PDM2, or TB groups (n = 17, 19, 15, and 9, respectively). Furthermore, OSM, PRKCD, and SOCS3 were associated with PDM2 susceptibility pathways toward TB-DM2 and formed a putative protein-protein interaction confirmed in STRING. Our results reveal potential molecular patterns where OSM, PRKCD, and SOCS3 are KRGs underlying the compromised immune response and susceptibility of patients with PDM2 to develop tuberculosis. Therefore, this work paved the way for fundamental research of new molecular targets in TB-DM2. Addressing their cellular implications, and the impact on the diagnosis, treatment, and clinical management of TB-DM2 could help improve the strategy to end tuberculosis for this vulnerable population.

Ligand- and Structure-Based Virtual Screening Identifies New Inhibitors of the Interaction of the SARS-CoV-2 Spike Protein with the ACE2 Host Receptor.

The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a fast-spreading viral pathogen and poses a serious threat to human health. New SARS-CoV-2 variants have been arising worldwide; therefore, is necessary to explore more therapeutic options. The interaction of the viral spike (S) protein with the angiotensin-converting enzyme 2 (ACE2) host receptor is an attractive drug target to prevent the infection via the inhibition of virus cell entry. In this study, Ligand- and Structure-Based Virtual Screening (LBVS and SBVS) was performed to propose potential inhibitors capable of blocking the S receptor-binding domain (RBD) and ACE2 interaction. The best five lead compounds were confirmed as inhibitors through ELISA-based enzyme assays. The docking studies and molecular dynamic (MD) simulations of the selected compounds maintained the molecular interaction and stability (RMSD fluctuations less than 5 Å) with key residues of the S protein. The compounds DRI-1, DRI-2, DRI-3, DRI-4, and DRI-5 efficiently block the interaction between the SARS-CoV-2 spike protein and receptor ACE2 (from 69.90 to 99.65% of inhibition) at 50 µM. The most potent inhibitors were DRI-2 (IC50 = 8.8 µM) and DRI-3 (IC50 = 2.1 µM) and have an acceptable profile of cytotoxicity (CC50 > 90 µM). Therefore, these compounds could be good candidates for further SARS-CoV-2 preclinical experiments.

Structure-based Virtual Screening from Natural Products as Inhibitors of SARS-CoV-2 Spike Protein and ACE2-h Receptor Binding and their Biological Evaluation In vitro.

BACKGROUND: In the last years, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused more than 760 million infections and 6.9 million deaths. Currently, remains a public health problem with limited pharmacological treatments. Among the virus drug targets, the SARS-CoV-2 spike protein attracts the development of new anti-SARS-CoV-2 agents. OBJECTIVE: The aim of this work was to identify new compounds derived from natural products (BIOFACQUIM and Selleckchem databases) as potential inhibitors of the spike receptor binding domain (RBD)-ACE2h binding complex. METHODS: Molecular docking, molecular dynamics simulations, and ADME-Tox analysis were performed to screen and select the potential inhibitors. ELISA-based enzyme assay was done to confirm our predictive model. RESULTS: Twenty compounds were identified as potential binders of RBD of the spike protein. In vitro assay showed compound B-8 caused 48% inhibition at 50 µM, and their binding pattern exhibited interactions via hydrogen bonds with the key amino acid residues present on the RBD. CONCLUSION: Compound B-8 can be used as a scaffold to develop new and more efficient antiviral drugs.

Histone deacetylase (HDAC) inhibitors- based drugs are effective to control Mycobacterium tuberculosis infection and promote the sensibility for rifampicin in MDR strain.

BACKGROUND: Tuberculosis (TB) is a major public health problem, which has been aggravated by the alarming growth of drug-resistant tuberculosis. Therefore, the development of a safer and more effective treatment is needed. OBJECTIVES: The aim of this work was repositioning and evaluate histone deacetylases (HDAC) inhibitors- based drugs with potential antimycobacterial activity. METHODS: Using an in silico pharmacological repositioning strategy, three molecules that bind to the catalytic site of histone deacetylase were selected. Pneumocytes type II and macrophages were infected with Mycobacterium tuberculosis and treated with pre-selected HDAC inhibitors (HDACi). Subsequently, the ability of each of these molecules to directly promote the elimination of M. tuberculosis was evaluated by colony-forming unit (CFU)/mL. We assessed the expression of antimicrobial peptides and respiratory burst using reverse transcription-quantitative polymerase chain reaction (RT-qPCR). FINDINGS: Aminoacetanilide (ACE), N-Boc-1,2-phenylenediamine (N-BOC), 1,3-Diphenylurea (DFU), reduce bacillary loads in macrophages and increase the production of ß-defensin-2, LL-37, superoxide dismutase (SOD) 3 and inducible nitric oxide synthase (iNOS). While only the use of ACE in type II pneumocytes decreases the bacterial load through increasing LL-37 expression. Furthermore, the use of ACE and rifampicin inhibited the survival of intracellular multi-drug resistance M. tuberculosis. MAIN CONCLUSIONS: Our data support the usefulness of in silico approaches for drug repositioning to provide a potential adjunctive therapy for TB.

Genomic epidemiology analysis of drug-resistant Mycobacterium tuberculosis distributed in Mexico.

Genomics has significantly revolutionized pathogen surveillance, particularly in epidemiological studies, the detection of drug-resistant strains, and disease control. Despite its potential, the representation of Latin American countries in the genomic catalogues of Mycobacterium tuberculosis (Mtb), the bacteria responsible for Tuberculosis (TB), remains limited. In this study, we present a whole genome sequencing (WGS)-based analysis of 85 Mtb clinical strains from 17 Mexican states, providing insights into local adaptations and drug resistance signatures in the region. Our results reveal that the Euro-American lineage (L4) accounts for 94% of our dataset, showing 4.1.2.1 (Haarlem, n = 32), and 4.1.1.3 (X-type, n = 34) sublineages as the most prevalent. We report the presence of the 4.1.1.3 sublineage, which is endemic to Mexico, in six additional locations beyond previous reports. Phenotypic drug resistance tests showed that 34 out of 85 Mtb samples were resistant, exhibiting a variety of resistance profiles to the first-line antibiotics tested. We observed high levels of discrepancy between phenotype and genotype associated with drug resistance in our dataset, including pyrazinamide-monoresistant Mtb strains lacking canonical variants of drug resistance. Expanding the Latin American Mtb genome databases will enhance our understanding of TB epidemiology and potentially provide new avenues for controlling the disease in the region.

Daytime Resting Activity of Aedes Aegypti and Culex Quinquefasciatus Populations in Northern Mexico.

Aedes aegypti and Culex quinquefasciatus are disease vectors distributed throughout much of the world and are responsible for a high burden of vector-borne disease, which has increased during the last 2 decades. Most pathogens vectored by these mosquitoes do not have therapeutic remedies; thus, combating these diseases is dependent upon vector control. Improvements in vector control strategies are urgently needed, but these hinge on understanding the biology and ecology of Ae. aegypti and Cx. quinquefasciatus. Both species have been extensively investigated, but further knowledge on diel resting activity of these vectors can improve vector surveillance and control tools for targeting resting vector populations. From April to December 2021, we determined outdoor daytime resting habits of Ae. aegypti and Cx. quinquefasciatus male, female, and blood-fed female populations in Reynosa, Mexico, using large red odor-baited wooden box traps. The daytime resting activity for Ae. aegypti males, females, and blood-fed females was restricted to a period between 0900 h and 1300 h, with a peak at 0900 h, while the resting activity of Cx. quinquefasciatus male, female, and blood-fed females was between 0700 h and 1100 h, with a peak at 0700 h. A generalized additive model was developed to relate relative humidity and temperature to resting Cx. quinquefasciatus and Ae. aegypti male, female, and blood-fed populations caught in traps. This study advances the understanding of outdoor resting behavior for 2 important vector mosquito species and discusses future studies to fill additional knowledge gaps.

Triose Phosphate Isomerase Structure-Based Virtual Screening and In Vitro Biological Activity of Natural Products as Leishmania mexicana Inhibitors.

Cutaneous leishmaniasis (CL) is a public health problem affecting more than 98 countries worldwide. No vaccine is available to prevent the disease, and available medical treatments cause serious side effects. Additionally, treatment failure and parasite resistance have made the development of new drugs against CL necessary. In this work, a virtual screening of natural products from the BIOFACQUIM and Selleckchem databases was performed using the method of molecular docking at the triosephosphate isomerase (TIM) enzyme interface of Leishmania mexicana (L. mexicana). Finally, the in vitro leishmanicidal activity of selected compounds against two strains of L. mexicana, their cytotoxicity, and selectivity index were determined. The top ten compounds were obtained based on the docking results. Four were selected for further in silico analysis. The ADME-Tox analysis of the selected compounds predicted favorable physicochemical and toxicological properties. Among these four compounds, S-8 (IC50 = 55 µM) demonstrated a two-fold higher activity against the promastigote of both L. mexicana strains than the reference drug glucantime (IC50 = 133 µM). This finding encourages the screening of natural products as new anti-leishmania agents.

Ligand-Based and Structure-Based Virtual Screening of New Sodium Glucose Cotransporter Type 2 Inhibitors.

BACKGROUND: Diabetes mellitus is a metabolic disease that causes multiple complications and common comorbidities, which decreases the quality of life for people affected by the disease. Sodium glucose cotransporter type 2 (SGLT2) participates in the reabsorption of 90% of glucose in the kidneys; therefore, it is an attractive drug target for controlling blood glucose levels. OBJECTIVE: The aim in this work was to obtain new potential SGLT2 inhibitors. METHODS: A ligand-based virtual screening (LBVS) from the ZINC15, PubChem and ChemSpider databases using the maximum common substructure (MCS) scaffold was performed. RESULT: A total of 341 compounds were obtained and analyzed by molecular docking on the active site of SGLT2. Subsequently, 15 compounds were selected for molecular dynamics (MD) simulation analysis. The compounds derived of spiroketal Sa1, Sa4, and Sa9 (≤ 3.5 Å) in complex with the receptor SGLT2 showed good stability during 120 ns of MD. CONCLUSION: These compounds are proposed as potential SGLT2 inhibitors.

Ligand-Based Virtual Screening, Molecular Docking, and Molecular Dynamic Simulations of New ß-Estrogen Receptor Activators with Potential for Pharmacological Obesity Treatment.

Obesity is a pandemic and a serious health problem in developed and undeveloped countries. Activation of estrogen receptor beta (ERß) has been shown to promote weight loss without modifying caloric intake, making it an attractive target for developing new drugs against obesity. This work aimed to predict new small molecules as potential ERß activators. A ligand-based virtual screening of the ZINC15, PubChem, and Molport databases by substructure and similarity was carried out using the three-dimensional organization of known ligands as a reference. A molecular docking screening of FDA-approved drugs was also conducted as a repositioning strategy. Finally, selected compounds were evaluated by molecular dynamic simulations. Compounds 1 (-24.27 ± 0.34 kcal/mol), 2 (-23.33 ± 0.3 kcal/mol), and 6 (-29.55 ± 0.51 kcal/mol) showed the best stability on the active site in complex with ERß with an RMSD < 3.3 Å. RMSF analysis showed that these compounds do not affect the fluctuation of the Cα of ERß nor the compactness according to the radius of gyration. Finally, an in silico evaluation of ADMET showed they are safe molecules. These results suggest that new ERß ligands could be promising molecules for obesity control.

Virtual Screening of Benzimidazole Derivatives as Potential Triose Phosphate Isomerase Inhibitors with Biological Activity against Leishmania mexicana.

Leishmania mexicana (L. mexicana) is a causal agent of cutaneous leishmaniasis (CL), a "Neglected disease", for which the search for new drugs is a priority. Benzimidazole is a scaffold used to develop antiparasitic drugs; therefore, it is interesting molecule against L. mexicana. In this work, a ligand-based virtual screening (LBVS) of the ZINC15 database was performed. Subsequently, molecular docking was used to predict the compounds with potential binding at the dimer interface of triosephosphate isomerase (TIM) of L. mexicana (LmTIM). Compounds were selected on binding patterns, cost, and commercial availability for in vitro assays against L. mexicana blood promastigotes. The compounds were analyzed by molecular dynamics simulation on LmTIM and its homologous human TIM. Finally, the physicochemical and pharmacokinetic properties were determined in silico. A total of 175 molecules with docking scores between -10.8 and -9.0 Kcal/mol were obtained. Compound E2 showed the best leishmanicidal activity (IC50 = 4.04 µM) with a value similar to the reference drug pentamidine (IC50 = 2.23 µM). Molecular dynamics analysis predicted low affinity for human TIM. Furthermore, the pharmacokinetic and toxicological properties of the compounds were suitable for developing new leishmanicidal agents.

Bioinformatic prediction of the molecular links between Alzheimer's disease and diabetes mellitus.

Background: Alzheimer's disease (AD) and type 2 diabetes mellitus (DM2) are chronic degenerative diseases with complex molecular processes that are potentially interconnected. The aim of this work was to predict the potential molecular links between AD and DM2 from different sources of biological information. Materials and Methods: In this work, data mining of nine databases (DisGeNET, Ensembl, OMIM, Protein Data Bank, The Human Protein Atlas, UniProt, Gene Expression Omnibus, Human Cell Atlas, and PubMed) was performed to identify gene and protein information that was shared in AD and DM2. Next, the information was mapped to human protein-protein interaction (PPI) networks based on experimental data using the STRING web platform. Then, gene ontology biological process (GOBP) and pathway analyses with EnrichR showed its specific and shared biological process and pathway deregulations. Finally, potential biomarkers and drug targets were predicted with the Metascape platform. Results: A total of 1,551 genes shared in AD and DM2 were identified. The highest average degree of nodes within the PPI was for DM2 (average = 2.97), followed by AD (average degree = 2.35). GOBP for AD was related to specific transcriptional and translation genetic terms occurring in neurons cells. The GOBP and pathway information for the association AD-DM2 were linked mainly to bioenergetics and cytokine signaling. Within the AD-DM2 association, 10 hub proteins were identified, seven of which were predicted to be present in plasma and exhibit pharmacological interaction with monoclonal antibodies in use, anticancer drugs, and flavonoid derivatives. Conclusion: Our data mining and analysis strategy showed that there are a plenty of biological information based on experiments that links AD and DM2, which could provide a rational guide to design further diagnosis and treatment for AD and DM2.

Transcriptome Analysis Identifies Oxidative Stress Injury Biomarkers for Diabetic Nephropathy.

BACKGROUND: The early diagnosis of diabetic nephropathy (DN) is essential for improving the prognosis and effectively manage patients affected with this disease. The standard biomarkers, including albuminuria and glomerular filtration rate, are not very precise. New molecular biomarkers are needed to more accurately identify DN and better predict disease progression. Characteristic DN biomarkers can be identified using transcriptomic analysis. AIM OF THE STUDY: To evaluate the transcriptomic profile of controls (CTRLs, n = 15), patients with prediabetes (PREDM, n = 15), patients with type-2 diabetes mellitus (DM2, n = 15), and patients with DN (n = 15) by microarray analysis to find new biomarkers. RT-PCR was then used to confirm gene biomarkers specific for DN. MATERIALS AND METHODS: Blood samples were used to isolate RNA for microarray expression analysis. 26,803 unique gene sequences and 30,606 LncRNA sequences were evaluated-Selected gene biomarkers for DN were validated using qPCR assays. Sensitivity, specificity, and area under the curve (AUC) were calculated as measures of diagnostic accuracy. RESULTS: The DN transcriptome was composed of 300 induced genes, compared to CTRLs, PREDM, and DM-2 groups. RT-qPCR assays validated that METLL22, PFKL, CCNB1 and CASP2 genes were induced in the DN group compared to CTRLs, PREDM, and DM-2 groups. The ROC analysis for these four genes showed 0.9719, 0.8853, 0.8533 and 0.7748 AUC values, respectively. CONCLUSION: Among induced genes in the DN group, we found that CASP2, PFKL and CCNB1 may potentially be used as biomarkers to diagnose DN. Of these, METLL22 had the highest AUC score, at 0.9719.

Histone deacetylase (HDAC) inhibitors- based drugs are effective to control Mycobacterium tuberculosis infection and promote the sensibility for rifampicin in MDR strain

BACKGROUND Tuberculosis (TB) is a major public health problem, which has been aggravated by the alarming growth of drug-resistant tuberculosis. Therefore, the development of a safer and more effective treatment is needed. OBJECTIVES The aim of this work was repositioning and evaluate histone deacetylases (HDAC) inhibitors- based drugs with potential antimycobacterial activity. METHODS Using an in silico pharmacological repositioning strategy, three molecules that bind to the catalytic site of histone deacetylase were selected. Pneumocytes type II and macrophages were infected with Mycobacterium tuberculosis and treated with pre-selected HDAC inhibitors (HDACi). Subsequently, the ability of each of these molecules to directly promote the elimination of M. tuberculosis was evaluated by colony-forming unit (CFU)/mL. We assessed the expression of antimicrobial peptides and respiratory burst using reverse transcription-quantitative polymerase chain reaction (RT-qPCR) FINDINGS Aminoacetanilide (ACE), N-Boc-1,2-phenylenediamine (N-BOC), 1,3-Diphenylurea (DFU), reduce bacillary loads in macrophages and increase the production of β-defensin-2, LL-37, superoxide dismutase (SOD) 3 and inducible nitric oxide synthase (iNOS). While only the use of ACE in type II pneumocytes decreases the bacterial load through increasing LL-37 expression. Furthermore, the use of ACE and rifampicin inhibited the survival of intracellular multi-drug resistance M. tuberculosis. MAIN CONCLUSIONS Our data support the usefulness of in silico approaches for drug repositioning to provide a potential adjunctive therapy for TB.

GPR15 expressed in T lymphocytes from RA patients is involved in leukocyte chemotaxis to the synovium.

The rheumatoid arthritis (RA) inflammatory process occurs in the joints where immune cells are attracted into the synovium to promote remodeling and tissue damage. GPR15 is a G protein-coupled receptor (GPCR) located on chromosome 3 and has similarity in its sequence with chemokine receptors. Recent evidence indicates that GPR15 may be associated with modulation of the chronic inflammatory response. We evaluated the expression of GPR15 and GPR15L in blood and synovial tissue samples from RA patients, as well as to perform a functional migration assay in response to GPR15L. The expression of GPR15 and c10orf99/gpr15l mRNA was analyzed by RT-qPCR. Samples of synovial fluid and peripheral blood were analyzed for CD45+CD3+CD4+GPR15+ and CD45+CD3+CD8+GPR15+ T cell frequency comparing RA patients versus control subjects by flow cytometry. Migration assays were performed using PBMCs isolated from these individuals in response to the synthetic GPR15 ligand. Statistical analysis included Kruskal-Wallis test, T-test, or Mann-Whitney U test, according to data distribution. A higher expression in the mRNA for GPR15 was identified in early RA subjects. The frequencies of CD4+/CD8+ GPR15+ T lymphocytes are higher in RA patients comparing with healthy subjects. Also, the frequency CD4+/CD8+ GPR15+ T lymphocytes are higher in synovial fluid of established RA patients comparing with OA patients. GPR15 and GPR15L are present in the synovial tissue of RA patients and GPR15L promotes migration of PBMCs from RA patients and healthy subjects. Our results suggest that GPR15/GPR15L have a pathogenic role in RA and their antagonizing could be a therapeutic approach in RA.

[Clinical cases of Guillain-Barré and Miller-Fisher syndromes linked to COVID-19]. / Casos clínicos de los síndromes de Guillain-Barré y Miller-Fisher relacionados con la COVID-19.

coronavirus disease 2019 (COVID-19), caused by the new coronavirus SARS-CoV-2, has been associated with the development of neurological diseases such as Guillain-Barré syndrome (GBS) and its variants. In the present work, two cases of demyelinating syndromes associated with COVID-19 are reported. Clinical cases: 53-year-old male with GBS and and 29-year-old female with Miller-Fisher syndrome (MFS) variant, respectively. Both patients presented the classic neurological signs and symptoms of demyelinating polyneuropathy that characterizes the syndromes. From the paraclinical biochemical tests, the increase of proteins in cerebrospinal fluid was distinctive. The positivity of the RT-qPCR for SARS-CoV-2 suggested the association of GBS and MFS with COVID-19. Both patients were treated with intravenous immunoglobulin showing improvement. Electromyography performed weeks ahead still showed chronic demyelinating involvement. Conclusion: The cases of GBS and MFS, along with other similar cases reported around the world, provide further evidence for SARS-CoV-2 as a new possible etiology of these rare neurological diseases.

Introducción: la enfermedad por coronavirus del 2019 (COVID-19), causada por el nuevo coronavirus SARS-CoV-2, se ha asociado con el desarrollo de enfermedades neurológicas como el síndrome de Guillain-Barré (SGB) y sus variantes. En el presente trabajo se reportan dos casos de síndromes desmielizantes asociados con la COVID-19. Casos clínicos: hombre de 53 años con SGB y mujer de 29 años con la variante del síndrome de Miller-Fisher (SMF), respectivamente. Ambos presentaron los signos y síntomas neurológicos clásicos de polineuropatía desmielinizante que caracterizan a estos síndromes. De las pruebas bioquímicas paraclínicas, el aumento de proteínas en líquido cefalorraquídeo fue distintiva. La positividad de la RT-qPCR para el SARS-CoV-2 indicó la asociación de los SGB y SMF con la COVID-19. Ambos pacientes se trataron con inmunoglobulina intravenosa y mostraron mejoría. La electromiografía realizada en semanas posteriores aún mostraba afectación desmielinizante crónica. Conclusión: los casos de los SGB y SMF, junto con otros casos similares reportados en todo el mundo, proporcionan más evidencia para el SARS-CoV-2 como nueva posible etiología de estas raras enfermedades neurológicas.

Recent Advances in the Development of Type 2 Sodium-Glucose Cotransporter Inhibitors for the Treatment of Type 2 Diabetes Mellitus.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is one of the most serious and prevalent diseases worldwide. In the last decade, type 2 sodium-glucose cotransporter inhibitors (iSGLT2) were approved as alternative drugs for the pharmacological treatment of T2DM. The anti-hyperglycemic mechanism of action of these drugs involves glycosuria. In addition, SGLT2 inhibitors cause beneficial effects such as weight loss, a decrease in blood pressure, and others. OBJECTIVE: This review aimed to describe the origin of SGLT2 inhibitors and analyze their recent development in preclinical and clinical trials. RESULTS: In 2013, the FDA approved SGLT2 inhibitors as a new alternative for the treatment of T2DM. These drugs have shown good tolerance with few adverse effects in clinical trials. Additionally, new potential anti-T2DM agents based on iSGLT2 (O-, C-, and N-glucosides) have exhibited a favorable profile in preclinical evaluations, making them candidates for advanced clinical trials. CONCLUSION: The clinical results of SGLT2 inhibitors show the importance of this drug class as new anti-T2DM agents with a potential dual effect. Additionally, the preclinical results of SGLT2 inhibitors favor the design and development of more selective new agents. However, several adverse effects could be a potential risk for patients.

Casos clínicos de los síndromes de Guillain-Barré y Miller-Fisher relacionados con la COVID-19 / Clinical cases of Guillain-Barré and Miller-Fisher syndromes linked to COVID-19

Introducción: la enfermedad por coronavirus del 2019 (COVID-19), causada por el nuevo coronavirus SARSCoV-2, se ha asociado con el desarrollo de enfermedades neurológicas como el síndrome de Guillain-Barré (SGB) y sus variantes. En el presente trabajo se reportan dos casos de síndromes desmielizantes asociados con la COVID-19. Casos clínicos: hombre de 53 años con SGB y mujer de 29 años con la variante del síndrome de Miller-Fisher (SMF), respectivamente. Ambos presentaron los signos y síntomas neurológicos clásicos de polineuropatía desmielinizante que caracterizan a estos síndromes. De las pruebas bioquímicas paraclínicas, el aumento de proteínas en líquido cefalorraquídeo fue distintiva. La positividad de la RT-qPCR para el SARS-CoV-2 indicó la asociación de los SGB y SMF con la COVID-19. Ambos pacientes se trataron con inmunoglobulina intravenosa y mostraron mejoría. La electromiografía realizada en semanas posteriores aún mostrabaafectación desmielinizante crónica. Conclusión: los casos de los SGB y SMF, junto con otros casos similares reportados en todo el mundo, proporcionan más evidencia para el SARS-CoV-2 como nueva posible etiología de estas raras enfermedades neurológicas.

Background: coronavirus disease 2019 (COVID-19), caused by the new coronavirus SARS CoV-2, has been associated with the development of neurological diseases such as Guillain-Barré syndrome (GBS) and its variants. In the present work, two cases of demyelinating syndromes associated with COVID-19 are reported. Clinical cases: 53-year-old male with GBS and and 29-yearold female with Miller-Fisher syndrome (MFS) variant, respectively. Both patients presented the classic neurological signs and symptoms of demyelinating polyneuropathy that characterizes the syndromes. From the paraclinical biochemical tests, the increase of proteins in cerebrospinal fluid was distinctive. The positivity of the RT-qPCR for SARSCoV-2 suggested the association of GBS and MFS with COVID-19. Both patients were treated with intravenous immunoglobulin showing improvement. Electromyography performed weeks ahead still showed chronic demyelinating involvement. Conclusion: The cases of GBS and MFS, along with other similar cases reported around the world, provide further evidence for SARS-CoV-2 as a new possible etiology of these rare neurological diseases.

Virtual Screening of FDA-Approved Drugs against Triose Phosphate Isomerase from Entamoeba histolytica and Giardia lamblia Identifies Inhibitors of Their Trophozoite Growth Phase.

Infectious diseases caused by intestinal protozoan, such as Entamoeba histolytica (E. histolytica) and Giardia lamblia (G. lamblia) are a worldwide public health issue. They affect more than 70 million people every year. They colonize intestines causing primarily diarrhea; nevertheless, these infections can lead to more serious complications. The treatment of choice, metronidazole, is in doubt due to adverse effects and resistance. Therefore, there is a need for new compounds against these parasites. In this work, a structure-based virtual screening of FDA-approved drugs was performed to identify compounds with antiprotozoal activity. The glycolytic enzyme triosephosphate isomerase, present in both E. histolytica and G. lamblia, was used as the drug target. The compounds with the best average docking score on both structures were selected for the in vitro evaluation. Three compounds, chlorhexidine, tolcapone, and imatinib, were capable of inhibit growth on G. lamblia trophozoites (0.05-4.935 µg/mL), while folic acid showed activity against E. histolytica (0.186 µg/mL) and G. lamblia (5.342 µg/mL).

The analysis on the human protein domain targets and host-like interacting motifs for the MERS-CoV and SARS-CoV/CoV-2 infers the molecular mimicry of coronavirus.

The MERS-CoV, SARS-CoV, and SARS-CoV-2 are highly pathogenic viruses that can cause severe pneumonic diseases in humans. Unfortunately, there is a non-available effective treatment to combat these viruses. Domain-motif interactions (DMIs) are an essential means by which viruses mimic and hijack the biological processes of host cells. To disentangle how viruses achieve this process can help to develop new rational therapies. Data mining was performed to obtain DMIs stored as regular expressions (regexp) in 3DID and ELM databases. The mined regexp information was mapped on the coronaviruses' proteomes. Most motifs on viral protein that could interact with human proteins are shared across the coronavirus species, indicating that molecular mimicry is a common strategy for coronavirus infection. Enrichment ontology analysis for protein domains showed a shared biological process and molecular function terms related to carbon source utilization and potassium channel regulation. Some of the mapped motifs were nested on B, and T cell epitopes, suggesting that it could be as an alternative way for reverse vaccinology. The information obtained in this study could be used for further theoretic and experimental explorations on coronavirus infection mechanism and development of medicines for treatment.

Polyamines Influence Mouse Sperm Channels Activity.

Polyamines are ubiquitous polycationic compounds that are highly charged at physiological pH. While passing through the epididymis, sperm lose their capacity to synthesize the polyamines and, upon ejaculation, again come into contact with the polyamines contained in the seminal fluid, unleashing physiological events that improve sperm motility and capacitation. In the present work, we hypothesize about the influence of polyamines, namely, spermine, spermidine, and putrescine, on the activity of sperm channels, evaluating the intracellular concentrations of chloride [Cl-]i, calcium [Ca2+]i, sodium [Na+]i, potassium [K+]i, the membrane Vm, and pHi. The aim of this is to identify the possible regulatory mechanisms mediated by the polyamines on sperm-specific channels under capacitation and non-capacitation conditions. The results showed that the presence of polyamines did not directly influence the activity of calcium and chloride channels. However, the results suggested an interaction of polyamines with sodium and potassium channels, which may contribute to the membrane Vm during capacitation. In addition, alkalization of the pHi revealed the possible activation of sperm-specific Na+/H+ exchangers (NHEs) by the increased levels of cyclic AMP (cAMP), which were produced by soluble adenylate cyclase (sAC) and interact with the polyamines, evidence that is supported by in silico analysis.