RESUMO
Pseudomonas aeruginosa is an opportunistic ESKAPE pathogen that produces two lectins, LecA and LecB, as part of its large arsenal of virulence factors. Both carbohydrate-binding proteins are central to the initial and later persistent infection processes, i. e. bacterial adhesion and biofilm formation. The biofilm matrix is a major resistance determinant and protects the bacteria against external threats such as the host immune system or antibiotic treatment. Therefore, the development of drugs against the P. aeruginosa biofilm is of particular interest to restore efficacy of antimicrobials. Carbohydrate-based inhibitors for LecA and LecB were previously shown to efficiently reduce biofilm formations. Here, we report a new approach for inhibiting LecA with synthetic molecules bridging the established carbohydrate-binding site and a central cavity located between two LecA protomers of the lectin tetramer. Inspired by in silico design, we synthesized various galactosidic LecA inhibitors with aromatic moieties targeting this central pocket. These compounds reached low micromolar affinities, validated in different biophysical assays. Finally, X-ray diffraction analysis revealed the interactions of this compound class with LecA. This new mode of action paves the way to a novel route towards inhibition of P. aeruginosa biofilms.
Assuntos
Adesinas Bacterianas/metabolismo , Antibacterianos/farmacologia , Carboidratos/farmacologia , Pseudomonas aeruginosa/efeitos dos fármacos , Antibacterianos/química , Biofilmes/efeitos dos fármacos , Carboidratos/química , Relação Dose-Resposta a Droga , Testes de Sensibilidade Microbiana , Modelos Moleculares , Estrutura Molecular , Pseudomonas aeruginosa/metabolismo , Relação Estrutura-AtividadeRESUMO
Carbohydrate-binding proteins (lectins) are auspicious targets in drug discovery to combat antimicrobial resistance; however, their non-carbohydrate drug-like inhibitors are still unavailable. Here, we present a druggable pocket in a ß-propeller lectin BambL from Burkholderia ambifaria as a potential target for allosteric inhibitors. This site was identified employing 19 Fâ NMR fragment screening and a computational pocket prediction algorithm SiteMap. The structure-activity relationship study revealed the most promising fragment with a dissociation constant of 0.3±0.1â mM and a ligand efficiency of 0.3â kcal mol-1 HA-1 that affected the orthosteric site. This effect was substantiated by site-directed mutagenesis in the orthosteric and secondary pockets. Future drug-discovery campaigns that aim to develop small molecule inhibitors can benefit from allosteric sites in lectins as a new therapeutic approach against antibiotic-resistant pathogens.
Assuntos
Lectinas/antagonistas & inibidores , Bibliotecas de Moléculas Pequenas/farmacologia , Sítio Alostérico/efeitos dos fármacos , Burkholderia/química , Humanos , Lectinas/metabolismo , Estrutura Molecular , Bibliotecas de Moléculas Pequenas/químicaRESUMO
The carbohydrate-binding protein LecA (PA-IL) from Pseudomonas aeruginosa plays an important role in the formation of biofilms in chronic infections. Development of inhibitors to disrupt LecA-mediated biofilms is desired but it is limited to carbohydrate-based ligands. Moreover, discovery of drug-like ligands for LecA is challenging because of its weak affinities. Therefore, we established a protein-observed 19F (PrOF) nuclear magnetic resonance (NMR) to probe ligand binding to LecA. LecA was labeled with 5-fluoroindole to incorporate 5-fluorotryptophanes and the resonances were assigned by site-directed mutagenesis. This incorporation did not disrupt LecA preference for natural ligands, Ca2+ and d-galactose. Following NMR perturbation of W42, which is located in the carbohydrate-binding region of LecA, allowed to monitor binding of low-affinity ligands such as N-acetyl d-galactosamine (d-GalNAc, Kd = 780 ± 97 µM). Moreover, PrOF NMR titration with glycomimetic of LecA p-nitrophenyl ß-d-galactoside (pNPGal, Kd = 54 ± 6 µM) demonstrated a 6-fold improved binding of d-Gal proving this approach to be valuable for ligand design in future drug discovery campaigns that aim to generate inhibitors of LecA.
Assuntos
Adesinas Bacterianas/análise , Pseudomonas aeruginosa/química , Configuração de Carboidratos , Imagem por Ressonância Magnética de Flúor-19 , Modelos Moleculares , Proteínas Recombinantes/análiseRESUMO
Protein-glycan interactions mediate important biological processes, including pathogen host invasion and cellular communication. Herein, we showcase an expedite approach that integrates automated glycan assembly (AGA) of 19 F-labeled probes and high-throughput NMR methods, enabling the study of protein-glycan interactions. Synthetic Lewis typeâ 2 antigens were screened against seven glycan binding proteins (GBPs), including DC-SIGN and BambL, respectively involved in HIV-1 and lung infections in immunocompromised patients, confirming the preference for fucosylated glycans (Lex , Hâ typeâ 2, Ley ). Previously unknown glycan-lectin weak interactions were detected, and thermodynamic data were obtained. Enzymatic reactions were monitored in real-time, delivering kinetic parameters. These results demonstrate the utility of AGA combined with 19 Fâ NMR for the discovery and characterization of glycan-protein interactions, opening up new perspectives for 19 F-labeled complex glycans.
Assuntos
Proteínas de Bactérias/metabolismo , Moléculas de Adesão Celular/metabolismo , Flúor/química , Lectinas Tipo C/metabolismo , Lectinas/metabolismo , Ressonância Magnética Nuclear Biomolecular , Polissacarídeos/metabolismo , Receptores de Superfície Celular/metabolismo , Proteínas de Bactérias/química , Sítios de Ligação , Burkholderia/metabolismo , Moléculas de Adesão Celular/química , Glicosilação , Cinética , Lectinas/química , Lectinas Tipo C/química , Polissacarídeos/química , Ligação Proteica , Receptores de Superfície Celular/químicaRESUMO
Because of the antimicrobial resistance crisis, lectins are considered novel drug targets. Pseudomonas aeruginosa utilizes LecA and LecB in the infection process. Inhibition of both lectins with carbohydrate-derived molecules can reduce biofilm formation to restore antimicrobial susceptibility. Here, we focused on non-carbohydrate inhibitors for LecA to explore new avenues for lectin inhibition. From a screening cascade we obtained one experimentally confirmed hit, a catechol, belonging to the well-known PAINS compounds. Rigorous analyses validated electron-deficient catechols as millimolar LecA inhibitors. The first co-crystal structure of a non-carbohydrate inhibitor in complex with a bacterial lectin clearly demonstrates the catechol mimicking the binding of natural glycosides with LecA. Importantly, catechol 3 is the first non-carbohydrate lectin ligand that binds bacterial and mammalian calcium(II)-binding lectins, giving rise to this fundamentally new class of glycomimetics.
Assuntos
Adesinas Bacterianas/metabolismo , Antibacterianos/farmacologia , Cálcio/metabolismo , Glicosídeos/farmacologia , Pseudomonas aeruginosa/efeitos dos fármacos , Adesinas Bacterianas/química , Antibacterianos/química , Catecóis/química , Glicosídeos/química , Testes de Sensibilidade Microbiana , Modelos Moleculares , Estrutura Molecular , Pseudomonas aeruginosa/químicaRESUMO
Fragment-based drug discovery (FBDD) is a popular method in academia and the pharmaceutical industry for the discovery of early lead candidates. Despite its wide-spread use, the approach still suffers from laborious screening workflows and a limited diversity in the fragments applied. Presented here is the design, synthesis, and biological evaluation of the first fragment library specifically tailored to tackle both these challenges. The 3F library of 115 fluorinated, Fsp3 -rich fragments is shape diverse and natural-product-like with desirable physicochemical properties. The library is perfectly suited for rapid and efficient screening by NMR spectroscopy in a two-stage workflow of 19 Fâ NMR and subsequent 1 Hâ NMR methods. Hits against four diverse protein targets are widely distributed among the fragment scaffolds in the 3F library and a 67 % validation rate was achieved using secondary assays. This collection is the first synthetic fragment library tailor-made for 19 Fâ NMR screening and the results demonstrate that the approach should find broad application in the FBDD community.
Assuntos
Descoberta de Drogas/métodos , Flúor/química , Espectroscopia de Ressonância Magnética , Bibliotecas de Moléculas Pequenas/química , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Secretases da Proteína Precursora do Amiloide/metabolismo , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Ácido Aspártico Endopeptidases/metabolismo , Moléculas de Adesão Celular/antagonistas & inibidores , Moléculas de Adesão Celular/metabolismo , Reação de Cicloadição , Halogenação , Humanos , Lectinas Tipo C/antagonistas & inibidores , Lectinas Tipo C/metabolismo , Teoria Quântica , Receptores de Superfície Celular/antagonistas & inibidores , Receptores de Superfície Celular/metabolismo , Proteínas Quinases S6 Ribossômicas 70-kDa/antagonistas & inibidores , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismoRESUMO
The replacement of hydroxyl groups by fluorine atoms on hexopyranoside scaffolds may allow access to invaluable tools for studying various biochemical processes. As part of ongoing activities toward the preparation of fluorinated carbohydrates, a systematic investigation involving the synthesis and biological evaluation of a series of mono- and polyfluorinated galactopyranosides is described. Various monofluorogalactopyranosides, a trifluorinated, and a tetrafluorinated galactopyranoside have been prepared using a Chiron approach. Given the scarcity of these compounds in the literature, in addition to their synthesis, their biological profiles were evaluated. Firstly, the fluorinated compounds were investigated as antiproliferative agents using normal human and mouse cells in comparison with cancerous cells. Most of the fluorinated compounds showed no antiproliferative activity. Secondly, these carbohydrate probes were used as potential inhibitors of galactophilic lectins. The first transverse relaxation-optimized spectroscopy (TROSY) NMR experiments were performed on these interactions, examining chemical shift perturbations of the backbone resonances of LecA, a virulence factor from Pseudomonas aeruginosa. Moreover, taking advantage of the fluorine atom, the 19 Fâ NMR resonances of the monofluorogalactopyranosides were directly monitored in the presence and absence of LecA to assess ligand binding. Lastly, these results were corroborated with the binding potencies of the monofluorinated galactopyranoside derivatives by isothermal titration calorimetry experiments. Analogues with fluorine atoms at C-3 and C-4 showed weaker affinities with LecA as compared to those with the fluorine atom at C-2 or C-6. This research has focused on the chemical synthesis of "drug-like" low-molecular-weight inhibitors that circumvent drawbacks typically associated with natural oligosaccharides.
RESUMO
CD22, a sialic acid-binding Ig-type lectin (Siglec) family member, is an inhibitory coreceptor of the BCR with established roles in health and disease. The restricted expression pattern of CD22 on B cells and most B cell lymphomas has made CD22 a therapeutic target for B cell-mediated diseases. Models to better understand how in vivo targeting of CD22 translates to human disease are needed. In this article, we report the development of a transgenic mouse expressing human CD22 (hCD22) in B cells and assess its ability to functionally substitute for murine CD22 (mCD22) for regulation of BCR signaling, Ab responses, homing, and tolerance. Expression of hCD22 on transgenic murine B cells is comparable to expression on human primary B cells, and it colocalizes with mCD22 on the cell surface. Murine B cells expressing only hCD22 have identical calcium (Ca2+) flux responses to anti-IgM as mCD22-expressing wild-type B cells. Furthermore, hCD22 transgenic mice on an mCD22-/- background have restored levels of marginal zone B cells and Ab responses compared with deficiencies observed in CD22-/- mice. Consistent with these observations, hCD22 transgenic mice develop normal humoral responses in a peanut allergy oral sensitization model. Homing of B cells to Peyer's patches was partially rescued by expression of hCD22 compared with CD22-/- B cells, although not to wild-type levels. Notably, Siglec-engaging antigenic liposomes formulated with an hCD22 ligand were shown to prevent B cell activation, increase cell death, and induce tolerance in vivo. This hCD22 transgenic mouse will be a valuable model for investigating the function of hCD22 and preclinical studies targeting hCD22.
Assuntos
Linfócitos B/imunologia , Hipersensibilidade a Amendoim/imunologia , Nódulos Linfáticos Agregados/imunologia , Receptores de Antígenos de Linfócitos B/imunologia , Lectina 2 Semelhante a Ig de Ligação ao Ácido Siálico/imunologia , Transdução de Sinais/imunologia , Animais , Linfócitos B/patologia , Modelos Animais de Doenças , Humanos , Ativação Linfocitária/genética , Camundongos , Camundongos Transgênicos , Hipersensibilidade a Amendoim/genética , Hipersensibilidade a Amendoim/patologia , Nódulos Linfáticos Agregados/patologia , Receptores de Antígenos de Linfócitos B/genética , Lectina 2 Semelhante a Ig de Ligação ao Ácido Siálico/genética , Transdução de Sinais/genéticaRESUMO
DC-SIGN is a cell-surface receptor for several pathogenic threats, such as HIV, Ebola virus, or Mycobacterium tuberculosis. Multiple attempts to develop inhibitors of the underlying carbohydrate-protein interactions have been undertaken in the past fifteen years. Still, drug-like DC-SIGN ligands are sparse, which is most likely due to its hydrophilic, solvent-exposed carbohydrate-binding site. Herein, we report on a parallel fragment screening against DC-SIGN applying SPR and a reporter displacement assay, which complements previous screenings using 19 Fâ NMR spectroscopy and chemical fragment microarrays. Hit validation by SPR and 1 H-15 N HSQC NMR spectroscopy revealed that although no fragment bound in the primary carbohydrate site, five secondary sites are available to harbor drug-like molecules. Building on key interactions of the reported fragment hits, these pockets will be targeted in future approaches to accelerate the development of DC-SIGN inhibitors.
Assuntos
Moléculas de Adesão Celular/química , Lectinas Tipo C/química , Receptores de Superfície Celular/química , Carboidratos/química , Ligantes , Espectroscopia de Ressonância Magnética/métodos , Reprodutibilidade dos Testes , Ressonância de Plasmônio de SuperfícieRESUMO
Antigen uptake and processing by innate immune cells is crucial to initiate the immune response. Therein, the endocytic C-type lectin receptors serve as pattern recognition receptors, detecting pathogens by their glycan structures. Herein, we studied the carbohydrate recognition domain of Langerin, a C-type lectin receptor involved in the host defense against viruses such as HIV and influenza as well as bacteria and fungi. Using a combination of nuclear magnetic resonance and molecular dynamics simulations, we unraveled the molecular determinants underlying cargo capture and release encoded in the receptor architecture. Our findings revealed receptor dynamics over several time scales associated with binding and release of the essential cofactor Ca(2+) controlled by the coupled motions of two loops. Applying mutual information theory and site-directed mutagenesis, we identified an allosteric intradomain network that modulates the Ca(2+) affinity depending on the pH, thereby promoting fast ligand release.
Assuntos
Antígenos CD/química , Cálcio/química , Lectinas Tipo C/química , Lectinas de Ligação a Manose/química , Regulação Alostérica , Sequência de Aminoácidos , Cálcio/metabolismo , Concentração de Íons de Hidrogênio , Modelos Moleculares , Ligação Proteica , Conformação ProteicaRESUMO
Miller Fisher syndrome (MFS), variant of acute inflammatory demyelinating polyradiculoneuropathy, is recognized as clinical triad (ophthalmoplegia-ataxia-areflexia). Ganglioside antibodies play an important role in the pathogenesis of acute polyradiculoneuropathy including MFS. To our knowledge, there has been no report of MFS presenting with atypical alternating ptosis or with concurrent elevation of serum GD1 and asialo-GM1 antibody titers, and negative titers of GQ1b antibody such as our patient. Our objective is to report MFS with unusual symptoms and to share our diagnostic approach. We report a rare case of MFS presenting with alternating eyelid ptosis, paresthesia, and ataxia after a respiratory infection. Initial neurological examination revealed left eyelid ptosis, hyporeflexia, positive Romberg sign, and ataxia. The ice pack test was negative. Three days later, contralateral ptosis was observed, associated with areflexia and worsened ataxia. However, there was significant improvement of the previous left eyelid ptosis. Serology revealed elevated asialo-GM1 and GD1b antibodies. Acetylcholine receptor antibodies were negative. Cerebral spinal fluid revealed elevated IgG index. Nerve conduction studies (NCS) performed four days after the onset of symptoms showed normal nerve conduction velocities and F-waves, and absent bilateral H-reflexes. Repetitive nerve stimulation (3 Hz) showed no decrement of compound muscle action potentials. Trial with a single dose of pyridostigmine showed no clinical improvement. The symptoms resolved without intervention. NCS 18 days after onset of symptoms showed mildly prolonged F-waves and absent H-reflexes. This case highlights an atypical presentation of MFS and raises the awareness of a rare autoantibody associated with it.
Assuntos
Anticorpos/sangue , Blefaroptose/sangue , Gangliosídeo G(M1)/imunologia , Gangliosídeos/imunologia , Adulto , Blefaroptose/patologia , Feminino , HumanosRESUMO
Rapidly progressive dementia (RPD) is caused by a heterogeneous group of neurological disorders, and the prototype is Creutzfeldt-Jakob disease (CJD). However, treatable causes including autoimmune encephalitis are often underrecognized and undertreated. A 72-year-old female patient was admitted with a 10-month history of rapidly progressive cognitive decline, visual hallucinations, paranoid behavior, diarrhea, and an 18-kg unintentional weight loss. On the physical exam, she was only oriented to the person and demonstrated an exaggerated startle response with diffuse rigidity. The initial clinical suspicion included CJD versus autoimmune encephalitis. Comprehensive laboratory testing, thyroid peroxidase, thyroglobulin antibodies, and autoimmune encephalitis panel were negative. The EEG showed mild to moderate diffuse slowing without any epileptiform abnormalities. An MRI brain revealed mild hippocampal atrophy. CSF testing revealed mild lymphocytic pleocytosis; RT-QuIC analysis and 14-3-3 protein were negative. There was no clinical improvement after treatment with IV steroids and IVIG. Repeated autoimmune encephalitis panel testing performed on a research basis was positive for dipeptidyl-peptidase-like protein 6 (DPPX) antibodies in serum and CSF. Unfortunately, our patient passed away before additional treatment could be attempted. Anti-DPPX encephalitis is a rare autoimmune disorder and an unrecognized cause of RPD. Early diagnosis and rapid escalation of treatment are imperative to avoid devastating neurological consequences.
RESUMO
Carbohydrate-protein interactions are key for cell-cell and host-pathogen recognition and thus, emerged as viable therapeutic targets. However, their hydrophilic nature poses major limitations to the conventional development of drug-like inhibitors. To address this shortcoming, four fragment libraries were screened to identify metal-binding pharmacophores (MBPs) as novel scaffolds for inhibition of Ca2+-dependent carbohydrate-protein interactions. Here, we show the effect of MBPs on the clinically relevant lectins DC-SIGN, Langerin, LecA and LecB. Detailed structural and biochemical investigations revealed the specificity of MBPs for different Ca2+-dependent lectins. Exploring the structure-activity relationships of several fragments uncovered the functional groups in the MBPs suitable for modification to further improve lectin binding and selectivity. Selected inhibitors bound efficiently to DC-SIGN-expressing cells. Altogether, the discovery of MBPs as a promising class of Ca2+-dependent lectin inhibitors creates a foundation for fragment-based ligand design for future drug discovery campaigns.
RESUMO
BACKGROUND: Gabapentin is a commonly used medication for neuropathic pain and epilepsy that is prescribed by a wide range of medical specialties. Adverse effects including asterixis and myoclonus have been described in patients with chronic kidney disease, but myokymia has not been previously reported. CASE PRESENTATION: A 69-year-old man with a history of traumatic brain injury, peripheral neuropathy, amnesia, and posttraumatic stress disorder presented to the hospital after multiple falls attributed to acute onset muscle spasms. He reported taking a total daily dose of 9600 mg of gabapentin, as prescribed. Physical examination demonstrated stimulus-sensitive myoclonus, painful muscle spasms in all extremities, and myokymia in his bilateral calves. Diffuse action tremors, as well as tongue tremors, were also observed.Initial workup, including basic laboratory investigations, brain imaging, and electroencephalogram, was unrevealing. Gabapentin toxicity was suspected, and a gabapentin holiday was initiated with the improvement of myokymia by hospital day 3. The patient was found to have a high gabapentin level (25.8 µg/mL; reference range, 2.0-20.0 µg/mL) measured the morning after hospital presentation. After restarting on a lower dose of gabapentin with multimodal pain control, the patient continued to improve with diminution of his myoclonus, tremor, and gait instability. CONCLUSIONS: Myokymia is a newly described motor symptom associated with gabapentin toxicity. The mechanism of gabapentin-associated myokymia is currently unknown. A brief medication holiday resulted in the resolution of motor symptoms without significant withdrawal symptoms. Knowledge of this newly reported adverse manifestation can aid physicians in the diagnosis of gabapentin toxicity and prompt treatment, as gabapentin levels are not widely or immediately available.
Assuntos
Ácidos Cicloexanocarboxílicos , Mioquimia , Idoso , Aminas/efeitos adversos , Animais , Bovinos , Ácidos Cicloexanocarboxílicos/efeitos adversos , Gabapentina , Humanos , Masculino , Ácido gama-Aminobutírico/efeitos adversosRESUMO
Background: Paraneoplastic stiff-limb syndrome (SLS) is a rare manifestation of underlying malignancy and could have distinctive features different from the classic stiff-person syndrome (SPS). Case Description: We present a case of anti-amphiphysin antibody (Ab)-associated paraneoplastic SLS, in an 83-year-old woman with invasive ductal carcinoma of the breast. She presented with stiffness, painful spasms of the distal legs, and asymmetrical fixed posturing of the foot. There are coexisting long-tract disturbance and lower-extremity weakness. Treatment with diazepam provided symptomatic relief while plasma exchange (PLEX) did not lead to significant clinical improvement. The patient was bedridden within 3 months and passed away within 6 months from symptom onset. Conclusion: This case highlights the importance of recognition of uncommon presentation of SPS and its oncological significance. This entity requires a high degree of suspicion for initiation of the proper workup. The rapid identification and treatment of the underlying tumor might offer the best chance for recovery.
RESUMO
Coccidioidomycosis, a fungal infection caused by inhaling spores of Coccidioides immitis/posadasii, is endemic to the southwestern states of the United States, Northern Mexico and some parts of Central and South America. It is primarily a pulmonary infection with less than 0.5% of symptomatic cases showing dissemination. Skin, lymph nodes and bone are the commonest sites. Neurological involvement is rare and commonly presents as strokes, abscesses or meningoencephalitis. We present the case of a previously healthy 23-year-old African American male, presented with a four-month history of progressive right upper extremity weakness that initially started with right shoulder pain followed by worsening weakness and loss of muscle mass. Electromyography (EMG) demonstrated right brachial plexopathy with moderate-to-severe active denervation changes. MRI cervical spine revealed a 9-cm contrast enhancing extradural mass extending through the neural foramen from C4-T1 roots and forming a 4-cm right apical lung mass subsequently seen on MRI of the brachial plexus. All trunks, divisions and cords were thickened, hyperintense and showed contrast enhancement on MRI. Neuromuscular ultrasound (NUS) demonstrated enlargement of peripheral nerves. Differentials prior to biopsy of the mass ranged from neurofibromas to pancoast lung tumors. Coccidioidomycosis did not figure on the initial list of differentials. Patient underwent subsequent biopsy of the extradural and lung masses that showed coccidiodes. Serum coccidioides antibody titers were elevated. The patient was treated with high-dose intravenous fluconazole and aggressive mass debridement. His weakness improved on four months follow-up evaluation with significant resolution of EMG abnormalities and decreased swelling on NUS.
RESUMO
The tyrosine phosphatase SHP2 controls the activity of pivotal signaling pathways, including MAPK, JAK-STAT, and PI3K-Akt. Aberrant SHP2 activity leads to uncontrolled cell proliferation, tumorigenesis, and metastasis. SHP2 signaling was recently linked to drug resistance against cancer medications such as MEK and BRAF inhibitors. In this work, we present the development of a novel class of azaindole SHP2 inhibitors. We applied scaffold hopping and bioisosteric replacement concepts to eliminate unwanted structural motifs and to improve the inhibitor characteristics of the previously reported pyrazolone SHP2 inhibitors. The most potent azaindole 45 inhibits SHP2 with an IC50 = 0.031 µM in an enzymatic assay and with an IC50 = 2.6 µM in human pancreas cells (HPAF-II). Evaluation in a series of cellular assays for metastasis and drug resistance demonstrated efficient SHP2 blockade. Finally, 45 inhibited proliferation of two cancer cell lines that are resistant to cancer drugs and diminished ERK signaling.
Assuntos
Inibidores Enzimáticos/farmacologia , Indóis/farmacologia , Proteína Tirosina Fosfatase não Receptora Tipo 11/antagonistas & inibidores , Pirazolonas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Domínio Catalítico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/metabolismo , Humanos , Indóis/síntese química , Indóis/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Estrutura Molecular , Ligação Proteica , Proteína Tirosina Fosfatase não Receptora Tipo 11/química , Proteína Tirosina Fosfatase não Receptora Tipo 11/metabolismo , Pirazolonas/síntese química , Pirazolonas/metabolismo , Relação Estrutura-AtividadeRESUMO
Autoimmune mechanisms are implicated in both myasthenia gravis (MG) and multiple sclerosis (MS), and hypothesis of a common immunological mechanism of pathogenesis is supported by the fact that this rare combination of the two diseases occurs more frequently than expected by random association. Although MS is primarily mediated by T lymphocytes and MG primarily involves the destruction of the neuromuscular junction by antibodies, there are evidences that support both cell-mediated and humoral immunity are involved in the pathogenesis of both diseases. Different studies have shown dysfunction of T cells as well as B cells involved in the pathogenesis of both disorders. Previous case reports, mainly present female patients who had a mild presentation of MG, either prior or after diagnosis of MS. In this article, in addition to presenting a unique male patient with a previous diagnosis of MS, who presented with MG crisis, we aimed to review the literature to find the common immunological mechanisms involved in the pathogenesis of MG and MS.
Assuntos
Esclerose Múltipla/complicações , Esclerose Múltipla/imunologia , Miastenia Gravis/complicações , Miastenia Gravis/imunologia , Diagnóstico Diferencial , Humanos , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/diagnóstico , Esclerose Múltipla/terapia , Miastenia Gravis/diagnóstico , Miastenia Gravis/terapiaRESUMO
PURPOSE OF REVIEW: Brachial plexopathies (BPs) are a heterogeneous group of diseases which can profoundly affect person's function and quality of life. This review targets current approaches to treatment of different BP types. RECENT FINDINGS: Although there are multiple BP etiologies, non-traumatic causes are particularly unrecognized by clinicians, leading to misdiagnoses and delay in appropriate therapies. Recent data suggests that idiopathic neuralgic amyotrophy may be 50-fold more common than previously thought, with poorer outcomes than reported unless rapid diagnosis is followed by a multidisciplinary approach to treatment, including surgery for refractory cases. Advances in diagnostic imaging reduce time to treatment, if proper recognition by primary providers leads to rapid referral to neurologists. Due to rarity, heterogeneity, and overlap of different BP syndromes, development of treatment strategies is still based on case series and retrospective studies. Despite advances in surgical therapies, there are no randomized trials to guide optimal approaches to treatment in either traumatic or non-traumatic cases. Recent advances in imaging and surgical therapies may significantly improve clinical outcomes for patients with BPs, if rapid diagnosis of these often under-recognized conditions can be substantially improved to optimize approach to management. Controlled trials are still needed to optimize therapeutic strategies.