Resveratrol Regulates Mitochondrial Biogenesis and Fission/Fusion to Attenuate Rotenone-Induced Neurotoxicity

It has been confirmed that mitochondrial impairment may underlie both sporadic and familial Parkinson’s disease (PD). Mitochondrial fission/fusion and biogenesis are key processes in regulating mitochondrial homeostasis. Therefore, we explored whether the protective effect of resveratrol in rotenone-induced neurotoxicity was associated with mitochondrial fission/fusion and biogenesis. The results showed that resveratrol could not only promote mitochondrial mass and DNA copy number but also improve mitochondrial homeostasis and neuron function in rats and PC12 cells damaged by rotenone. We also observed effects with alterations in proteins known to regulate mitochondrial fission/fusion and biogenesis in rotenone-induced neurotoxicity. Therefore, our findings suggest that resveratrol may prevent rotenone-induced neurotoxicity through regulating mitochondrial fission/fusion and biogenesis

Reactive Type II Pneumocyte Hyperplasia Versus Adenocarcinoma

Reactive type II pneumocyte hyperplasia is a nonspecific reactive proliferation of type II pneumocytes in response to a variety of lung injuries and to repair and restore alveolar epithelial integrity. Type II pneumocyte hyperplasia, when exuberant, can exhibit overlapping cytomorphology with adenocarcinoma. The underlying lung injuries sometimes can present as a mass lesion clinically. In the setting of limited biopsy specimens, it is important to differentiate reactive type II pneumocyte hyperplasia from adenocarcinomas with lepidic or acinar growth patterns to avoid over- or underdiagnosis. This chapter will explore the differential features between these two entities. The identification of underlying acute lung injury is an important factor to support reactive type II pneumocyte hyperplasia. The proliferating type II pneumocytes typically have uniformly enlarged nonoverlapping vesicular nuclei with a regular and smooth nuclear membrane and a single prominent nucleolus. The N/C ratio and apical-basal polarity are maintained. The overall configuration of the alveoli is preserved. The septa are usually slightly thickened by reactive stromal cells including reactive endothelial cells and inflammatory cell infiltrates

Ligand-Based Drug Design of Novel Antimicrobials against Staphylococcus aureus by Targeting Bacterial Transcription

Staphylococcus aureus is a common human commensal pathogen that causes a wide range of infectious diseases. Due to the generation of antimicrobial resistance, the pathogen becomes resistant to more and more antibiotics, resulting in methicillin-resistant S. aureus (MRSA) and even multidrug-resistant S. aureus (MDRSA), namely ‘superbugs’. This situation highlights the urgent need for novel antimicrobials. Bacterial transcription, which is responsible for bacterial RNA synthesis, is a valid but underutilized target for developing antimicrobials. Previously, we reported a novel class of antimicrobials, coined nusbiarylins, that inhibited bacterial transcription by interrupting the protein–protein interaction (PPI) between two transcription factors NusB and NusE. In this work, we developed a ligand-based workflow based on the chemical structures of nusbiarylins and their activity against S. aureus. The ligand-based models—including the pharmacophore model, 3D QSAR, AutoQSAR, and ADME/T calculation—were integrated and used in the following virtual screening of the ChemDiv PPI database. As a result, four compounds, including J098-0498, 1067-0401, M013-0558, and F186-026, were identified as potential antimicrobials against S. aureus, with predicted pMIC values ranging from 3.8 to 4.2. The docking study showed that these molecules bound to NusB tightly with the binding free energy ranging from −58 to −66 kcal/mol

First-In-Class Inhibitors Targeting the Interaction between Bacterial RNA Polymerase and Sigma Initiation Factor Affect the Viability and Toxin Release of Streptococcus pneumoniae

Novel antimicrobial classes are in desperate need for clinical management of infections caused by increasingly prevalent multi-drug resistant pathogens. The protein-protein interaction between bacterial RNA polymerase (RNAP) and the housekeeping sigma initiation factor is essential to transcription and bacterial viability. It also presents a potential target for antimicrobial discovery, for which a hit compound (C3) was previously identified from a pharmacophore model-based in silico screen. In this study, the hit compound was experimentally assessed with some rationally designed derivatives for the antimicrobial activities, in particular against Streptococcus pneumoniae and other pathogens. One compound, C3-005, shows dramatically improved activity against pneumococci compared to C3. C3-005 also attenuates S. pneumoniae toxin production more strongly than existing classes of antibiotics tested. Here we demonstrate a newly validated antimicrobial agent to address an overlooked target in the hit-to-lead process, which may pave the way for further antimicrobial development

Ligand-Based Drug Design of Novel Antimicrobials against <i>Staphylococcus aureus</i> by Targeting Bacterial Transcription

Staphylococcus aureus is a common human commensal pathogen that causes a wide range of infectious diseases. Due to the generation of antimicrobial resistance, the pathogen becomes resistant to more and more antibiotics, resulting in methicillin-resistant S. aureus (MRSA) and even multidrug-resistant S. aureus (MDRSA), namely ‘superbugs’. This situation highlights the urgent need for novel antimicrobials. Bacterial transcription, which is responsible for bacterial RNA synthesis, is a valid but underutilized target for developing antimicrobials. Previously, we reported a novel class of antimicrobials, coined nusbiarylins, that inhibited bacterial transcription by interrupting the protein–protein interaction (PPI) between two transcription factors NusB and NusE. In this work, we developed a ligand-based workflow based on the chemical structures of nusbiarylins and their activity against S. aureus. The ligand-based models—including the pharmacophore model, 3D QSAR, AutoQSAR, and ADME/T calculation—were integrated and used in the following virtual screening of the ChemDiv PPI database. As a result, four compounds, including J098-0498, 1067-0401, M013-0558, and F186-026, were identified as potential antimicrobials against S. aureus, with predicted pMIC values ranging from 3.8 to 4.2. The docking study showed that these molecules bound to NusB tightly with the binding free energy ranging from −58 to −66 kcal/mol

Severe recurrent Streptobacillus moniliformis endocarditis in a pregnant woman, and review of the literature

BACKGROUND: Rat bite fever is a systemic febrile illness caused by infection with the Gram-negative bacillus Streptobacillus moniliformis following a bite, scratch, or contact with excrement. Only 26 cases of native valve endocarditis have been reported to date. We could find no other reports of severe Streptobacillus endocarditis requiring valve replacement in a young, pregnant patient. CASE PRESENTATION: A pregnant patient sought care for right leg pain, fevers, left upper quadrant pain, generalized weakness, fatigue, and inability to bear weight on her right leg. She had a syncopal episode 9 months earlier, resulting in a mandibular fracture and internal fixation hardware. Her pregnancy was complicated by hyperemesis and weight loss. Her pets included a rescued wild bird, a cat, and four rats. Her parents rescued stray cats, and she recalled multiple cat bites and scratches since childhood. She denied injection drug use. Ultrasound indicated a right popliteal artery thrombus. Transesophageal echocardiogram revealed a 2 cm × 0.7 cm vegetation. Angiography demonstrated multiple splenic infarcts and bilateral renal infarcts. She underwent mitral valve repair. The mitral valve Gram stain demonstrated 2+ Gram-negative rods, rare Gram-positive rods, and moderate white blood cells. Propionibacterium spp. was isolated from the mitral valve tissue on Columbia agar incubated anaerobically. Anaerobic and aerobic cultures of the valve tissue on all other broths and agars remained negative at 14 days. Hematoxylin and eosin stains showed a fibro-inflammatory vegetation. Aggregates of rod-shaped bacteria were identified on Warthin Starry/Steiner stain. Bartonella titers were positive for B. henselae IgG 1:256, IgM \u3c 1:20. Brown-Hopps Gram stain, AFB, and GMS stains for bacterial and fungal microorganisms were negative. Broad range bacterial PCR and sequencing of a segment of 16 s rRNA gene of the valve tissue matched to Streptobacillus sp. (genus level) and most closely related to Streptobacillus moniliformis. CONCLUSION: This case demonstrates diagnostic and therapeutic challenges associated with a relatively uncommon cause of endocarditis. The diagnosis of rat bite fever was delayed due to symptoms of a concomitant pregnancy. Other confounders included possible alternative sources or co-infections with another zoonosis from multiple pets, and an odontogenic source due to presence of exposed jaw hardware