Structural insight into DNA joining: from conserved mechanisms to diverse scaffolds

Abstract DNA ligases are diverse enzymes with essential functions in replication and repair of DNA; here we review recent advances in their structure and distribution and discuss how this contributes to understanding their biological roles and technological potential. Recent high-resolution crystal structures of DNA ligases from different organisms, including DNA-bound states and reaction intermediates, have provided considerable insight into their enzymatic mechanism and substrate interactions. All cellular organisms possess at least one DNA ligase, but many species encode multiple forms some of which are modular multifunctional enzymes. New experimental evidence for participation of DNA ligases in pathways with additional DNA modifying enzymes is defining their participation in non-redundant repair processes enabling elucidation of their biological functions. Coupled with identification of a wealth of DNA ligase sequences through genomic data, our increased appreciation of the structural diversity and phylogenetic distribution of DNA ligases has the potential to uncover new biotechnological tools and provide new treatment options for bacterial pathogens.

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Mycobacterium abscessus l,d-Transpeptidases Are Susceptible to Inactivation by Carbapenems and Cephalosporins but Not Penicillins

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00866-17 ◽

2017 ◽

Vol 61 (10) ◽

Cited By ~ 20

Author(s):

Pankaj Kumar ◽

Varsha Chauhan ◽

José Rogério A. Silva ◽

Jerônimo Lameira ◽

Felipe B. d'Andrea ◽

...

Keyword(s):

Treatment Options ◽

Mycobacterium Abscessus ◽

Clinical Isolates ◽

Drug Resistant ◽

Computational Simulations ◽

Content Type ◽

Resistant Strains ◽

New Treatment ◽

Drug Resistant Strains ◽

Insight Into

ABSTRACT As a growing number of clinical isolates of Mycobacterium abscessus are resistant to most antibiotics, new treatment options that are effective against these drug-resistant strains are desperately needed. The majority of the linkages in the cell wall peptidoglycan of M. abscessus are synthesized by nonclassical transpeptidases, namely, the l,d-transpeptidases. Emerging evidence suggests that these enzymes represent a new molecular vulnerability in this pathogen. Recent studies have demonstrated that inhibition of these enzymes by the carbapenem class of β-lactams determines their activity against Mycobacterium tuberculosis. Here, we studied the interactions of β-lactams with two l,d-transpeptidases in M. abscessus, namely, LdtMab1 and LdtMab2, and found that both the carbapenem and cephalosporin, but not penicillin, subclasses of β-lactams inhibit these enzymes. Contrary to the commonly held belief that combination therapy with β-lactams is redundant, doripenem and cefdinir exhibit synergy against both pansusceptible M. abscessus and clinical isolates that are resistant to most antibiotics, which suggests that dual-β-lactam therapy has potential for the treatment of M. abscessus. Finally, we solved the first crystal structure of an M. abscessus l,d-transpeptidase, LdtMab2, and using substitutions of critical amino acids in the catalytic site and computational simulations, we describe the key molecular interactions between this enzyme and β-lactams, which provide an insight into the molecular basis for the relative efficacy of different β-lactams against M. abscessus.

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Structure-based engineering of substrate specificity for pinoresinol-lariciresinol reductases

Nature Communications ◽

10.1038/s41467-021-23095-y ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Ying Xiao ◽

Kai Shao ◽

Jingwen Zhou ◽

Lian Wang ◽

Xueqi Ma ◽

...

Keyword(s):

Substrate Specificity ◽

Bound States ◽

Large Scale ◽

Structural Diversity ◽

Structural Elements ◽

Isatis Indigotica ◽

Substrate Specificities ◽

Lignan Biosynthesis ◽

Insight Into

AbstractPinoresinol–lariciresinol reductases (PLRs) are enzymes involved in the lignan biosynthesis after the initial dimerization of two monolignols, and this represents the entry point for the synthesis of 8-8′ lignans and contributes greatly to their structural diversity. Of particular interest has been the determination of how differing substrate specificities are achieved with these enzymes. Here, we present crystal structures of IiPLR1 from Isatis indigotica and pinoresinol reductases (PrRs) AtPrR1 and AtPrR2 from Arabidopsis thaliana, in the apo, substrate-bound and product-bound states. Each structure contains a head-to-tail homodimer, and the catalytic pocket comprises structural elements from both monomers. β4 loop covers the top of the pocket, and residue 98 from the loop governs catalytic specificity. The substrate specificities of IiPLR1 and AtPrR2 can be switched via structure-guided mutagenesis. Our study provides insight into the molecular mechanism underlying the substrate specificity of PLRs/PrRs and suggests an efficient strategy for the large-scale commercial production of the pharmaceutically valuable compound lariciresinol.

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Management of thoracic aortic lesions - the future is endovascular

VASA ◽

10.1024/0301-1526/a000183 ◽

2012 ◽

Vol 41 (3) ◽

pp. 163-176 ◽

Cited By ~ 6

Author(s):

Weidenhagen ◽

Bombien ◽

Meimarakis ◽

Geisler ◽

A. Koeppel

Keyword(s):

Thoracic Aorta ◽

Clinical Decision Making ◽

Treatment Options ◽

Clinical Decision ◽

Clinical Results ◽

Treatment Modalities ◽

Traumatic Rupture ◽

Descending Thoracic Aorta ◽

New Treatment ◽

Aneurysm Dissection

Open surgical repair of lesions of the descending thoracic aorta, such as aneurysm, dissection and traumatic rupture, has been the state-of-the-art treatment for many decades. However, in specialized cardiovascular centers, thoracic endovascular aortic repair and hybrid aortic procedures have been implemented as novel treatment options. The current clinical results show that these procedures can be performed with low morbidity and mortality rates. However, due to a lack of randomized trials, the level of reliability of these new treatment modalities remains a matter of discussion. Clinical decision-making is generally based on the experience of the vascular center as well as on individual factors, such as life expectancy, comorbidity, aneurysm aetiology, aortic diameter and morphology. This article will review and discuss recent publications of open surgical, hybrid thoracic aortic (in case of aortic arch involvement) and endovascular repair in complex pathologies of the descending thoracic aorta.

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A Genomic Approach to Characterize the Vulnerable Patient – a Clinical Update

Journal of Interdisciplinary Medicine ◽

10.2478/jim-2019-0023 ◽

2019 ◽

Vol 4 (3) ◽

pp. 141-144

Author(s):

Evelin Szabó ◽

Zsolt Parajkó ◽

Diana Opincariu ◽

Monica Chițu ◽

Nóra Raț ◽

...

Keyword(s):

Risk Factors ◽

Myocardial Ischemia ◽

Treatment Options ◽

Ischemic Heart ◽

Pathophysiological Mechanism ◽

Ischemia And Reperfusion Injury ◽

Myocardial Ischemia And Reperfusion ◽

Vulnerable Patient ◽

Traditional Risk Factors ◽

New Treatment

Abstract Atherosclerosis is the elemental precondition for any cardiovascular disease and the predominant cause of ischemic heart disease that often leads to myocardial infarction. Systemic risk factors play an important role in the starting and progression of atherosclerosis. The complexity of the disease is caused by its multifactorial origin. Besides the traditional risk factors, genetic predisposition is also a strong risk factor. Many studies have intensively researched cardioprotective drugs, which can relieve myocardial ischemia and reperfusion injury, thereby reducing infarct size. A better understanding of abnormal epigenetic pathways in the myocardial pathology may result in new treatment options. Individualized therapy based on genome sequencing is important for an effective future medical treatment. Studies based on multiomics help to better understand the pathophysiological mechanism of several diseases at a molecular level. Epigenomic, transcriptomic, proteomic, and metabolomic research may be essential in detecting the pathological phenotype of myocardial ischemia and ischemic heart failure.

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Proteomic Analysis of the Vitreous Body in Proliferative and Non-Proliferative Diabetic Retinopathy

Current Proteomics ◽

10.2174/1570164617666200302101442 ◽

2020 ◽

Vol 17 ◽

Cited By ~ 1

Author(s):

Van-An Duong ◽

Jeeyun Ahn ◽

Na-Young Han ◽

Jong-Moon Park ◽

Jeong-Hun Mok ◽

...

Keyword(s):

Diabetic Retinopathy ◽

Proliferative Diabetic Retinopathy ◽

Microvascular Complications ◽

Treatment Options ◽

Vitreous Body ◽

Control Group ◽

Diabetic Patients ◽

Protein Protein Interaction ◽

Alpha Beta ◽

New Treatment

Background: Diabetic Retinopathy (DR), one of the major microvascular complications commonly occurring in diabetic patients, can be classified into Proliferative Diabetic Retinopathy (PDR) and Non-Proliferative Diabetic Retinopathy (NPDR). Currently available therapies are only targeted for later stages of the disease in which some pathologic changes may be irreversible. Thus, there is a need to develop new treatment options for earlier stages of DR through revealing pathological mechanisms of PDR and NPDR. Objective: The purpose of this study was to characterize proteomes of diabetic through quantitative analysis of PDR and NPDR. Methods: Vitreous body was collected from three groups: control (non-diabetes mellitus), NPDR, and PDR. Vitreous proteins were digested to peptide mixtures and analyzed using LC-MS/MS. MaxQuant was used to search against the database and statistical analyses were performed using Perseus. Gene ontology analysis, related-disease identification, and protein-protein interaction were performed using the differential expressed proteins. Results: Twenty proteins were identified as critical in PDR and NPDR. The NPDR group showed different expressions of kininogen-1, serotransferrin, ribonuclease pancreatic, osteopontin, keratin type II cytoskeletal 2 epidermal, and transthyretin. Also, prothrombin, signal transducer and activator of transcription 4, hemoglobin subunit alpha, beta, and delta were particularly up-regulated proteins for PDR group. The up-regulated proteins related to complement and coagulation cascades. Statherin was down-regulated in PDR and NPDR compared with the control group. Transthyretin was the unique protein that increased its abundance in NPDR compared with the PDR and control group. Conclusion: This study confirmed the different expressions of some proteins in PDR and NPDR. Additionally, we revealed uniquely expressed proteins of PDR and NPDR, which would be differential biomarkers: prothrombin, alpha-2-HS-glycoprotein, hemoglobin subunit alpha, beta, and transthyretin.

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Immunotherapy and potential predictive biomarkers in the treatment of neuroendocrine neoplasia

Future Oncology ◽

10.2217/fon-2020-0703 ◽

2020 ◽

Author(s):

Guanghui Xu ◽

Yuhao Wang ◽

Hushan Zhang ◽

Xueke She ◽

Jianjun Yang

Keyword(s):

Current Knowledge ◽

Checkpoint Inhibitors ◽

Treatment Options ◽

Predictive Biomarkers ◽

The Body ◽

Low Grade ◽

Ablative Therapies ◽

Cancer Types ◽

New Treatment ◽

Well Differentiated

Neuroendocrine neoplasias (NENs) are a heterogeneous group of rare tumors scattered throughout the body. Surgery, locoregional or ablative therapies as well as maintenance treatments are applied in well-differentiated, low-grade NENs, whereas cytotoxic chemotherapy is usually applied in high-grade neuroendocrine carcinomas. However, treatment options for patients with advanced or metastatic NENs are limited. Immunotherapy has provided new treatment approaches for many cancer types, including neuroendocrine tumors, but predictive biomarkers of immune checkpoint inhibitors (ICIs) in the treatment of NENs have not been fully reported. By reviewing the literature and international congress abstracts, we summarize the current knowledge of ICIs, potential predicative biomarkers in the treatment of NENs, implications and efficacy of ICIs as well as biomarkers for NENs of gastroenteropancreatic system, lung NENs and Merkel cell carcinoma in clinical practice.

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Inhibition of Proinflammatory Cytokines in Cutibacterium acnes-Induced Inflammation in HaCaT Cells by Using Buddleja davidii Aqueous Extract

International Journal of Inflammation ◽

10.1155/2020/8063289 ◽

2020 ◽

Vol 2020 ◽

pp. 1-8

Author(s):

Anh Thu Nguyen ◽

Ki-young Kim

Keyword(s):

Proinflammatory Cytokines ◽

Proinflammatory Cytokine ◽

Treatment Options ◽

Mapk Signaling ◽

Cytokine Expression ◽

Proinflammatory Cytokine Expression ◽

Cutibacterium Acnes ◽

Anti Inflammatory ◽

New Treatment ◽

Hacat Keratinocyte

Acne is an inflammatory skin disorder; although some anti-inflammatory medicines for treating acne are available in a market, they have considerable side effects; therefore, new treatment options are needed. In the present study, among the 16 aqueous extracts of plants collected from Jeju Island in Korea which are used to test anti-inflammatory activity, B. davidii showed the strong decline of the proinflammatory cytokine expression against the inflammatory process caused by C. acnes in Human HaCaT keratinocyte cells. B. davidii downregulated the expression of 57% of COX-2, 41% of iNOS, and proinflammatory cytokines 29% of TNF-α, 32% of IL-1β, 21% of IL-6, and 35% of IL-8. Furthermore, B. davidii inhibited NF-κB and MAPK signaling cascades in keratinocytes that activated by toll-like receptor 2 (TLR-2) in response to C. acnes. Given those results, B. davidii is a potential agent to reduce the proinflammatory cytokine expression against C. acnes-induced inflammation and might provide an alternative to the current medications.

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Cancer Vaccines for Genitourinary Tumors: Recent Progresses and Future Possibilities

Vaccines ◽

10.3390/vaccines9060623 ◽

2021 ◽

Vol 9 (6) ◽

pp. 623

Author(s):

Brigida Anna Maiorano ◽

Giovanni Schinzari ◽

Davide Ciardiello ◽

Maria Grazia Rodriquenz ◽

Antonio Cisternino ◽

...

Keyword(s):

Cancer Vaccines ◽

Viral Vectors ◽

Checkpoint Inhibitors ◽

Treatment Options ◽

Tumor Development ◽

Resistance Mechanisms ◽

High Morbidity ◽

Therapeutic Vaccines ◽

Combination Strategies ◽

New Treatment

Background: In the last years, many new treatment options have widened the therapeutic scenario of genitourinary malignancies. Immunotherapy has shown efficacy, especially in the urothelial and renal cell carcinomas, with no particular relevance in prostate cancer. However, despite the use of immune checkpoint inhibitors, there is still high morbidity and mortality among these neoplasms. Cancer vaccines represent another way to activate the immune system. We sought to summarize the most recent advances in vaccine therapy for genitourinary malignancies with this review. Methods: We searched PubMed, Embase and Cochrane Database for clinical trials conducted in the last ten years, focusing on cancer vaccines in the prostate, urothelial and renal cancer. Results: Various therapeutic vaccines, including DNA-based, RNA-based, peptide-based, dendritic cells, viral vectors and modified tumor cells, have been demonstrated to induce specific immune responses in a variable percentage of patients. However, these responses rarely corresponded to significant survival improvements. Conclusions: Further preclinical and clinical studies will improve the knowledge about cancer vaccines in genitourinary malignancies to optimize dosage, select targets with a driver role for tumor development and growth, and finally overcome resistance mechanisms. Combination strategies represent possibly more effective and long-lasting treatments.

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Real-world treatment patterns in relapsed/refractory multiple myeloma: Clinical and economic outcomes in patients treated with pomalidomide or daratumumab

Journal of Oncology Pharmacy Practice ◽

10.1177/1078155221995532 ◽

2021 ◽

pp. 107815522199553

Author(s):

Joshua Richter ◽

Vamshi Ruthwik Anupindi ◽

Jason Yeaw ◽

Suneel Kudaravalli ◽

Stojan Zavisic ◽

...

Keyword(s):

Multiple Myeloma ◽

Real World ◽

Treatment Options ◽

Proteasome Inhibitors ◽

Economic Outcomes ◽

Office Visits ◽

Refractory Multiple Myeloma ◽

Kaplan Meier ◽

Real World Evidence ◽

New Treatment

Introduction Real-world evidence on later line treatment of relapsed/refractory multiple myeloma (RRMM) is sparse. We evaluated clinical outcomes among RRMM patients in the 1-year following treatment with pomalidomide or daratumumab and compared economic outcomes between RRMM patients and non-MM patients. Patient and Methods Adult patients with ≥1 claim of pomalidomide or daratumumab were identified between January 2012 and February 2018 using IQVIA PharMetrics® Plus US claims database. Patients were required to have a diagnosis or treatment for MM and a claim of any immunomodulatory drugs and proteasome inhibitors before the index date. Mean time to new therapy, overall survival (OS) using Kaplan-Meier curve and adverse events (AEs) were reported over the 1-year post-index period. RRMM patients were also matched to a non-MM comparator cohort and economic outcomes were compared between the two cohorts. Results 289 RRMM patients were matched to 1,445 patients without MM. Most prevalent hematological AE was anemia (72.0%) and non-hematological AE was infections (75.4%). Mean (SD) time to a new treatment was 4.7 (5.3) months and median OS was 14.6 months. RRMM patients had significantly higher hospitalizations and physician office visits (Both P < .0001) compared to non-MM patients. Adjusting for baseline characteristics, patients with RRMM had 4.9 times (95% CI 3.8-6.4, P < .0001) the total healthcare costs compared with patients without MM. The major driver of total costs among RRMM patients was pharmacy costs (67.3%). Conclusion RRMM patients showed a high frequency of AEs, low OS, and a substantial economic burden suggesting need for effective treatment options.

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Biomimetic nanotherapy: core–shell structured nanocomplexes based on the neutrophil membrane for targeted therapy of lymphoma

Journal of Nanobiotechnology ◽

10.1186/s12951-021-00922-4 ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Qiangqiang Zhao ◽

Duanfeng Jiang ◽

Xiaoying Sun ◽

Qiuyu Mo ◽

Shaobin Chen ◽

...

Keyword(s):

Mesoporous Silica Nanoparticles ◽

Treatment Options ◽

Inflammatory Factors ◽

Main Method ◽

Tnf Α ◽

Good Biocompatibility ◽

Inflammatory Drugs ◽

Anti Inflammatory ◽

New Treatment ◽

Lymphoma Therapy

Abstract Background Non-Hodgkin’s lymphoma (NHL) is a malignant disease of lymphoid tissue. At present, chemotherapy is still the main method for the treatment of NHL. R-CHOP can significantly improve the survival rate of patients. Unfortunately, DOX is the main cytotoxic drug in R-CHOP and it can lead to adverse reactions. Therefore, it is particularly important to uncover new treatment options for NHL. Results In this study, a novel anti-tumor nanoparticle complex Nm@MSNs-DOX/SM was designed and constructed in this study. Mesoporous silica nanoparticles (MSNs) loaded with Doxorubicin (DOX) and anti-inflammatory drugs Shanzhiside methylester (SM) were used as the core of nanoparticles. Neutrophil membrane (Nm) can be coated with multiple nanonuclei as a shell. DOX combined with SM can enhance the anti-tumor effect, and induce apoptosis of lymphoma cells and inhibit the expression of inflammatory factors related to tumorigenesis depending on the regulation of Bcl-2 family-mediated mitochondrial pathways, such as TNF-α and IL-1β. Consequently, the tumor microenvironment (TME) was reshaped, and the anti-tumor effect of DOX was amplified. Besides, Nm has good biocompatibility and can enhance the EPR effect of Nm@MSNs-DOX/SM and increase the effect of active targeting tumors. Conclusions This suggests that the Nm-modified drug delivery system Nm@MSNs-DOX/SM is a promising targeted chemotherapy and anti-inflammatory therapy nanocomplex, and may be employed as a specific and efficient anti-Lymphoma therapy.

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