Current treatment options for leptospirosis: a mini-review.

Leptospirosis, one of the most common global zoonotic infections, significantly impacts global human health, infecting more than a million people and causing approximately 60,000 deaths annually. This mini-review explores effective treatment strategies for leptospirosis, considering its epidemiology, clinical manifestations, and current therapeutic approaches. Emphasis is placed on antibiotic therapy, including recommendations for mild and severe cases, as well as the role of probiotics in modulating the gut microbiota. Furthermore, novel treatment options, such as bacteriophages and newly synthesized/natural compounds, are discussed, and the findings are expected to provide insights into promising approaches for combating leptospirosis.

Pan-Genome Plasticity and Virulence Factors: A Natural Treasure Trove for Acinetobacter baumannii.

Acinetobacter baumannii is a Gram-negative pathogen responsible for a variety of community- and hospital-acquired infections. It is recognized as a life-threatening pathogen among hospitalized individuals and, in particular, immunocompromised patients in many countries. A. baumannii, as a member of the ESKAPE group, encompasses high genomic plasticity and simultaneously is predisposed to receive and exchange the mobile genetic elements (MGEs) through horizontal genetic transfer (HGT). Indeed, A. baumannii is a treasure trove that contains a high number of virulence factors. In accordance with these unique pathogenic characteristics of A. baumannii, the authors aim to discuss the natural treasure trove of pan-genome and virulence factors pertaining to this bacterial monster and try to highlight the reasons why this bacterium is a great concern in the global public health system.

Unraveling the Potential of ALK-Targeted Therapies in Non-Small Cell Lung Cancer: Comprehensive Insights and Future Directions.

Background and Objective: This review comprehensively explores the intricate landscape of anaplastic lymphoma kinase (ALK), focusing specifically on its pivotal role in non-small cell lung cancer (NSCLC). Tracing ALK's discovery, from its fusion with nucleolar phosphoprotein (NPM)-1 in anaplastic large cell non-Hodgkin's lymphoma (ALCL) in 1994, the review elucidates the subsequent impact of ALK gene alterations in various malignancies, including inflammatory myofibroblastoma and NSCLC. Approximately 3-5% of NSCLC patients exhibit complex ALK rearrangements, leading to the approval of six ALK-tyrosine kinase inhibitors (TKIs) by 2022, revolutionizing the treatment landscape for advanced metastatic ALK + NSCLC. Notably, second-generation TKIs such as alectinib, ceritinib, and brigatinib have emerged to address resistance issues initially associated with the pioneer ALK-TKI, crizotinib. Methods: To ensure comprehensiveness, we extensively reviewed clinical trials on ALK inhibitors for NSCLC by 2023. Additionally, we systematically searched PubMed, prioritizing studies where the terms "ALK" AND "non-small cell lung cancer" AND/OR "NSCLC" featured prominently in the titles. This approach aimed to encompass a spectrum of relevant research studies, ensuring our review incorporates the latest and most pertinent information on innovative and alternative therapeutics for ALK + NSCLC. Key Content and Findings: Beyond exploring the intricate details of ALK structure and signaling, the review explores the convergence of ALK-targeted therapy and immunotherapy, investigating the potential of immune checkpoint inhibitors in ALK-altered NSCLC tumors. Despite encouraging preclinical data, challenges observed in trials assessing combinations such as nivolumab-crizotinib, mainly due to severe hepatic toxicity, emphasize the necessity for cautious exploration of these novel approaches. Additionally, the review explores innovative directions such as ALK molecular diagnostics, ALK vaccines, and biosensors, shedding light on their promising potential within ALK-driven cancers. Conclusions: This comprehensive analysis covers molecular mechanisms, therapeutic strategies, and immune interactions associated with ALK-rearranged NSCLC. As a pivotal resource, the review guides future research and therapeutic interventions in ALK-targeted therapy for NSCLC.

Multifactorial action of lavender and lavandin oils against filamentous fungi.

AIMS: In this study, five essential oils (EOs) from different species of Lavandula hybrida abrialis, for Lavandula hybrida R.C., Lavandula hybrida 'super A', Lavandula hybrida 'super Z' and Lavandula vera and its hybrids Lavender were evaluated against 26 dust-isolated fungal strains from North Africa. METHODS AND RESULTS: The composition of the different EOs was determined from volume to dry weight. The photochemical analyses were performed via gas chromatography (GC). The cytotoxic effect of five lavender EOs on human epithelial colorectal adenocarcinoma cells (Caco-2) cell line was done. A total of 26 strains of filamentous fungi including Aspergillus spp., Botrytis cinerea, Ceriporia spp., Fusarium spp. and Penicillium glabrum were isolated from sand dust samples via molecular diagnostic tool of PCR. Fungal strains with the lowest minimal lethal concentration (MLC) were Penicillium glabrum, Ceriporia spp. and a strain of Aspergillus spp. CONCLUSIONS: More studies are needed to verify the activity of this EO against more different fungal species, and determine the active ingredients.Significance and impact of study: MIC of the antifungal efficacy relating to EOs was evaluated. The EOs tests showed no cytotoxic effect at very low concentrations, ranging from 0.03% (IC50 0.9132 mg/mL) (L. hybrid Abrialis) to 0.001% (IC50 1.631 mg/mL) (L. hybrid R.C.).

Toll-like receptor-guided therapeutic intervention of human cancers: molecular and immunological perspectives.

Toll-like receptors (TLRs) serve as the body's first line of defense, recognizing both pathogen-expressed molecules and host-derived molecules released from damaged or dying cells. The wide distribution of different cell types, ranging from epithelial to immune cells, highlights the crucial roles of TLRs in linking innate and adaptive immunity. Upon stimulation, TLRs binding mediates the expression of several adapter proteins and downstream kinases, that lead to the induction of several other signaling molecules such as key pro-inflammatory mediators. Indeed, extraordinary progress in immunobiological research has suggested that TLRs could represent promising targets for the therapeutic intervention of inflammation-associated diseases, autoimmune diseases, microbial infections as well as human cancers. So far, for the prevention and possible treatment of inflammatory diseases, various TLR antagonists/inhibitors have shown to be efficacious at several stages from pre-clinical evaluation to clinical trials. Therefore, the fascinating role of TLRs in modulating the human immune responses at innate as well as adaptive levels directed the scientists to opt for these immune sensor proteins as suitable targets for developing chemotherapeutics and immunotherapeutics against cancer. Hitherto, several TLR-targeting small molecules (e.g., Pam3CSK4, Poly (I:C), Poly (A:U)), chemical compounds, phytocompounds (e.g., Curcumin), peptides, and antibodies have been found to confer protection against several types of cancers. However, administration of inappropriate doses of such TLR-modulating therapeutics or a wrong infusion administration is reported to induce detrimental outcomes. This review summarizes the current findings on the molecular and structural biology of TLRs and gives an overview of the potency and promises of TLR-directed therapeutic strategies against cancers by discussing the findings from established and pipeline discoveries.

Studying the effect of gene fusion of A and C types capsular synthesizing enzymes and anticancer sequence on inducing the expression of apoptotic BCL-2, BAX, and Caspase-3 genes by Real-time RT-PCR method.

Background: Today, uterine cancer is one of the most important causes of death in the world and is one of the major problems in human health. There have been numerous reports of the effect of Streptococcus agalactiae peptide and capsular products against cancer cell lines. Objective: This study aimed to research recombinant peptide CPSA-CPSC-L-ACAN and investigate its apoptotic effect against the HeLa cell line by Real-Time-RT PCR. Design: In this study confirmation of the recombinant fusion peptide was performed by Western blotting. The effect of cytotoxicity of different concentrations of recombinant fusion peptide against the HeLa cell line was investigated by the MTT technique. The expression of apoptotic genes including BAX, BCL-2, and Caspase-3 in comparison with the GAPDH reference gene before and after exposure to recombinant fusion peptide was measured by Real-Time RT-PCR. Results: Recombinant fusion peptide at a concentration of 63 µg/ml destroyed 50% of the HeLa cell line in 24 h and cell treatment with this concentration increased gene expression of Caspase-3 genes by 16 times, bax by 6 times and decreased the expression of bcl-2 by 0.176 times. Conclusions: The results showed that treatment of the HeLa cell line with recombinant fusion peptide induced an apoptotic effect. The recombinant fusion peptide could probably help the medical community as a prophylactic or therapeutic treatment for cervical cancer.

Carbapenem-Resistant Klebsiella pneumoniae: Virulence Factors, Molecular Epidemiology and Latest Updates in Treatment Options.

Klebsiella pneumoniae is a Gram-negative opportunistic pathogen responsible for a variety of community and hospital infections. Infections caused by carbapenem-resistant K. pneumoniae (CRKP) constitute a major threat for public health and are strongly associated with high rates of mortality, especially in immunocompromised and critically ill patients. Adhesive fimbriae, capsule, lipopolysaccharide (LPS), and siderophores or iron carriers constitute the main virulence factors which contribute to the pathogenicity of K. pneumoniae. Colistin and tigecycline constitute some of the last resorts for the treatment of CRKP infections. Carbapenemase production, especially K. pneumoniae carbapenemase (KPC) and metallo-ß-lactamase (MBL), constitutes the basic molecular mechanism of CRKP emergence. Knowledge of the mechanism of CRKP appearance is crucial, as it can determine the selection of the most suitable antimicrobial agent among those most recently launched. Plazomicin, eravacycline, cefiderocol, temocillin, ceftolozane-tazobactam, imipenem-cilastatin/relebactam, meropenem-vaborbactam, ceftazidime-avibactam and aztreonam-avibactam constitute potent alternatives for treating CRKP infections. The aim of the current review is to highlight the virulence factors and molecular pathogenesis of CRKP and provide recent updates on the molecular epidemiology and antimicrobial treatment options.

Molecular Detection of gyrA Mutation in Clinical Strains of Klebsiella pneumoniae.

Background: Multi-drug resistant (MDR) Klebsiella pneumoniae strains cause the majority of community acquired and life-threatening infections. We aimed to detect the gyrA mutations in the clinical strains of nalidixic acid and ciprofloxacin resistant K. pneumoniae isolated from the patients with urinary tract infections. Methods: Bacterial strains were isolated from the patients with urinary tract infections admitted to a major hospital in Tehran, Iran (2017-2018). Bacterial identification was done according to standard microbiological tests. Antimicrobial susceptibility testing for quinolones and fluoroquinolone antibiotics was done using both disc diffusion and minimal inhibitory concentrations (MICs) methods. PCR-RFLP was used to detect the probable mutation in the gyrA gene in nalidixic acid and ciprofloxacin resistant strains. Finally sequencing was performed to detect point mutations in isolated K. pneumoniae strains. Results: One hundred K. pneumonia isolates were recovered from the urine samples of the clinical cases. Antibiotic resistance testing showed that among all K. pneumoniae isolates, 26% and 19% of the strains were resistant to nalidixic acid and ciprofloxacin respectively. MIC value was ≥4 µg/ml for ciprofloxacin resistant isolates. The results of RFLP on gyrA PCR amplicons using HinfI restriction enzyme showed point mutation in this gene in 46% of nalidixic acid and ciprofloxacin resistant K. pneumonia. The data obtained from the sequencing confirmed the RFLP results and indicated the presence of point mutations in codons 83 and 87 in the gyrA gene which leads to the substitution of different amino acids in gyrA protein. Conclusion: Our findings indicated a relative increased rate of resistance against quinolones and fluoroquinolone antibiotics that raised a concern about extensive dissemination of clinical strains of nalidixic acid and ciprofloxacin resistant K. pneumonia. Point mutation of gyrA gene was responsible for the resistance in our strains however to gain more insight into the molecular characterization of quinolone-resistant isolates, other possible mechanisms of the resistance should also be investigated.

Relationship between Biofilm-Formation, Phenotypic Virulence Factors and Antibiotic Resistance in Environmental Pseudomonas aeruginosa

The formation of a protective biofilm by Pseudomonas aeruginosa (PA) is one of the hallmarks of their survival both in vivo and in harsh environmental conditions, thus, biofilm-eradication has relevance from therapeutic perspectives and for infection control. The aim of our study was to investigate the possible relationship between antibiotic resistance, biofilm-forming capacity and virulence factors in n = 166 PA isolates of environmental origin. Antimicrobial susceptibility testing and the phenotypic detection of resistance determinants were carried out using standard protocols. The biofilm-forming capacity of PA was tested using a standardized crystal violet microtiter plate-based method. Motility (swimming, swarming, and twitching) and siderophore production of the isolates were also assessed. Resistance rates were highest for ciprofloxacin (46.98%), levofloxacin (45.18%), ceftazidime (31.92%) and cefepime (30.12%); 19.28% of isolates met the criteria to be classified as multidrug-resistant (MDR). Efflux pump overexpression, AmpC overexpression, and modified Hodge-test positivity were noted in 28.31%, 18.07% and 3.61%, respectively. 22.89% of isolates were weak/non-biofilm producers, while 27.71% and 49.40% were moderate and strong biofilm producers, respectively. Based on MDR status of the isolates, no significant differences in biofilm-production were shown among environmental PA (non-MDR OD570 [mean ± SD]: 0.416 ± 0.167 vs. MDR OD570: 0.399 ± 0.192; p > 0.05). No significant association was observed between either motility types in the context of drug resistance or biofilm-forming capacity (p > 0.05). 83.13% of isolates tested were positive for siderophore production. The importance of PA as a pathogen in chronic and healthcare-associated infections has been described extensively, while there is increasing awareness of PA as an environmental agent in agriculture and aquaculture. Additional studies in this field would be an important undertaking to understand the interrelated nature of biofilm production and antimicrobial resistance, as these insights may become relevant bases for developing novel therapeutics and eradication strategies against PA.

The Use of Monoclonal Antibody-Based Proprotein Convertase Subtilisin-Kexin Type 9 (PCSK9) Inhibitors in the Treatment of Hypercholesterolemia.

In this review, we evaluated several studies in the literature to analyze the benefits and deleterious effects of the use of monoclonal antibodies (MABs)-based proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors in patients with hypercholesterolemia. Increased low-density lipoprotein cholesterol (LDL-C) levels lead to an increase in the risk of cardiovascular (CV) disease. Statins are the cornerstones of hypercholesterolemia treatment, but the patient response may often vary, and additional therapies may be needed to control the increased LDL-C levels. MABs bind to PCSK9 receptors, causing a reduction in LDL-C levels. MAB-based PCSK9 inhibitors such as alirocumab and evolocumab have been approved for use in hypercholesterolemia in combination with statins. Studies have suggested that both alirocumab and evolocumab are effective in lowering LDL-C levels, have favorable side effect profiles, and can be administered at convenient dosing intervals; however, further double-blind, randomized trials evaluating the long-term safety and efficacy of both the agents could assist with clinical decision-making.

The Interleukin-1 (IL-1) Superfamily Cytokines and Their Single Nucleotide Polymorphisms (SNPs).

Interleukins (ILs)-which are important members of cytokines-consist of a vast group of molecules, including a wide range of immune mediators that contribute to the immunological responses of many cells and tissues. ILs are immune-glycoproteins, which directly contribute to the growth, activation, adhesion, differentiation, migration, proliferation, and maturation of immune cells; and subsequently, they are involved in the pro and anti-inflammatory responses of the body, by their interaction with a wide range of receptors. Due to the importance of immune system in different organisms, the genes belonging to immune elements, such as ILs, have been studied vigorously. The results of recent investigations showed that the genes pertaining to the immune system undergo progressive evolution with a constant rate. The occurrence of any mutation or polymorphism in IL genes may result in substantial changes in their biology and function and may be associated with a wide range of diseases and disorders. Among these abnormalities, single nucleotide polymorphisms (SNPs) can represent as important disruptive factors. The present review aims at concisely summarizing the current knowledge available on the occurrence, properties, role, and biological consequences of SNPs within the IL-1 family members.

Anti-hyperglycemic effects of Eryngium billardierei F. Delaroche extract on insulin-resistance HepG2 cells in vitro.

BACKGROUND: Insulin resistance as a major problem is associated with type 2 diabetes mellitus. This study investigated the effect of Eryngium billardierei on insulin-resistance induced HepG2 cells. METHODS AND RESULTS: MTT method was used to evaluate the viability of HepG2 cells treated with various doses of E. billardierei extract. An insulin-resistance model was established in HepG2 cells. Next, MTT assay and Acridine orange staining were performed to investigate the viability of cells in the vicinity of different concentrations of insulin, pioglitazone, and E. billardierei extract in an insulin-resistance media. The glucose uptake test was performed to select the optimal insulin concentration. Expression levels of IR, G6Pase, and PEPCK genes were assessed by real-time RT-PCR. According to obtained data, E. billardierei at concentrations of 0.5 and 1 mg/mL show no toxicity on cells. Furthermore, based on MTT assay and glucose uptake test 10-5 mol/L insulin was chosen as the model group to induce insulin-resistance in HepG2 cells for gene expression analysis. Finally, 1 mg/mL E. billardierei not only induced no cytotoxicity but also showed an increase in the expression of IR as well as a reduction in G6Pase and PEPCK level compared to the control and model groups. CONCLUSIONS: The obtained data indicated that 1 mg/mL E. billardierei might have an anti-insulin resistance effect on insulin-resistance HepG2 cells in vitro and could be a promising candidate with anti-hyperglycemic properties for diabetes treatments.

Virulence factors, antibiotic resistance patterns, and molecular types of clinical isolates of Klebsiella Pneumoniae.

BACKGROUND: Klebsiella pneumoniae is armed with a wide range of antibiotic resistance mechanisms that mostly challenge effective treatment. The aims of the current study were to identify the clinical strains of K. pneumoniaealso to determine their phenotypes and molecular characterization related to antimicrobial resistance and virulence genes. RESEARCH DESIGN AND METHODS: In this investigation, clinical specimens from different hospitals located in Tehran, Iran, were collected during a nine-month period (December 2018 to August 2019). The K. pneumoniae strains were isolated and identified through standard microbial and biochemical assays. Additionally, disk diffusion, combined disk, Modified Hodge Test (MHT) and PCR were performed for antibiotic resistance and virulence gene analysis, respectively. RESULTS: Eighty-four isolates of K. pneumoniae were subjected to the study. According to the combined disk and modified Hodge test results, 27 (52%) and 15 pathotypes (62.5%) out of resistant strains of isolated K. pneumoniae were detected as ESBL and KPC producers. The virulence genes of mrkD (94%) and magA (11%) were the highest and lowest among isolates, respectively. CONCLUSIONS: The high prevalence of antibiotic resistance and virulence genes in conjunction with a significant relationship between the strains revealed a high pathogenic capacity of the isolated pathotypes of K. pneumoniae.

Worldwide Protein Data Bank (wwPDB): A virtual treasure for research in biotechnology.

The Research Collaboratory for Structural Bioinformatics Protein Data Bank (RSCB PDB) provides a wide range of digital data regarding biology and biomedicine. This huge internet resource involves a wide range of important biological data, obtained from experiments around the globe by different scientists. The Worldwide Protein Data Bank (wwPDB) represents a brilliant collection of 3D structure data associated with important and vital biomolecules including nucleic acids (RNAs and DNAs) and proteins. Moreover, this database accumulates knowledge regarding function and evolution of biomacromolecules which supports different disciplines such as biotechnology. 3D structure, functional characteristics and phylogenetic properties of biomacromolecules give a deep understanding of the biomolecules' characteristics. An important advantage of the wwPDB database is the data updating time, which is done every week. This updating process helps users to have the newest data and information for their projects. The data and information in wwPDB can be a great support to have an accurate imagination and illustrations of the biomacromolecules in biotechnology. As demonstrated by the SARS-CoV-2 pandemic, rapidly reliable and accessible biological data for microbiology, immunology, vaccinology, and drug development are critical to address many healthcare-related challenges that are facing humanity. The aim of this paper is to introduce the readers to wwPDB, and to highlight the importance of this database in biotechnology, with the expectation that the number of scientists interested in the utilization of Protein Data Bank's resources will increase substantially in the coming years.

Writing a strong scientific paper in medicine and the biomedical sciences: a checklist and recommendations for early career researchers.

Scientific writing is an important skill in both academia and clinical practice. The skills for writing a strong scientific paper are necessary for researchers (comprising academic staff and health-care professionals). The process of a scientific research will be completed by reporting the obtained results in the form of a strong scholarly publication. Therefore, an insufficiency in scientific writing skills may lead to consequential rejections. This feature results in undesirable impact for their academic careers, promotions and credits. Although there are different types of papers, the original article is normally the outcome of experimental/epidemiological research. On the one hand, scientific writing is part of the curricula for many medical programs. On the other hand, not every physician may have adequate knowledge on formulating research results for publication adequately. Hence, the present review aimed to introduce the details of creating a strong original article for publication (especially for novice or early career researchers).

Toll-Like Receptors: General Molecular and Structural Biology.

BACKGROUND/AIM: Toll-like receptors (TLRs) are pivotal biomolecules in the immune system. Today, we are all aware of the importance of TLRs in bridging innate and adaptive immune system to each other. The TLRs are activated through binding to damage/danger-associated molecular patterns (DAMPs), microbial/microbe-associated molecular patterns (MAMPs), pathogen-associated molecular patterns (PAMPs), and xenobiotic-associated molecular patterns (XAMPs). The immunogenetic molecules of TLRs have their own functions, structures, coreceptors, and ligands which make them unique. These properties of TLRs give us an opportunity to find out how we can employ this knowledge for ligand-drug discovery strategies to control TLRs functions and contribution, signaling pathways, and indirect activities. Hence, the authors of this paper have a deep observation on the molecular and structural biology of human TLRs (hTLRs). METHODS AND MATERIALS: To prepare this paper and fulfill our goals, different search engines (e.g., GOOGLE SCHOLAR), Databases (e.g., MEDLINE), and websites (e.g., SCOPUS) were recruited to search and find effective papers and investigations. To reach this purpose, we tried with papers published in the English language with no limitation in time. The iCite bibliometrics was exploited to check the quality of the collected publications. RESULTS: Each TLR molecule has its own molecular and structural biology, coreceptor(s), and abilities which make them unique or a complementary portion of the others. These immunogenetic molecules have remarkable roles and are much more important in different sections of immune and nonimmune systems rather than that we understand to date. CONCLUSION: TLRs are suitable targets for ligand-drug discovery strategies to establish new therapeutics in the fields of infectious and autoimmune diseases, cancers, and other inflammatory diseases and disorders.