New Mechanism Of Action Research Articles

The Design, Synthesis and Mechanism of Action of Paxlovid, a Protease Inhibitor Drug Combination for the Treatment of COVID-19.

The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has presented an enormous challenge to health care systems and medicine. As a result of global research efforts aimed at preventing and effectively treating SARS-CoV-2 infection, vaccines with fundamentally new mechanisms of action and some small-molecule antiviral drugs targeting key proteins in the viral cycle have been developed. The most effective small-molecule drug approved to date for the treatment of COVID-19 is PaxlovidTM, which is a combination of two protease inhibitors, nirmatrelvir and ritonavir. Nirmatrelvir is a reversible covalent peptidomimetic inhibitor of the main protease (Mpro) of SARS-CoV-2, which enzyme plays a crucial role in viral reproduction. In this combination, ritonavir serves as a pharmacokinetic enhancer, it irreversibly inhibits the cytochrome CYP3A4 enzyme responsible for the rapid metabolism of nirmatrelvir, thereby increasing the half-life and bioavailability of nirmatrelvir. In this tutorial review, we summarize the development and pharmaceutical chemistry aspects of Paxlovid, covering the evolution of protease inhibitors, the warhead design, synthesis and the mechanism of action of nirmatrelvir, as well as the synthesis of ritonavir and its CYP3A4 inhibition mechanism. The efficacy of Paxlovid to novel virus mutants is also overviewed.

Subsequent therapy and outcomes in patients with newly diagnosed multiple myeloma experiencing disease progression after quadruplet combinations.

The combination of anti-CD38 monoclonal antibodies to a proteasome inhibitor, an immunomodulatory agent and dexamethasone (quadruplet-QUAD) in sequence with autologous stem cell transplantation (ASCT) leads to deep and durable responses in newly diagnosed multiple myeloma (NDMM). Disease progression in the first year post-QUADs is uncommon. We analysed 274 consecutive NDMM patients treated with QUADs + ASCT. After a median follow-up of 21.3 months, 20 patients had disease progression <18 months and 21 had progression ≥18 months after the onset of a QUAD regimen. All patients received subsequent anti-MM therapy, and 38 were evaluated for response. Nine (22.0%) received T-cell redirecting therapy as the next treatment, and 21 (51.2%) at some point in the treatment course. Response to next therapy was 26.3% for patients with progression <18 months and 52.6% for those with progression ≥18 months after the onset of a QUAD regimen. Median PFS on the next therapy was 2.5 months (95% CI 1.5-3.4) for those with progression <18 months and 7.0 months (95% CI 3.6-10.5) for those with progression ≥18 months. Efforts should focus on the early deployment of therapies with new mechanism of action for patients experiencing treatment failure after QUADs.

Epacadostat stabilizes the apo-form of IDO1 and signals a pro-tumorigenic pathway in human ovarian cancer cells.

The tryptophan-degrading enzyme indoleamine 2,3-dioxygenase 1 (IDO1) is a plastic immune checkpoint molecule that potently orchestrates immune responses within the tumor microenvironment (TME). As a heme-containing protein, IDO1 catalyzes the conversion of the essential amino acid tryptophan into immunoactive metabolites, called kynurenines. By depleting tryptophan and enriching the TME with kynurenines, IDO1 catalytic activity shapes an immunosuppressive TME. Accordingly, the inducible or constitutive IDO1 expression in cancer correlates with a negative prognosis for patients, representing one of the critical tumor-escape mechanisms. However, clinically trialed IDO1 catalytic inhibitors disappointed the expected anti-tumor efficacy. Interestingly, the non-enzymatic apo-form of IDO1 is still active as a transducing protein, capable of promoting an immunoregulatory phenotype in dendritic cells (DCs) as well as a pro-tumorigenic behavior in murine melanoma. Moreover, the IDO1 catalytic inhibitor epacadostat can induce a tolerogenic phenotype in plasmacytoid DCs, overcoming the catalytic inhibition of IDO1. Based on this recent evidence, IDO1 plasticity was investigated in the human ovarian cancer cell line, SKOV-3, that constitutively expresses IDO1 in a dynamic balance between the holo- and apo-protein, and thus potentially endowed with a dual function (i.e., enzymatic and non-enzymatic). Besides inhibiting the catalytic activity, epacadostat persistently stabilizes the apo-form of IDO1 protein, favoring its tyrosine-phosphorylation and promoting its association with the phosphatase SHP-2. In SKOV-3 cells, both these early molecular events activate a signaling pathway transduced by IDO1 apo-protein, which is independent of its catalytic activity and contributes to the tumorigenic phenotype of SKOV-3 cells. Overall, our findings unveiled a new mechanism of action of epacadostat on IDO1 target, repositioning the catalytic inhibitor as a stabilizer of the apo-form of IDO1, still capable of transducing a pro-tumorigenic pathway in SKOV-3 tumor. This mechanism could contribute to clarify the lack of effectiveness of epacadostat in clinical trials and shed light on innovative immunotherapeutic strategies to tackle IDO1 target.

Dose Optimization for Novel Oncology Agents: Design Options and Strategies

Over the past decade, drug development in oncology has shifted from cytotoxic agents to drugs with new mechanisms of action, such as cancer immunotherapies, targeted therapeutics, T-cell engagers and others. The conventional maximum tolerated dose (MTD) based dose-finding paradigm is not suitable for the development of these new agents. Further, health authorities, especially the FDA, are requesting more thorough dose optimization prior to the initiation of pivotal trials, and initiatives such as the FDA’s project Optimus have been launched to accelerate this paradigm shift. Dose optimization is more complicated than finding the MTD and requires consideration of complex mechanisms of action, schedule optimization, long-term drug tolerability, and possibly novel pharmacodynamic endpoints. Thus, thoughtful study designs, translational data, and statistical modeling play an increasingly important role to achieve the goal of dose optimization. This article captures opinions from the 2022 ASA biophamaceutical section regulatory-industry statistics workshop session “Dose finding and optimization for novel oncology agents—the new challenges and novel technologies.” We present general design options for dose optimization. Pros and cons of these design options are discussed, and a real-world case study is provided to illustrate a strategy of dose optimization. Discussions focused on practical considerations are included.

Плейотропные эффекты ацетилсалициловой кислоты

Currently, researchers are investigating new mechanisms of action and potential applications of acetylsalicylic acid (ASA). This article summarizes recent studies on the use of ASA for primary prevention of cardiovascular complications (CVC), cancer, and chronic obstructive pulmonary disease (COPD) in progressive chronic kidney disease (CKD). The article discusses the efficacy and safety of ASA in patients with diabetes, COPD, CKD, and subclinical atherosclerosis of brachiocephalic arteries. ASA is a promising tool for primary prevention of CVC and progression of COPD and its complications, as well as malignant diseases. The safety profile of ASA is also addressed. The optimal dosage form of ASA that is both effective and safe is an important factor that should be considered when prescribing ASA for long-term use. Enteric-coated ASA is now widely used due to its diminished negative effect on gastrointestinal mucosa and improved safety. KEYWORDS: primary prevention, acetylsalicylic acid, antiplatelet therapy, cardiovascular complications, chronic kidney disease, chronic obstructive pulmonary disease, diabetes FOR CITATION: Smirnova M.D. Pleiotropic effects of acetylsalicylic acid. Russian Medical Inquiry. 2024;8(1):31–36 (in Russ.). DOI: 10.32364/2587-6821-2024-8-1-5.

Современные возможности лечения доброкачественной гиперплазии предстательной железы и симптомов нижних мочевыводящих путей: новые данные и опыт клинического применения гексанового экстракта плодов Serenoa repens

The article discusses the pharmacological properties and results concerning the clinical use of a medicinal herbal preparation — hexane extract of Serenoa repens (HESr) (creeping palm fruit). In recent years, quite a lot of research data has been accumulated indicating a multicomponent mechanism of drug action. It has been found to have antiandrogenic, antiproliferative and anti-inflammatory effects in the tissues of the prostate gland (pancreas). Studies have been published describing a new mechanism of action of HESr — antineurogenic, the implementation of which helps to reduce infravesical obstruction, leads to inhibition of α1-adrenergic, thromboxane-induced and cholinergic contraction of the pancreatic and detrusor smooth muscles, and also inhibits the growth of pancreatic stromal cells. At present, there is evidence proving the highest clinical efficacy level of the HESr (data from several meta-analyses). The listed effects and patterns of HESr are illustrated by clinical examples of prescribing this drug to patients with lower urinary tract symptoms and benign pancreatic hyperplasia. The safety of use in conditions of polypragmasy in a comorbid patient, the possibility of long-term use without the adverse events occurrence and ensuring a higher life quality while maintaining full sexual function are also particularly noted. KEYWORDS: lower urinary tract symptoms, benign prostatic hyperplasia, chronic bacterial prostatitis, hexane extract of Serenoa repens fruit, ejaculation, life quality. FOR CITATION: Amdiy R.E., Simanov R.N. Modern treatment options for benign prostatic hyperplasia and lower urinary tract symptoms: new data and clinical picture of the hexane extract of Serenoa repens fruit. Russian Medical Inquiry. 2024;8(4):228–234 (in Russ.). DOI: 10.32364/2587-6821-2024-8-4-7.

MODERN VIEW ON THE PROBLEM OF ANTIBIOTIC RESISTANCE IN PULMONOLOGY AND PHTHISIATRY (LITERATURE REVIEW)

Introduction. The problem of antibiotic resistance (AR) is threatening for patients with respiratory tract diseases (RTD). The use of antibiotics in the treatment of pneumonia, which can be prescribed in the schemes for the tuberculosis (TB) treatment, creates the prerequisites for the formation of chemoresistance of mycobacterium tuberculosis (MBT). The purpose of our research is to analyze the scientific literature on the causes and factors of the occurrence of AR of the сommon RTD pathogens (pneumonia, tuberculosis). Materials and methods. The information on AR of pneumonia and tuberculosis causative agents obtained from scientific publications published in the «pubmed» and «scopus» databases has been analyzed. Results. The main factors causing AR in European countries today are: low awareness of the public and medical professionals about AR, over-the-counter purchase of antibiotics, use of antibiotic residues, the desire of doctors to avoid complications of the disease, advertising of pharmaceutical products, frequent lack of diagnostic tests to detect common infections. The vast majority of antibiotic prescriptions in ambulatory practice are for the treatment of respiratory tract infections, but up to 90% of them are unwarranted. Сoncomitant diseases of the patient (chronic kidney disease, bronchopulmonary diseases, liver diseases), previous colonization of the oropharynx with AR pathogens, bedridden state, age up to 2 years can be risk factors for AR of pneumonia pathogens. The physician should be alert for M. tuberculosis infection and perform appropriate diagnosis in patients with suspected pneumonia, especially in children, the elderly, and patients with HIV and comorbidities. It has been established that less than 65 years of age, living in a large family, history of TB treatment, contact with TB patients, history of hospitalization and visits to medical institutions, TB/HIV co‑infection, bad habits (smoking, alcohol consumption), glycosylated hemoglobin level ˃ 7% were risk factors for chemoresistant TB in adults. Risk factors for chemoresistant extrapulmonary TB in children were: up to 1 year of age, living in a village, poor family income, contact with bacterial isolates of resistant MBT strains, lack of BCG vaccination, concomitant pathology. Conclusions. In order to reduce the prevalence of AR of the RTD pathogens, clear algorithms for prescribing antibiotics should be developed, patients should be trained in their correct use, and methods of diagnosing common infections should be improved. In order to overcome CR TB, it is necessary to detect patients in time and block the transmission of infection, develop clear control algorithms for the detection and treatment of CR TB in risk groups, for example, among patients with diabetes, intensify the development of drugs with new mechanisms of action, initiate testing for the detection of TB in risk groups with suspected pneumonia.

Exploration of SAM-I riboswitch inhibitors: In-Silico discovery of ligands to a new target employing multistage CADD approaches

Targeting riboswitches, regulatory elements responsible for the expression of essential genes, is taking central stage in the new era of antibacterial medications discovery due to the emergence of antibiotic resistance. The S-Adenosyl methionine-I (SAM-I) riboswitch works through transcription termination in a negative feedback manner modulated by the natural ligand SAM. SAM-I riboswitch is specific to bacteria and found mainly in gram-positive bacteria such as Bacillus anthracis. Analyzing the interactions of the co-crystallized structure of SAM-I riboswitch aptamer with its native ligand SAM clarified the needed chemical structural features to achieve binding. Acknowledging those features, structure-based and ligand-based pharmacophore models were built for filtration use in screening the OTAVA Chemical library and the Pubchem database. For further filtration enhancement, the physicochemical properties of SAM were used as a second filtration criterion. Compounds obtained as output from previous steps were energy minimized, and the lowest energy conformer structures were docked to SAM-I using MOE, v.2019.01. S-score and ligand interactions were used to assess the best hits. This yielded eight promising compounds to which molecular dynamics (MD) simulations with SAM-I aptamer were applied using GROMACS 2020.3 package affirming stable binding interactions and binding energetics similar to SAM. Moreover, pharmacokinetic and drug-like properties of those eight hits were assessed using SWISS-ADME. According to the combined computational methods and PK/Tox assessment, compound 20 was the most promising and thus can be considered a lead for future evaluation and optimization as a candidate new antibacterial agent targeting a new biomolecule eliciting a new mechanism of action.

Effect of antiglaucomatous eye drops on corneal endothelium

First choice therapy for reducing the intraocular pressure in context of glaucoma remains the applications of eye drops. Longterm exposure to topical therapy can clearly have an impact on the ocular surface, but as the medications penetrate through the cornea and are present in humour aqueous, also on all other layers of cornea, including corneal endothelium. In general, none of the medications from the standard pharmacological groups influences significantly an otherwise healthy corneal endothelium in an eye with glaucoma or ocular hypertension – be it in terms of central corneal thickness, be it in terms of endothelial cell density and morphology, be it for beta blockers, carbonic anhydrase inhibitors, pilocarpine, alpha2 agonists or prostaglandin analogues. The situation changes in diseased corneas, such as in Fuchs endothelial dystrophy, where topically applied carbonic anhydrase inhibitors can lead to increase in corneal thickness. Benzalkonium chloride has been proven toxic for corneal endothelial cells in vitro. However, in the daily practice and under real life circumstances, it is from the specific point of view on the corneal endothelium still not clear whether using non‐preserved topical glaucoma medications is an absolute imperative. One separate topic here is also a group of Rho‐kinase inhibiting topical medications. Apart from new mechanisms of action for reducing the intraocular pressure, this group of medications has also a direct influence on the corneal structures – from cornea verticillata on the epithelium corneal level, to mobilizing peripheral endothelial corneal cells as a possible therapeutic path for Fuchs endothelial dystrophy. One part of the lecture will address also these issues.

Ethnomedicinal Uses, Geographical Distribution, Botanical Description, Phytochemistry, Pharmacology, and Quality Control of Laportea bulbifera (Sieb. et Zucc.) Wedd.: A Review.

Laportea bulbifera (Sieb. et Zucc.) Wedd. (L. bulbifera) is a significant plant in the Laportea genus. Traditionally, it has been used in ethnomedicine for treating various conditions such as rheumatic arthralgia, fractures, falling injuries, nephritis dropsy, limb numbness, pruritus, fatigue-induced internal imbalances, and irregular menstruation. Modern pharmacological studies have confirmed its therapeutic potential, including anti-inflammatory, immunosuppressive, analgesic, and anti-rheumatoid arthritis properties. To gather comprehensive information on L. bulbifera, a thorough literature search was conducted using databases like Web of Science, PubMed, ProQuest, and CNKI. This review aims to provide a comprehensive understanding of L. bulbifera, covering various aspects such as ethnomedicinal uses, geographical distribution, botanical description, phytochemistry, pharmacology, and quality control. The goal is to establish a solid foundation and propose new research avenues for exploring and developing potential applications of L. bulbifera. So far, a total of one hundred and eighty-nine compounds have been isolated and identified from L. bulbifera, including flavonoids, phenolics, nitrogen compounds, steroids, terpenoids, coumarins, phenylpropanoids, fatty acids and their derivatives, and other compounds. Notably, flavonoids and fatty acids have demonstrated remarkable antioxidant and anti-inflammatory properties. Additionally, these compounds show promising potential in activities such as analgesia, hypoglycemia, and hypolipidemia, as well as toxicity. Despite extensive fundamental studies on L. bulbifera, further research is still needed to enhance our understanding of its mechanism of action and improve quality control. This requires more comprehensive investigations to explore the specific material basis, uncover new mechanisms of action, and refine quality control methods related to L. bulbifera. By doing so, we could contribute to the further development and utilization of this plant.

Cell Membrane-Anchored DNA Nanoinhibitor for Inhibition of Receptor Tyrosine Kinase Signaling Pathways via Steric Hindrance and Lysosome-Induced Protein Degradation.

Receptor tyrosine kinase (RTK) plays a crucial role in cancer progression, and it has been identified as a key drug target for cancer targeted therapy. Although traditional RTK-targeting drugs are effective, there are some limitations that potentially hinder the further development of RTK-targeting drugs. Therefore, it is urgently needed to develop novel, simple, and general RTK-targeting inhibitors with a new mechanism of action for cancer targeted therapy. Here, a cell membrane-anchored RTK-targeting DNA nanoinhibitor is developed to inhibit RTK function. By using a DNA tetrahedron as a framework, RTK-specific aptamers as the recognition elements, and cholesterol as anchoring molecules, this DNA nanoinhibitor could rapidly anchor on the cell membrane and specifically bind to RTK. Compared with traditional RTK-targeting inhibitors, this DNA nanoinhibitor does not need to bind at a limited domain on RTK, which increases the possibilities of developing RTK inhibitors. With the cellular-mesenchymal to epithelial transition factor (c-Met) as a target RTK, the DNA nanoinhibitor can not only induce steric hindrance effects to inhibit c-Met activation but also reduce the c-Met level via lysosome-mediated protein degradation and thus inhibition of c-Met signaling pathways and related cell behaviors. Moreover, the DNA nanoinhibitor is feasible for other RTKs by just replacing aptamers. This work may provide a novel, simple, and general RTK-targeting nanoinhibitor and possess great value in RTK-targeted cancer therapy.

Elotuzumab in the treatment of patients with refractory and relapsed multiple myeloma Experience of the Lapino Clinical Hospital Oncohematology Department

Despite the therapy advances, largely due to the study of molecular biology, multiple myeloma remains an incurable disease, and refractory course or relapses significantly worsen the prognosis. In this regard, the development of effective therapeutic agents with fundamentally new mechanisms of action that provide increased survival is currently an urgent task. One potential immunotherapeutic target is signaling lymphocyte activation molecules (SLAMs), and the anti-SLAMF7 monoclonal antibody elotuzumab is used in combination with either lenalidomide and dexamethasone (Elo-Rd regimen) after 1 prior line of therapy, or with pomalidomide and dexamethasone (Elo-Pd regimen) after 2 or more lines of therapy. The results of studies demonstrated a survival benefit in all subgroups of patients with refractory or relapsed multiple myeloma when using elotuzumab. A manageable safety profile and a low frequency of grade III–IV induced myelosuppression were noted, which allows the use of elotuzumab in combination with lenalidomide or pomalidomide and dexamethasone in elderly and debilitated patients. We present our own experience of using elotuzumab in the treatment of patients with refractory/recurrent multiple myeloma. A clinical case of a patient in whom treatment with elotuzumab was initiated at an early stage (after 1 line of previous therapy) is presented; the effectiveness and safety of using the monoclonal antibody are assessed. A significant improvement in the patient’s clinical condition and positive dynamics according to laboratory data were noted already during the 1st cycle of Elo-Rd regimen with a further progressive deepening of the antitumor response along with satisfactory tolerability and the absence of significant adverse events.

Use of daratumumab drug formulation for subcutaneous administration in multiple myeloma therapy: Literature review and clinical observation

Study of the molecular pathogenesis of multiple myeloma led to development and introduction of antitumor agents with new mechanisms of action and their combinations into clinical practice. According to several trials, use of anti-CD38 monoclonal antibody daratumumab as part of triplet therapies at an early stage leads to deep and long-term antitumor response, achievement of MRD-negative status, and, as a result, increased survival and improved prognosis in all patient subgroups. High effectiveness of daratumumab subcutaneous formulation close to intravenous formulation has favorable safety profile, short administration time and low rate of infusion reactions which improves patients’ quality of life, affects their treatment compliance, and decreases healthcare costs.We present a clinical observation of a 60-year-old patient with newly diagnosed multiple myeloma who previously underwent treatment for another lymphoproliferative disorder which included autologous hematopoietic stem cell transplantation leading to complete and long-term remission. After 9 intravenous daratumumab infusions (with recommended dose of 16 mg/kg) in accordance to the D-Rd regimen, evaluation of antitumor effect and consideration of socially active lifestyle of the patient, daratumumab formulation for intravenous administration was replaced with subcutaneous formulation of fixed dose 1800 mg. Further deepening of the antitumor response was observed along with manageable safety profile and absence of significant adverse events which allowed to maintain intercourse intervals and improve the patient’s quality of life.

Catalytic Antibodies May Contribute to Demyelination in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.

Here we report preliminary data demonstrating that some patients with myalgic encephalomyelitis/chronic fatiguesyndrome (ME/CFS) may have catalytic autoantibodies that cause the breakdown of myelin basic protein (MBP). We propose that these MBP-degradative antibodies are important to the pathophysiology of ME/CFS, particularly in the occurrence of white matter disease/demyelination. This is supported by magnetic resonance imagining studies that show these findings in patients with ME/CFS and could explain symptoms of nerve pain and muscle weakness. In this work, we performed a series of experiments on patient plasma samples where we isolated and characterized substrate-specific antibodies that digest MBP. We also tested glatiramer acetate (copaxone), an FDA approved immunomodulator to treat multiple sclerosis, and found that it inhibits ME/CFS antibody digestion of MBP. Furthermore, we found that aprotinin, which is a specific serine protease inhibitor, specifically prevents breakdown of MBP while the other classes of protease inhibitors had no effect. This coincides with the published literature describing catalytic antibodies as having serine protease-like activity. Postpandemic research has also provided several reports of demyelination in COVID-19. Because COVID-19 has been described as a trigger for ME/CFS, demyelination could play a bigger role in patient symptoms for those recently diagnosed with ME/CFS. Therefore, by studying proteolytic antibodies in ME/CFS, their target substrates, and inhibitors, a new mechanism of action could lead to better treatment and a possible cure for the disease.

Solubilization of 3-hydroxyquinazoline derivative with antitumor activity

Background. Increasing the solubility of new pharmacologically active substances is one of the main tasks of pharmacy. It becomes even more relevant in the field of creating dosage forms for difficult-to-solubilise substances with a new mechanism of action, as in the case of 3-hydroxyquinazoline derivatives, which have shown in vivo experiments the ability to activate tumour cell death by ferroptosis. This includes OVF-009 – an original domestic substance. Due to the solubility of this compound in oils, the technology of its solubilisation using modified castor oil (Kolliphor® ELP, BASF, Germany), approved for parenteral use, was proposed.Aim. To create a model dosage form for a new hydrophobic quinazoline derivative in order to further evaluate the spectrum of its antitumour activity in in vivo experiments.Materials and methods. OVF-009, Kolliphor® ELP, 95 % ethanol, Kollidon 17 PF (BASF, Germany), sodium hydroxide, phosphate buffer, water for injection; spontaneous micelle formation, ultrasound, potentiometry, dynamic light scattering, electrophoretic method, viscometry method, etc.Results. The main properties of micelle-forming solubiliser Kolliphor® ELP and its aqueous solutions were considered; 10 model solutions OVF-009 based only on Kolliphor® ELP and with addition of ethanol and Kollidon 17PF in different concentrations were obtained; the quality of the obtained compositions was evaluated by parameters – appearance, solution transparency, pH, stability over time and tolerability by laboratory animals. As a result, two formulations prepared on phosphate buffer were chosen: formulation No 5, which contains 10 % Kolliphor® ELP and additionally 10 % polyvinylpyrrolidone, and formulation No 8, in which in addition to the main solubiliser 10 % ethanol and 16 % polyvinylpyrrolidone were added. Both formulations have neutral pH, can be stored for 24 h and are tolerated by laboratory animals.Conclusion. The selected model compositions for solubilisation of the substance OVF-009 on the basis of Kolliphor® ELP allowed to provide the concentration of the active substance in the solution suitable for further biological experiments on animals.

Comparative Study on the Antimicrobial Activities and Metabolic Profiles of Five Usnea Species from the Philippines.

The rapid emergence of resistant bacteria is occurring worldwide, endangering the efficacy of antibiotics. Hence, there is a need to search for new sources of antibiotics that either exhibit novel structures or express a new mechanism of action. The lichen Usnea, with its wide range of unique, biologically potent secondary metabolites, may solve this problem. In this study, Usnea species were collected in the Northern Philippines, identified through combined morphological and biochemical characterization, and tested for antimicrobial activities against the multidrug-resistant ESKAPE pathogens, i.e., Enterococcus faecalis, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter cloacae, two standard antibiotic-sensitive test bacteria, and a yeast. A total of 46 lichen specimens were collected and later identified as Usnea baileyi (10), U. diffracta (10), U. glabrata (12), U. longissima (4), and U. rubicunda (10). The results show that the crude extracts of the Usnea species exhibited promising in vitro inhibitory activities against standard antibiotic-sensitive (E. faecalis ATCC 29212) and multidrug-resistant (methicillin-resistant S. aureus and E. faecalis) Gram-positive bacteria. Additionally, lichen compounds of representative specimens per species were identified and profiled using thin-layer chromatography (TLC) and high-performance liquid chromatography (HPLC). The detection of lichen acids (LA) via HPLC showed the presence of 24 peaks of lichen acids. TLC-bioautography identified the bioactive lichen acids as alectronic acid, connorstictic acid, consalazinic acid, diffractaic acid, echinocarpic acid, erythrin acid, galbinic acid, hypoconstictic acid, hyposalazinic acid, hypostictic acid, lobaric acid, menegazzaic acid, micareic acid, pannarin, salazinic acid, stictic acid, and usnic acid. Our study highlighted the wide spectrum of opportunities for using lichens for the discovery of potential antimicrobial agents.

Novel Scaffolds Based on Bis-thiazole Connected to Quinoxaline or Thienothiophene through 2-Phenoxy-N-arylacetamide Groups as New Hybrid Molecules: Synthesis, Antibacterial Activity, and Molecular Docking Investigations.

The resistance of microorganisms to antimicrobials has endangered the health of many people across the world. Overcoming the resistance problem will require the invention of molecules with a new mechanism of action so that no cross-resistance with existing therapies occurs. Because of their powerful antibacterial activity against a wide spectrum of Gram-positive and Gram-negative bacterial strains, heterocyclic compounds are appealing candidates for medicinal chemists. In this regard, as unique hybrid compounds, we synthesized a novel family of bis-thiazoles linked to quinoxaline or thienothiophene via the 2-phenoxy-N-arylacetamide moiety. The target compounds were synthesized by reacting the relevant bis(α-haloketones) with the corresponding thiosemicarbazones in EtOH at reflux with a few drops of TEA. Under comparable reaction conditions, the isomeric bis(thiazoles) were synthesized by reacting the appropriate bis(thiosemicarbazone) with the respective α-haloketones. The structures of the novel compounds were confirmed using elements and spectral data. All of the synthesized compounds were tested for antibacterial activity in vitro. With an inhibitory zone width of 12 mm, compound 12a had the same activity as the reference medication tobramycin against Staphylococcus aureus. Compound 12b showed 20 mg/mL as a minimum inhibitory concentration (MIC) against Bacillus subtilis. Some of the synthesized compounds were tested via molecular docking against two bacterial proteins (dihydrofolate reductase and tyrosyl-tRNA synthetase).

Sirtuins: The NAD+-Dependent Multifaceted Modulators of Inflammation.

Significance: Sirtuins are NAD+-dependent histone deacetylases regulating important processes in cellular biology such as inflammation, metabolism, oxidative stress, and apoptosis. Recent Advances: Despite initially being discovered to regulate transcription and life span via histone deacetylase activities, emerging data continually uncover new targets and propose additional roles. Due to the outstanding importance of the sirtuins in the control of the inflammatory response, their roles in the pathogenesis of several inflammatory-based diseases have become an area of intense research. Although sirtuins have been traditionally regarded as anti-inflammatory players, several recent findings suggest that their role in inflammation is complex and that in some cases sirtuins can indeed promote inflammation. Critical Issues: In this article, we provide an update on the latest findings concerning the new mechanisms of action and concepts about the role of sirtuins during inflammation. We focus on the impact that inflammatory-based processes exert on the liver, adipose tissue, and nervous system as well as on macrophage function and activation. Also, we discuss available data pointing to the dual role that, in particular contexts, sirtuins may have on inflammation control. Future Directions: Since the knowledge of sirtuin impact on metabolism is continually expanding, new venues of research arise. Besides become being regarded as candidates of therapeutic targets, posttranscriptional control of sirtuin expression by means of microRNAs challenges our traditional concepts of sirtuin regulation; importantly, the emerging role of NAD+ metabolism in aging and longevity has added a new dimension to the interest in sirtuin function. Antioxid. Redox Signal. 39, 1185-1208.

Extracorporeal Shock Wave Therapy for the Treatment of Musculoskeletal Pain: A Narrative Review.

Extracorporeal shock waves have been used for pain treatment for various sub-acute and chronic musculoskeletal (MSK) problems since 2000. The aim of this article is to update information on the role of extracorporeal shock wave therapy (ESWT) in the treatment of various pathologies that cause MSK pain. Given that in the last two years, articles of interest (including systematic reviews and meta-analyses) have been published on less known indications, such as low back pain, nerve entrapments, osteoarthritis and bone vascular diseases, a literature search was conducted in PubMed, the Cochrane Database, EMBASE, CINAHL and PEDro, with the aim of developing a narrative review of the current literature on this topic. The purposes of the review were to review possible new mechanisms of action, update the level of evidence for known indications and assess possible new indications that have emerged in recent years. Although extracorporeal shock waves have mechanical effects, their main mechanism of action is biological, through a phenomenon called mechanotransduction. There is solid evidence that supports their use to improve pain in many MSK pathologies, such as different tendinopathies (epicondylar, trochanteric, patellar, Achilles or calcific shoulder), plantar fasciitis, axial pain (myofascial, lumbar or coccygodynia), osteoarthritis and bone lesions (delayed union, osteonecrosis of the femoral head, Kienbock's disease, bone marrow edema syndrome of the hip, pubis osteitis or carpal tunnel syndrome). Of the clinical indications mentioned in this review, five have a level of evidence of 1+, eight have a level of evidence of 1-, one indication has a level of evidence of 2- and two indications have a level of evidence of 3. The current literature shows that ESWT is a safe treatment, with hardly any adverse effects reported. Furthermore, it can be used alone or in conjunction with other physical therapies such as eccentric strengthening exercises or static stretching, which can enhance its therapeutic effect.

Diagnosis and treatment of depression according to the functional recovery paradigm

Since the appearance of the first antidepressants, ideas about the goals of long-term treatment of depression have changed considerably. The prevailing priority in the 1960s to 1980s of relieving current depressive symptoms and ending the current episode – shifted to achieving remission in the early 1990s and functional recovery in the mid-2010s. The general recognition of a new approach to the treatment of depression is reflected in the inclusion of functional disorder in the ICD-11 diagnostic criteria for a depressive episode. The paradigm shift in therapy has been driven by advances in the field of psychopharmacology that have led to the development of antidepressants with a fundamentally new mechanism of action that provides a broader therapeutic effect combined with a more favorable tolerability profile. Agomelatine provides a harmonious and complete reduction of depression symptoms, including those resistant to other antidepressants, and a stable clinical and functional remission of high quality, i.e., it allows the achievement of all three therapeutic goals.