Different Mechanisms Of Action Research Articles

Search for new biologically active compounds: in vitro studies of antitumor and antimicrobial activity of dirhodium(II,II) paddlewheel complexes.

Four neutral Rh1-Rh4 complexes of the general formula [Rh2(CH3COO)4L2], where L is an N-alkylimidazole ligand, were synthesized and characterized using various spectroscopic techniques, and in the case of Rh4 the crystal structure was confirmed. Investigation of the interactions of these complexes with HSA by fluorescence spectroscopy revealed that the binding constants Kb are moderately strong (∼104 M-1), and site-marker competition experiments showed that the complexes bind to Heme site III (subdomain IB). Competitive binding studies for CT DNA using EB and HOE showed that the complexes bind to the minor groove, which was also confirmed by viscosity experiments. Molecular docking confirmed the experimental data for HSA and CT DNA. Antimicrobial tests showed that the Rh2-Rh4 complexes exerted a strong inhibitory effect on G+ bacteria B. cereus and G- bacteria V. parahaemolyticus as well as on the yeast C. tropicalis, which showed a higher sensitivity compared to fluconazole. The cytotoxic activity of Rh1-Rh4 complexes tested on three cancer cell lines (HeLa, HCT116 and MDA-MB-231) and on healthy MRC-5 cells showed that all investigated complexes elicited more efficient cytotoxicity on all tested tumor cells than on control cells. Investigation of the mechanism of action revealed that the Rh1-Rh4 complexes inhibit cell proliferation via different mechanisms of action, namely apoptosis (increase in expression of the pro-apoptotic Bax protein and caspase-3 protein in HeLa and HCT116 cells; changes in mitochondrial potential and mitochondrial damage; release of cytochrome c from the mitochondria; cell cycle arrest in G2/M phase in both HeLa and HCT116 cells together with a decrease in the expression of cyclin A and cyclin B) and autophagy (reduction in the expression of the protein p62 in HeLa and HCT116 cells).

MORPHOLOGICAL CHANGES IN RAT SKIN AFTER THERMAL BURNS

Every day around the world, children and adults suffer from burn injuries. Burn injury is one of the global health problems due to its high prevalence and mortality. The skin is the largest multifunctional human organ. The area of the entire skin is on average 1.7-1.9 square meters. The skin has a wide variety of functions from protective to energy-saving and tactile. Burns have a long history, but new methods of study are needed, this is due to the increase in the frequency of burns in everyday life, production, as well as the complexity of the pathogenesis and treatment of burn disease. Pathological changes that occur in the body of burned animals lead to the fact that in the first hours with extensive burn injury, circulatory disorders occur in parenchymal organs, especially in the liver, lungs and adrenal glands. In the future, with severe intoxication, severe dystrophic processes occur in the muscles of the heart and other internal organs. Recently, the main areas of research into the pathogenesis of inflammation have become immunological, at the morphological level it has not been sufficiently studied. The article shows the morphological features of the study in thermal burns of the skin of rats during treatment with a different mechanism of action. Rats in the amount of 15 pieces were divided into 3 groups: the first control group with a burn without treatment, the second group with a thermal burn, to which levomekol gel was applied to the burn area, the third group was treated with powder from the medicinal plant yarrow Achillea millefolium L. On the 3rd, 7th, 14th, and 21st days, the rats were taken out of the experiment, after which the skin pieces were fixed in 10% formalin for further histological examination.

Risk of urolithiasis associated with allopurinol versus benzbromarone among patients with gout: a population-based cohort study.

To compare the risk of urolithiasis in gout patients initiating allopurinol, a xanthine oxidase inhibitor, vs benzbromarone, a uricosuric. Using the 2011-2020 Korea National Health Insurance Service database, we conducted a cohort study on gout patients initiating allopurinol vs benzbromarone as the 1st-line urate-lowering treatment (ULT). The primary outcome was a new onset urinary stone. The secondary outcome was a stone requiring intervention. We estimated hazard ratios (HRs) and 95% confidence intervals (CIs) using Cox proportional hazard models with a 5:1 ratio propensity-score matching on > 80 variables. Subgroup analyses were done by age, sex, thiazide use, and cardiovascular (CV) risk. 61 300 allopurinol initiators PS-matched on 12 260 benzbromarone initiators were included (mean age 59 years, 79% male). During a mean follow-up of 322 days, 619 urolithiasis cases occurred with an incidence rate of 0.87 per 100 person-years in allopurinol and 1.39 in benzbromarone initiators, showing a HR of 0.64 (95% CI, 0.51-0.80). ∼44% of urinary stones required intervention with a HR of 0.61 (95% CI 0.43-0.88). The lower risk associated with allopurinol compared with benzbromarone persisted across subgroups but was greater in the high than non-high CV risk subgroup (p for interaction = 0.02). This population-based cohort study found that allopurinol compared with benzbromarone was associated with a substantially lower risk of urolithiasis particularly in the presence of the high CV risk. This finding provides important safety information for clinicians' decision-making on ULTs of different mechanisms of action.

Using wavelet phase coherence of heart rate variability and blood flow oscillations to compare mechanisms of action between Tai Chi mind-body exercise and brisk walking aerobic exercise

Tai Chi exercise has been demonstrated to be beneficial for health and quality of life. However, the mind–body effect of Tai Chi on modulating interactions of the cardiovascular components has not been investigated. This study aimed to differentiate the effect of Tai Chi (mind–body exercise) and brisk walking (aerobic exercise) on modulating skin blood flow oscillations (BFO) of the upper and lower limbs and heart rate variability (HRV). Bafa Wubu of Tai Chi for 15 min and brisk walking for 15 min were performed by 30 adults in two different days. Wavelet phase coherence was employed to assess the coordination between HRV and BFO before and after exercise. Two indices were proposed to quantify the coherence, i.e., the area (Aϕ) and maximal difference (dmax) between the coherence function and the threshold obtained by surrogate test. The results demonstrated that Tai Chi resulted in a significant decrease in phase coherence between HRV and BFO of the upper limb in the frequency interval 0.05–0.15 Hz (Aϕ baseline 0.1600 ± 0.0288, post-exercise 0.0486 ± 0.0220, p < 0.001; dmax baseline 0.3222 ± 0.0220, post-exercise 0.2578 ± 0.0219, p < 0.005), but not between HRV and BFO of the lower limb. Brisk walking resulted in a significant increase in phase coherence between HRV and BFO of the lower limb in the frequency interval 0.05–0.15 Hz (Aϕ baseline 0.0455 ± 0.0251, post-exercise 0.1190 ± 0.0241, p < 0.05; dmax baseline 0.2191 ± 0.0225, post-exercise 0.3103 ± 0.0208, p < 0.05) but not between HRV and BFO of the upper limb. Our finding indicates that mind–body exercise and aerobic exercise modulate cardiovascular regulations through different mechanisms of action.

Efficacy and Safety of Xanomeline-Trospium Chloride in Schizophrenia

A significant need exists for new antipsychotic medications with different mechanisms of action, greater efficacy, and better tolerability than existing agents. Xanomeline is a dual M1/M4 preferring muscarinic receptor agonist with no direct D2 dopamine receptor blocking activity. KarXT combines xanomeline with the peripheral muscarinic receptor antagonist trospium chloride with the goal of reducing adverse events due to xanomeline-related peripheral muscarinic receptor activation. In prior trials, xanomeline-trospium chloride was effective in reducing symptoms of psychosis and generally well tolerated in people with schizophrenia. To evaluate the efficacy and safety of xanomeline-trospium vs placebo in adults with schizophrenia. EMERGENT-3 (NCT04738123) was a phase 3, multicenter, randomized, double-blind, placebo-controlled, 5-week trial of xanomeline-trospium in people with schizophrenia experiencing acute psychosis, conducted between April 1, 2021, and December 7, 2022, at 30 inpatient sites in the US and Ukraine. Data were analyzed from February to June 2023. Participants were randomized 1:1 to receive xanomeline-trospium chloride (maximum dose xanomeline 125 mg/trospium 30 mg) or placebo for 5 weeks. The prespecified primary end point was change from baseline to week 5 in Positive and Negative Syndrome Scale (PANSS) total score. Secondary outcome measures were change from baseline to week 5 in PANSS positive subscale score, PANSS negative subscale score, PANSS Marder negative factor score, Clinical Global Impression-Severity score, and proportion of participants with at least a 30% reduction in PANSS total score. Safety and tolerability were also evaluated. A total of 256 participants (mean [SD] age, 43.1 [11.8] years; 191 men [74.6%]; 156 of 256 participants [60.9%] were Black or African American, 98 [38.3%] were White, and 1 [0.4%] was Asian) were randomized (125 in xanomeline-trospium group and 131 in placebo group). At week 5, xanomeline-trospium significantly reduced PANSS total score compared with placebo (xanomeline-trospium , -20.6; placebo, -12.2; least squares mean difference, -8.4; 95% CI, -12.4 to -4.3; P < .001; Cohen d effect size, 0.60). Discontinuation rates due to treatment-emergent adverse events (TEAEs) were similar between the xanomeline-trospium (8 participants [6.4%]) and placebo (7 participants [5.5%]) groups. The most common TEAEs in the xanomeline-trospium vs placebo group were nausea (24 participants [19.2%] vs 2 participants [1.6%]), dyspepsia (20 participants [16.0%] vs 2 participants [1.6%]), vomiting (20 participants [16.0%] vs 1 participant [0.8%]), and constipation (16 participants [12.8%] vs 5 participants [3.9%]). Measures of extrapyramidal symptoms, weight gain, and somnolence were similar between treatment groups. Xanomeline-trospium was efficacious and well tolerated in people with schizophrenia experiencing acute psychosis. These findings, together with the previously reported and consistent results from the EMERGENT-1 and EMERGENT-2 trials, support the potential of xanomeline-trospium to be the first in a putative new class of antipsychotic medications without D2 dopamine receptor blocking activity. ClinicalTrials.gov Identifier: NCT04738123.

A sirtuin 6 activator in the pipeline: New perspectives in depressive disorder treatment

Major Depressive Disorder (MDD) is among the most prevalent mental illnesses worldwide. Its symptoms include persistent feelings of sadness, loss of interest in previously enjoyed activities, and a lack of motivation for daily tasks. While FDA-approved medications are available, they often come with side effects, especially those targeting monoamine neurotransmitters like SSRIs and SNRIs. Thus, there is a need for innovative medications with different mechanisms of action. Sp-624, a derivative of griseofulvin, is currently undergoing clinical trials for MDD treatment. It acts as a sirtuin 6 (SIRT6) activator, offering a novel approach to treating this disorder. This article discusses the biochemical aspects related to the mechanism of action of sp-624, provides a brief overview of related patents, and highlights ongoing clinical trials involving this substance.

Anesthesiological provision in hip and knee joint replacement (a scientific literature review)

Effective pain management during hip and knee replacement ensures the efficient and fast recovery of patients. Joint replacement surgery is typically accompanied by the use of general anesthesia or spinal anesthesia. Spinal anesthesia, despite certain risks, demonstrates better effectiveness compared to general anesthesia in hip and knee replacements. In other words, spinal anesthesia entails fewer perioperative complications. The addition of sedation and anesthesia monitoring during joint replacements using spinal anesthesia is of particular importance. After a successful surgical procedure of joint replacement, achieving adequate pain relief in the postoperative period is crucial. This is achieved through intravenous patient-controlled analgesia or epidural analgesia. A multimodal analgesia strategy combines analgesics with different mechanisms of action to enhance pain management. Intraoperative periarticular administration of multimodal agents is one of the most important procedures in the perioperative pain control during total hip arthroplasty. Peripheral nerve blocks have emerged recently as an alternative analgesic approach. During hip and knee replacements, various nerve blocks are utilized, including lumbar plexus block, fascia iliaca block, femoral and sciatic nerve block, adductor canal block, quadratus lumborum block, erector spinae plane block. Given the entire perioperative process, the use of preventive and multimodal therapy along with peripheral nerve blocks can help reduce the intensity of postoperative pain, thereby improving the functional status and quality of life for patients.

Iron-Based Nanoparticles Synthesis, Characterization, and Antimicrobial Effectiveness

Background: Antimicrobial resistance (AMR) has emerged as a significant and pressing public health concern, posing serious challenges to effectively preventing and treating persistent diseases. Developing new antibiotics with different mechanisms of action is crucial to effectively address challenges in treating infections. A lot of work has already been done on mono-metallic nanoparticles to address the issue.Methods: This study aimed to synthesize multi-metallic iron, silver, and chitosan-embedded nanoparticles using a green approach. Iron, silver, chitosan nanoparticles, and a composite of iron–silver–chitosan was also synthesized. The synthesized nanoparticles and composites were characterized through X-ray diffraction (XRD), scanning electron microscopy (SEM), energy-dispersive X-ray spectroscopy (EDX), and Fourier Transform Infrared Spectroscopy (FTIR) to evaluate their structural parameters. Their antimicrobial efficacy was investigated through MIC (minimum inhibitory concentration), MBC (minimum bactericidal concentration), and well-disk diffusion assays against Pseudomonas aeruginosa, Acinetobacter baumannii, Staphylococcus aureus, Staphylococcus epidermidis and Candida albicans.Results: The size of the Cu-NPs, Cu-Ag NPs, and Cu-Ag-CS NPs were found to be in the range of 32-40 nm size with a spherical shape. The nanocomposites' MIC and MBC were calculated to be 125 μg/mL and 500 μg/mL, respectively. The nanocomposites exhibited a range of clear inhibition zones, with a minimum diameter of 12 ± 0.5 mm and a maximum diameter of 22 ± 0.5 mm. Conclusion: The iron–silver–chitosan nanocomposite has been shown to have significant antimicrobial effects in the laboratory environment compared to other nanoparticles hence can be applied as potential biomedical/biological candidates in future.Keywords: Antibacterial; Antifungal Agents; Iron; Silver; Chitosan; Nanoparticles

Impact of novel herbicide based on synthetic auxins and ALS inhibitor on weed control.

Delayed sowing of winter cereals or unfavorable weather conditions in autumn may make it impossible to carry out herbicide treatment in autumn. In such cases, weed control should be started in the spring. During this time, the plantation should be protected as effectively as possible because the weeds are at an advanced stage of growth. Therefore, they are less sensitive to applied herbicides. In the treatment, it is worth using a mixture of different mechanisms of action. Studies were conducted to evaluate the effectiveness of a band of tribenuron-methyl, and MCPA applied as soluble granules in spring control of dicotyledonous in winter cereals. The biological efficacy of herbicides was estimated in the 25 field experiments on winter cereals in Poland. Postemergence, a spring application of tribenuron-methyl + MCPA, effectively controls the majority of weed species present in spring: Anthemis arvensis, Brassica napus, Capsella bursa-pastoris, Centaurea cyanus, Lamium purpureum, Matricaria chamomilla, Tripleurospermum inodorum, Stellaria media and Thlaspi arvense. Satisfactory control was confirmed for Veronica persica, Viola arvensis, and Galium aparine. Tribenuron-methyl with MCPA is recommended for application to winter cereals in spring. To prevent the development of resistance in weeds, it is advantageous to combine two active substances.

High Consistency Silicone Rubber Foams.

Silicone elastomers are high-performance plastics. In the extrusion process, only high-consistency silicone rubbers were used. In order to reduce the cost and weight, silicone rubbers can be foamed during processing. In this study, high-consistency silicone rubber is processed with different physical and chemical blowing agents. The resulting reaction kinetics, as well as the mechanical and morphological properties, had been investigated and compared with each other. This showed that the chemical blowing agent significantly influenced the crosslinking reaction compared to the microspheres and the water/silica mixture tested, but it also achieved the lowest density compared to the physical blowing agents. When evaluating the foam morphology, it became clear that the largest number of pores was achieved with the microspheres and the largest pores when using the water/silica mixture. Furthermore, it has been shown that the different mechanisms of action of the blowing agents have a major influence on the mechanical properties, such as the micro shore hardness and the foam morphology.

Hybrid Membrane-Coated Nanoparticles for Precise Targeting and Synergistic Therapy in Alzheimer's Disease.

The blood brain barrier (BBB) limits the application of most therapeutic drugs for neurological diseases (NDs). Hybrid cell membrane-coated nanoparticles derived from different cell types can mimic the surface properties and functionalities of the source cells, further enhancing their targeting precision and therapeutic efficacy. Neuroinflammation has been increasingly recognized as a critical factor in the pathogenesis of various NDs, especially Alzheimer's disease (AD). In this study, a novel cell membrane coating is designed by hybridizing the membrane from platelets and chemokine (C-C motif) receptor 2 (CCR2) cells are overexpressed to cross the BBB and target neuroinflammatory lesions. Past unsuccessful endeavors in AD drug development underscore the challenge of achieving favorable outcomes when utilizing single-mechanism drugs.Two drugs with different mechanisms of actions into liposomes are successfully loaded to realize multitargeting treatment. In a transgenic mouse model for familial AD (5xFAD), the administration of these drug-loaded hybrid cell membrane liposomes results in a significant reduction in amyloid plaque deposition, neuroinflammation, and cognitive impairments. Collectively, the hybrid cell membrane-coated nanomaterials offer new opportunities for precise drug delivery and disease-specific targeting, which represent a versatile platform for targeted therapy in AD.

Improving the power of drug toxicity measurements by quantitative nuclei imaging

Imaging-based anticancer drug screens are becoming more prevalent due to development of automated fluorescent microscopes and imaging stations, as well as rapid advancements in image processing software. Automated cell imaging provides many benefits such as their ability to provide high-content data, modularity, dynamics recording and the fact that imaging is the most direct way to access cell viability and cell proliferation. However, currently most publicly available large-scale anticancer drugs screens, such as GDSC, CTRP and NCI-60, provide cell viability data measured by assays based on colorimetric or luminometric measurements of NADH or ATP levels. Although such datasets provide valuable data, it is unclear how well drug toxicity measurements can be integrated with imaging data. Here we explored the relations between drug toxicity data obtained by XTT assay, two quantitative nuclei imaging methods and trypan blue dye exclusion assay using a set of four cancer cell lines with different morphologies and 30 drugs with different mechanisms of action. We show that imaging-based approaches provide high accuracy and the differences between results obtained by different methods highly depend on drug mechanism of action. Selecting AUC metrics over IC50 or comparing data where significantly drugs reduced cell numbers noticeably improves consistency between methods. Using automated cell segmentation protocols we analyzed mitochondria activity in more than 11 thousand drug-treated cells and showed that XTT assay produces unreliable data for CDK4/6, Aurora A, VEGFR and PARP inhibitors due induced cell size growth and increase in individual mitochondria activity. We also explored several benefits of image-based analysis such as ability to monitor cell number dynamics, dissect changes in total and individual mitochondria activity from cell proliferation, and ability to identify chromatin remodeling drugs. Finally, we provide a web tool that allows comparing results obtained by different methods.

Prenatal exposure to acid suppressor medications and development of ductus arteriosus in term newborn.

The ductus arteriosus normally closes after birth. Histamine2 Receptor Antagonist (H2RA) has been associated with patent ductus arteriosus (PDA). We aimed to study the characteristics of term infants with PDA and their possible association with prenatal exposure to antacids - Proton Pump Inhibitors (PPI) and H2RA. Population-based matched case-control study of mothers registered at "Clalit" Health Maintenance Organization (HMO) and their infants born at "Soroka" University Medical Center (SUMC) between 2001-2018. Cases are defined as term infants born with PDA diagnosed by echocardiography and registered in the post-delivery discharge form. Each case was matched with four term newborns without PDA diagnosis. Exposure window was defined by the timing of first purchase of H2RA or PPI during pregnancy and based on information from a computerized medication database (Clalit HMO, SUMC) Results. PDA was diagnosed in 1,884 term infants (4.9%). Characteristics included a significantly higher percentage of lack of prenatal care, cesarean section, in vitro fertilization, polyhydramnios, oligohydramnios, Apgar 1 minute <5, and prenatal exposure to H2RA (OR4.18) and PPIs (OR3.50) (all p<0.001). PDA association with exposure window was similar in each trimester (1.5-2%) for both H2RA and PPI. PDA Incidence in term infants in our population was greater than previously reported. PPI and H2RA are both anti-acids with different mechanisms of action. The similar OR for exposure to one as well as the other, and the lack of influence of the initial exposure period, are compatible with bias.

DNA-targeting short Argonautes complex with effector proteins for collateral nuclease activity and bacterial population immunity.

Two prokaryotic defence systems, prokaryotic Argonautes (pAgos) and CRISPR-Cas, detect and cleave invader nucleic acids using complementary guides and the nuclease activities of pAgo or Cas proteins. However, not all pAgos are active nucleases. A large clade of short pAgos bind nucleic acid guides but lack nuclease activity, suggesting a different mechanism of action. Here we investigate short pAgos associated with a putative effector nuclease, NbaAgo from Novosphingopyxis baekryungensis and CmeAgo from Cupriavidus metallidurans. We show that these pAgos form a heterodimeric complex with co-encoded effector nucleases (short prokaryotic Argonaute, DNase and RNase associated (SPARDA)). RNA-guided target DNA recognition unleashes the nuclease activity of SPARDA leading to indiscriminate collateral cleavage of DNA and RNA. Activation of SPARDA by plasmids or phages results in degradation of cellular DNA and cell death or dormancy, conferring target-specific population protection and expanding the range of known prokaryotic immune systems.

Understanding Antithrombotic Agents for Rehabilitation Therapy: A Comprehensive Narrative Review.

In rehabilitation medicine, attention must be paid to the medication. Among them, antithrombotic drugs are used for the initial treatment and secondary prevention of stroke, so as a basic knowledge, the pharmacological actions, characteristics, indications, and precautions for the use of antithrombotic drugs should be known. Antithrombotic agents are divided into antiplatelet agents and anticoagulants, and the appropriate antithrombotic agent is selected according to the main disease or condition. Antiplatelet agents include aspirin, clopidogrel, ticlopidine, prasugrel, ticagrelor, and cilostazol. Each antiplatelet agent has a different mechanism of action, characteristics, and indications, and should be prescribed with due consideration. Anticoagulants include heparin, synthetic Xa inhibitors, direct oral anticoagulants (DOACs), synthetic antithrombin agents, and warfarin. Knowledge of the mechanism of action, characteristics, and indications of each anticoagulant is necessary, as well as monitoring and dose adjustment. With regard to ischemic cerebrovascular disease (ICD) and antithrombotic agents, the first step is to classify cerebral infarction and to determine whether antiplatelet agents or anticoagulants should be used. Bleeding and recurrence prevention are important considerations in the selection of appropriate antithrombotic agents for the pathophysiology of ICD.

Alternating rabacfosadine and doxorubicin for treatment of naïve canine lymphoma.

The current standard of care treatment for canine lymphoma is a multi-agent, CHOP-based chemotherapy protocol. Single agent doxorubicin (DOX) is less burdensome; however, multi-agent chemotherapy protocols are often superior. The recently approved drug rabacfosadine (RAB, Tanovea) provides an attractive option for combination therapy with DOX, as both drugs demonstrate efficacy against lymphoma and possess different mechanisms of action. A previous study evaluating alternating RAB/DOX reported an overall response rate (ORR) of 84%, with a median progression-free survival time (PFS) of 194 days. The aim of this prospective trial was to evaluate the same protocol in an additional population of dogs. Fifty-nine dogs with treatment naïve lymphoma were enrolled. RAB (1.0 mg/kg IV) was alternated with DOX (30 mg/m2 IV) every 21 days for up to six total treatments (3 cycles). Response assessment and adverse event (AE) evaluation were performed every 21 days using VCOG criteria. The ORR was 93% (79% CR, 14% PR). The median time to maximal response was 21.5 days; median PFS was 199 days. T cell immunophenotype and lack of treatment response were predictive of inferior outcomes. AEs were mostly gastrointestinal. Six dogs developed presumed or confirmed pulmonary fibrosis; four were grade 5. One dog experienced grade 3 extravasation injury with RAB that resolved with supportive treatment. These data mirror those of the previously reported RAB/DOX study, and support the finding that alternating RAB/DOX is a reasonable treatment option for canine lymphoma.

Nature's Toolbox for Alzheimer's Disease: A Review on the Potential of Natural Products as Alzheimer's Disease Drugs

Numerous clinical trials involving natural products have been conducted to observe cognitive performances and biomarkers in Alzheimer's Disease (AD) patients. However, to date, no natural-based drugs have been approved by the FDA as treatments for AD. In this review, natural product-based compounds that were tested in clinical trials from 2011 to 2023, registered at www.clinicaltrials.gov were reviewed. Thirteen compounds, encompassing 7 different mechanisms of action were covered. Several observations were deduced, which are: i) several compounds showed cognitive improvement, but these improvements may not extend to AD, ii) compounds that are endogenous to the human body showed better outcomes, and iii) Docosahexaenoic acid (DHA) and cerebrolysin had the most potential as AD drugs among the 13 compounds. Based on the current findings, natural products may be more suitable as a supplement than AD drugs in most cases. However, the studies covered here were conducted in a relatively short amount of time, where compounds acting on AD pathways may take time to show any effect. Given the diverse pathways that these natural products are involved in, they may potentially produce synergistic effects that would be beneficial in treating AD. Additionally, natural products benefit from both physicochemical properties being in more favorable ranges and active transport playing a more significant role than it does for synthetic compounds.

The steroid-sparing effect of JAK inhibitors across multiple patient populations.

JAK-inhibitors (JAK-i) represent an effective treatment in Rheumatoid Arthritis (RA) and Psoriatic Arthritis (PsA). Oral glucocorticoids (OGC) are commonly used in combination with JAK-i to reach therapeutic target. We aimed to assess, in a real-life setting, the reduction of OGC dose during JAK-i treatment in active RA and PsA patients. We prospectively enrolled 103 patients (88 RA, 15 PsA) treated with JAK-i: 24% bio-naïve (b-naïve), 76% bDMARD-insufficient responders (bDMARD-IR) and 40% difficult to treat (D2T), defined as failure of ≥2 bDMARDs with different mechanism of action. Disease activity (DAS28 and DAPSA, VAS-pain, GH) and OGC dose was collected at baseline and after 3, 6 and 12 months (T3, T6, T12) of treatment. In all the cohort and in b-naïve patients we reported a reduction of OGC dose at all time-points; bDMARD-IR patients were able to reduce OGC dose at T3 and T12; D2T ones only at T3. We reported an improvement of disease activity and withdrawal of OGC as early as three months of therapy, at all time-points, regardless of line of bDMARD treatment. Chronic OGC may cause detrimental bone, metabolic, cardiovascular side effects and infections; therefore JAK-i steroid-sparing effect may be beneficial for patients in long-term treatment.

Dual acid-pump blocking as novel therapeutic approach to treatment of acid-related diseases

Proton-pump inhibitors are highly efficient in the treatment of acid-related disease; however, their efficacy in treating reflux symptoms, healing esophageal erosions and peptic ulcers and eradicating Helicobacter pylori is sometimes suboptimal. Potassium-competitive acid blockers have a different mechanism of action, resulting in higher and longer-lasting increases in intragastric pH, which is neither non-inferior or superior to those of proton-pump inhibitors. The pharmacology, metabolism and mechanism of action of these drugs are different, therefore, it is hypothesised, that their combined use might be of clinical benefit through increased intragastric pH. This hypothesis is supported by pharmacological, physiological and microbiological data. The combined administration of proton-pump inhibitors and potassium-competitive acid blockers should be investigated in short-term therapy (4–8 weeks); if their complementary or additive effect is proven, dual acid pump blocking can be of further benefit in managing gastroesophageal reflux disease, peptic ulcers and eradicating Helicobacter pylori infection, in cases refractory to current therapies. For safety reasons, long-term administration of this combination as maintenance treatment should be avoided.

Influenza C virus susceptibility to antivirals with different mechanisms of action.

Antiviral susceptibility of influenza viruses was assessed using a high-content imaging-based neutralization test. Cap-dependent endonuclease inhibitors, baloxavir and AV5116, were superior to AV5115 against type A viruses, and AV5116 was most effective against PA mutants tested. However, these three inhibitors displayed comparable activity (EC50 8-22 nM) against type C viruses from six lineages. Banana lectin and a monoclonal antibody, YA3, targeting the hemagglutinin-esterase protein effectively neutralized some, but not all, type C viruses.