Different Mechanisms Of Action Research Articles

Glucagon-like Peptide-1 Receptor Agonists and Diabetic Kidney Disease: From Bench to Bed-Side

Glucagon-like peptide-1 (GLP-1) receptor agonists are currently available for the management of type 2 diabetes mellitus. They have been shown to help with diabetic kidney diseases through multiple mechanisms. In this review, we will shed light on the different mechanisms of action through which GLP-1 receptor agonists may achieve their roles in renal protection in diabetics, both in animal and human studies, as well as review the renal outcomes when using these drugs and their safety profile in diabetic patients.

Pemphigus and Bullous Pemphigoid Following COVID-19 Vaccination: A Systematic Review

The COVID-19 pandemic has encouraged the rapid development and licensing of vaccines against SARS-CoV-2. Currently, numerous vaccines are available on a global scale and are based on different mechanisms of action, including mRNA technology, viral vectors, inactive viruses, and subunit particles. Mass vaccination conducted worldwide has highlighted the potential development of side effects, including ones with skin involvement. This review synthesizes data from 62 manuscripts, reporting a total of 142 cases of autoimmune blistering skin diseases (AIBDs) following COVID-19 vaccination, comprising 59 cases of pemphigus and 83 cases of bullous pemphigoid. Among the 83 bullous pemphigoid cases, 78 were BP, with additional cases including 2 oral mucous membrane pemphigoid, 1 pemphigoid gestationis, 1 anti-p200 BP, and 1 dyshidrosiform BP. The mean age of affected individuals was 72 ± 12.7 years, with an average symptom onset of 11 ± 10.8 days post-vaccination. Notably, 59% of cases followed vaccination with BNT162b2 (Pfizer-BioNTech), 51.8% were new diagnoses, and 45.8% occurred after the second dose. The purpose of our review is to analyze the cases of pemphigus and bullous pemphigoid associated with COVID-19 vaccination and to investigate the pathogenetic mechanisms underlying the new development or flare-up of these diseases in association with vaccination. Our results show that the association between COVID-19 vaccines and AIBDs is a possible event.

PCSK9 inhibitors – new era of dyslipidemia treatment - effectiveness in reducing low-density lipoprotein (LDL-C) and cardiovascular risk

Introduction: Abnormal blood cholesterol levels in patients with increased cardiovascular risk have a worse prognosis for patient survival. Treating dyslipidemia is important because it can improve patient comfort and safety. It sometimes happens that currently used drugs to lower cholesterol are not effective - patients develop tolerance or experience serious side effects. For this reason, scientists are looking for new drugs with a different mechanism of action. An example of such a group of drugs are PCSK9 inhibitors used to treat dyslipidemia. In this paper, we will look at the effectiveness of currently used PCSK9 inhibitors, but also at the potential risks associated with their use. Material and methods: We searched for materials for this work in the Pubmed and Google Scholar databases using the keywords: "dyslipidemia", "cardiovascular disease", "PCSK9 inhibitors", "statins". Then we analyzed the selected materials. Aim of the study: Evaluation of the Conclusion: PCSK9 inhibitors are drugs that are very effective in lowering low-density lipoprotein (LDL-C), while reducing cardiovascular risk and potentially having long-lasting effects. Scientists are looking for new PCSK9 inhibitors with different mechanisms of action, which will be an even more effective therapy in lowering LDL-C.

The Dose Rate of Corpuscular Ionizing Radiation Strongly Influences the Severity of DNA Damage, Cell Cycle Progression and Cellular Senescence in Human Epidermoid Carcinoma Cells

Modern radiotherapy utilizes a broad range of sources of ionizing radiation, both low-dose-rate (LDR) and high-dose-rate (HDR). However, the mechanisms underlying specific dose-rate effects remain unclear, especially for corpuscular radiation. To address this issue, we have irradiated human epidermoid carcinoma A431 cells under LDR and HDR regimes. Reducing the dose rate has lower lethality at equal doses with HDR irradiation. The half-lethal dose after HDR irradiation was three times less than after LDR irradiation. The study of mechanisms showed that under HDR irradiation, the radiation-induced halt of mitosis with the accompanying emergence of giant cells was recorded. No such changes were recorded after LDR irradiation. The level of DNA damage is significantly greater after HDR irradiation, which may be the main reason for the different mechanisms of action of HDR and LDR irradiations. Comparing the mechanisms of cell response to LDR and HDR irradiations may shed light on the mechanisms of tumor cell response to ionizing radiation and answer the question of whether different dose rates within the same dose range can cause different clinical effects.

Sensitivity of Septoria lycopersici Speg. isolates to fungicides in Brazil

Disease management using synthetic fungicides is the main strategy used by tomato growers to prevent tomato yield reductions caused by Septoria leaf spot (SLS). Despite the importance of this plant disease, there is little information about the sensitivity of Septoria lycopersici isolates to fungicides. The sensitivity of 94 isolates of S. lycopersici to azoxystrobin, chlorothalonil, tebuconazole, and thiophanate-methyl was assessed in experiments using fungicide-amended 96-well microtiter plates. The highest EC 50 values above 100 mg/L were detected for azoxystrobin, thiophanate-methyl, and tebuconazole. Based on these results, five isolates classified as resistant and five as sensitive to each fungicide were selected for the experiments. Tomato plants were inoculated with sensitive (S) and resistant (R) isolates and sprayed by the fungicides in three greenhouse assays. The differences in the values of the area under the progress curve of Septoria leaf spot (AUDPC), disease severity progress, and progress rates were not so pronounced between tomato plants sprayed and non-sprayed with fungicides. The AUDPC values for plants inoculated with S and R isolates and treated with chlorothalonil, tebuconazole, and thiophanate-methyl ranged from 10 to 320, 0 to 80, and 50 to 150, respectively. For azoxystrobin, the AUDPC values were around 200 in plants inoculated with S and R isolates. There is evidence of reduced sensitivity of individuals of S. lycopersici to azoxystrobin, tebuconazole, and thiophanate-methyl in the population in Brazil. Therefore, tomato growers should rotate and combine fungicides with different mechanisms of action and low-risk of resistance to control SLS.

An innovative phase 2 chronic pain master protocol design to assess novel mechanisms in multiple pain types.

The phase 2 chronic pain master protocol (CPMP) presented here provides a construct to accelerate the investigation of novel analgesics, broadly referred to here as mechanisms. Designed to address historical challenges in analgesic research and development, such as the choice of indication, this protocol enables the efficient evaluation of potential therapeutics with different mechanisms of action in 3 pain types: nociceptive pain (osteoarthritis), neuropathic pain (diabetic peripheral neuropathic pain), and mixed pain (chronic low back pain). The study design was determined before the identification of any specific molecule. Statistical simulations were conducted to optimize the methodology and design, the culmination of which were submitted to and accepted by the Complex Innovative Trial Design Pilot Meeting Program, a unique collaboration with the United States Food and Drug Administration. Benefits of the CPMP include limiting the number of study participants exposed to placebo and reducing the total sample size over time by leveraging placebo data across studies within a pain type and efficacy data across pain types for a specific molecule. The CPMP design enables: (1) efficient evaluation of multiple novel mechanisms of action; (2) the study of multiple molecules simultaneously or serially; (3) direct statistical comparison of molecules within a pain type; and (4) efficient planning and conduct of clinical studies. ClinicalTrials.gov ID NCT05986292. By evaluating novel mechanisms across different pain types, therapeutic potential can be assessed more efficiently compared with traditional individual clinical studies.

Sensitivity of the pathogen of barley brown rust (<i>Puccinia hordei</i> G.H. Otth.) to fungicides – derivatives of triazoles and strobilurins

The sensitivity of the North Caucasian population of the pathogen of barley brown rust (Puccinia hordei G.H. Otth.) to fungicides derived from triazoles and strobilurines (preparations Amistar Gold, SK; Amistar Extra, SK; Baliy, KME; Delaro, KS) was determined. The work was carried out under controlled conditions of the greenhouse complex of the Federal National Research and Development Fund on winter barley of the susceptible Vivat variety of the Agricultural Scientific Center “Donskoy”. Winter barley plants in the germination phase were infected with the North Caucasian population of the barley brown rust pathogen. Fungicide treatment was carried out at the first signs of the disease with application rates of 0 (control, without treatment), 50, 100, 150 and 200% (the recommended application rate is assumed to be 100%). It was found that when treating infected barley plants with the fungicide Baliy, KME with different application standards, the biological effectiveness varied from 87.3 to 100%, Delaro, KS – from 78.1 to 100%, Amistar Extra, SK – from 79.2 to 100%, Amistar Gold, SK – from 85.3 to 100%. The use of the recommended dose of treatment(100%) contributed to a decrease in the development of brown rust in all variants by more than 96.9%. When using increased rates of fungicides (150, 200%), the biological efficiency was 100%. The high sensitivity of the North Caucasian population of the pathogen P. hordei to the active substances of the studied fungicides has been proven. For all the studied drugs, the values of LC50 and LC95 were significantly lower in comparison with the recommended concentration in the working solution. The result obtained was due to the content of active substances in fungicides from different chemical classes with different mechanisms of action, which provided high efficiency in suppressing the development of barley brown rust and reduced the risk of resistance.

Validity evaluation of a rat model of monoiodoacetate-induced osteoarthritis with clinically effective drugs

BackgroundKnee osteoarthritis (KOA) is the most common type of joint disease in elderly people and is characterized by pain and dysfunction. Although the monoiodoacetate (MIA)-induced model is widely used as a rodent KOA model, it is important to acknowledge the inherent limitations of this model, as the MIA model develops complex pathological phases on a daily basis. An accurate understanding of this model and the selection of an appropriate time point according to the target for drug candidates can lead to the development of clinically effective drugs.MethodsChanges in the pathological state of the MIA model were assessed via histopathological evaluation. Clodronate, a bisphosphonate, and diclofenac, a nonsteroidal anti-inflammatory drug (NSAID), were selected as models of clinically effective drugs due to their different mechanisms of action. The analgesic effects of both drugs on the MIA model were evaluated. The long-term effect of clodronate on subchondral bone osteoclasts was also evaluated.ResultsHistopathological evaluation revealed that MIA-induced symptomatic behavior occurred in the early and late phases and was accompanied by synovial inflammation and osteoclast-related joint degeneration, respectively. Although clodronate inhibited symptomatic behavior and prevented cartilage degeneration from the early to late phases, diclofenac inhibited symptomatic behavior only in the early phase. Clodronate acted locally and inhibited the activation of subchondral osteoclasts.ConclusionsPathological changes, such as synovial changes in the early phase and knee joint degeneration in the late phase, in the MIA model are similar to those in human KOA. Our results indicate that the early phase in the MIA model is appropriate for evaluating the effects of anti-inflammatory agents such as NSAIDs and corticosteroids. The late phase in the MIA model is appropriate for evaluating the effects of drugs that act on cartilage and subchondral bone.

Possible Factor Xa Resistance in a Patient Who Failed Apixaban and Rivaroxaban.

This article aims to discuss the literature on switching to an anticoagulant with a different mechanism of action in case of treatment failure. We present a patient with atrial fibrillation who incurred an embolic stroke despite adequate anticoagulation with apixaban and developed a new symptomatic ischemic stroke during the same admission after switching to rivaroxaban, a factor Xa inhibitor with a similar mechanism of action. He had no new events at 3-months after switching to dabigatran, a direct thrombin inhibitor. We identified no apparent reason for anticoagulation failure in our patient. The literature on switching anticoagulants in case of failure is inconclusive with no strong supportive evidence. More research is needed to define anticoagulation failure and identify cases with factor Xa inhibitor resistance, in which switching to a different mechanism of anticoagulation may be appropriate.

Insights on treatment of adult ITP: algorithm for management and role of multimodal therapy.

The management of immune thrombocytopenia (ITP) is continuously evolving with the development and introduction of newer therapies and a better understanding of the disease. Corticosteroids still represent the cornerstone of first-line treatment. Patients who fail to achieve remission with a short course of corticosteroids require subsequent therapy. Most guidelines recommend starting with either a thrombopoietin receptor agonist (TPO-RA), rituximab, or fostamatinib since these agents have been investigated in randomized trials and have well-characterized efficacy and safety profiles. Patients' involvement to reach a shared decision regarding choice of therapy is essential as these treatments have different modes of administration and mechanisms of action. Less than 10% will fail to respond to and/or be intolerant of multiple second-line therapeutic options and thus be considered to have refractory ITP and require a third-line therapeutic option. Such patients may require drugs with different targets or a combination of drugs with different mechanisms of action. Combining a TPO-RA and an immunomodulatory agent may be an appropriate approach at this stage. Many studies have been conducted during the last 2 decades investigating the efficacy and safety of combinations strategies for first and later lines of therapies. Yet none of these are recommended by current guidelines or have gained wide acceptance and consensus.

What is the ideal approach-doublet, triplet, or quadruplet(s)?

Significant progress has been made in the treatment of multiple myeloma (MM), with the introduction of several new drugs with different mechanisms of action. The treatment of newly diagnosed MM has evolved dramatically with the development of highly effective combinations that include 1 or more of the new drugs. Despite the continuing improvement in the overall survival of patients with MM, nearly a quarter of the patients have significantly inferior survival, often driven by a combination of factors, including tumor genetics and host frailty. The focus of initial therapy remains rapid control of the disease with reversal of the symptoms and complications related to the disease with minimal toxicity and a reduction in early mortality. The selection of the specific regimen, to some extent, depends on the ability of the patient to tolerate the treatment and the underlying disease risk. It is typically guided by results of randomized clinical trials demonstrating improvements in progression-free and/or overall survival. While increasing risk calls for escalating the intensity of therapy by using quadruplet combinations that can provide the deepest possible response and the use of autologous stem cell transplant, increasing frailty calls for a reduction in the intensity and selective use of triplet or doublet regimens. The choice of subsequent consolidation treatments and maintenance approaches, including duration of treatment, also depends on these factors, particularly the underlying disease risk. The treatment approaches for newly diagnosed myeloma continue to evolve, with ongoing trials exploring bispecific antibodies as part of initial therapy and CAR T cells for consolidation.

Pediatric Chronic Heart Failure: Age-Specific Considerations of Medical Therapy

Chronic heart failure (CHF) is a rare entity in children but carries a burden of high mortality and morbidity. Medical treatment of pediatric CHF is largely based on guidelines for the adult population. In contrast to adults, evidence for the efficacy of medications in treating CHF in children is sparse. This may be due to the difficulty of conducting high-powered studies in children or to true differences in the mechanisms of CHF pathophysiology. Recent observations suggest that CHF in children differs from adults at the molecular and cellular levels. Different pathways are involved, leading to less fibrosis and hypertrophy than in adults, with potential implications for therapy. The main pathophysiological goals of medical treatment of pediatric CHF due to systemic left ventricular dysfunction are discussed in this review. These include preload and afterload optimization, diminishing cardiomyocyte apoptosis and necrosis as well as interstitial fibrosis, and optimizing myocardial oxygen consumption. The pediatric myocardium should be provided with optimal conditions to achieve its regenerative potential. The cornerstones of medical CHF therapy are angiotensin converting enzyme inhibitors (ACEI), beta blockers and mineralocorticoid receptor antagonists. There are potential benefits of tissue ACEI and β1-selective beta blockers in children. Angiotensin receptor blockers are an alternative to ACEI and their slightly different mechanism of action may confer certain advantages and disadvantages. Diuretics are employed to achieve a euvolemic state. Digoxin is used more frequently in children than in adults. Promising new drugs already routinely used in adults include angiotensin receptor-neprilysin inhibitors and sodium-glucose contransporter 2 inhibitors.

Antioxidant and Anti-Inflammatory Effects of Opuntia Extracts on a Model of Diet-Induced Steatosis.

Oxidative stress and inflammation are widely recognised as factors that can initiate and facilitate the development of MAFLD. The aim of this study is to analyse the effect of low and high doses of Opuntia stricta var. dillenii peel extract (L-OD and H-OD, respectively) and Opuntia ficus-indica var. colorada pulp extract (L-OFI and H-OFI, respectively), which are rich in betalains and phenolic compounds, on oxidative stress, inflammation, DNA damage and apoptosis in rat livers with diet-induced steatosis. Steatotic diet led to increased final body and liver weight, serum transaminases, hepatic TG content, oxidative status and cell death. H-OFI treatment decreased serum AST levels, while L-OFI reduced hepatic TG accumulation. Oxidative stress was partially prevented with H-OD and H-OFI supplementation, and pro-inflammatory cytokines levels were especially improved with H-OFI treatment. Moreover, H-OFI appears to prevent DNA damage markers. Finally, H-OD and L-OFI supplementation down-regulated the apoptotic pathway. In conclusion, both H-OD and H-OFI supplementation were effective in regulating the progression to metabolic steatohepatitis, triggering different mechanisms of action.

Anticholinesterase and Anti-Inflammatory Activities of the Essential Oils of Sawdust and Resin-Rich Bark from Azorean Cryptomeria japonica (Cupressaceae): In Vitro and In Silico Studies.

Alzheimer's disease (AD), a multifactorial neurodegenerative disorder characterized by severe cognitive impairment, affects millions of people worldwide. However, AD therapy remains limited and mainly symptomatic-focused, with acetylcholinesterase (AChE) inhibitors being the major available drugs. Thus, AD is considered by the WHO as a disorder of public health priority. Among several strategies that have been identified to combat AD, the use of natural multi-target drug ligands (MTDLs) appears to be a promising approach. In this context, we previously found that the essential oils (EOs), obtained via hydrodistillation, from Azorean Cryptomeria japonica sawdust (CJS) and resin-rich bark (CJRRB) were able to exert antioxidant activity via different mechanisms of action. Therefore, in the present work, these EOs were screened for their (i) in vitro anti-AChE and anti-butyrylcholinesterase (BChE) activities, evaluated by a modified Ellman's assay; (ii) in vitro anti-inflammatory potential, using the albumin denaturation method; and (iii) toxicity against Artemia salina. The CJRRB-EO exhibited both anti-AChE and anti-BChE activities (IC50: 1935 and 600 µg/mL, respectively), whereas the CJS-EO only displayed anti-BChE activity, but it was 3.77-fold higher than that of the CJRRB-EO. Molecular docking suggested that α-pinene and ferruginol compounds contributed to the anti-AChE and anti-BChE activities, respectively. Moreover, the anti-inflammatory activity of the CJS-EO, the CJRRB-EO, and diclofenac was 51%, 70%, and 59% (at a concentration of only 2.21 μg/mL), respectively, with the latter two presenting comparable activity. Concerning the EOs' potential toxicity, the CJRRB-EO exhibited a lower effect than the CJS-EO (LC50: 313 and 73 µg/mL, respectively). Overall, the EOs from C. japonica biomass residues, chiefly the CJRRB-EO, displayed antioxidant, anticholinesterase, and anti-inflammatory activities in a concentration-dependent manner. These properties demonstrate that these residues may be suitable natural MTDLs for AD complementary therapy when administered through aromatherapy, or, alternatively, could serve as low-cost sources of valuable ingredients, such as α-pinene.

Antimicrobial peptides-a promising novel antimicrobial agent

Abstract. Antibiotic resistance has become one of the most critical public health problems in the 21st century, and infections caused by drug-resistant bacteria severely threaten human health. Otherwise, the development rate of conventional antibiotics has been unable to keep up with the speed at which bacteria develop resistance. Therefore, it is urgent to develop antimicrobial agents with novel mechanisms of action. Antimicrobial peptides (AMPs) are naturally occurring polypeptides with antibacterial activity, which have different mechanisms of action from existing antibiotics and thus have incomparable advantages over traditional antibiotics in treating infections caused by drug-resistant bacteria. Up to now, AMPs have been used in several clinical studies to destroy drug-resistant bacteria. The review introduces the basic properties of AMPs and their therapeutic mechanisms, summarizes some advances in preclinical studies and clinical applications, and analyzes the factors limiting their application in clinical treatment. In addition, some new strategies to overcome the shortcomings of AMPs in clinical applications are also introduced. Efficient and diverse synthesis technologies and optimization strategies keep coming to overcome the difficulties of clinical applications for AMPs, which may become an important weapon against drug-resistant bacterial infections in the future.

A case of karyomegalic interstitial nephritis without FAN1 mutations in the setting of brentuximab, ifosfamide, and carboplatin exposure

BackgroundKaryomegalic interstitial nephritis (KIN) is a rare renal diagnosis associated with both genetic and medication etiologies. The primary gene associated with KIN is the FAN1 gene which encodes a protein responsible for DNA interstrand repair. Common medication triggers of KIN are chemotherapeutic agents, especially those which disrupt DNA structure such as carboplatin. Despite overlap between these mechanisms, it has not clearly been established if medication usage requires an underlying genetic predisposition for triggering KIN or if medications alone are sufficient. This ambiguous pathogenesis can make it difficult to appropriately assess risk of KIN development when starting patients on one of the known KIN-inducing therapies. Additionally, brentuximab vedotin, an antibody–drug conjugate directed against CD30, has not been previously implicated in KIN development.Case presentation.We present a 49-year-old woman previously diagnosed with metastatic Hodgkin’s lymphoma who was treated with doxorubicin, bleomycin, vinblastine, and dacarbazine, then 3 cycles of ifosfamide, carboplatin, etoposide, all of which were discontinued due to side effects. Following an episode of acute kidney injury, the serum creatinine was 1.09 mg/dL. She then received 2 doses of brentuximab, the serum creatinine rose, and the drug was discontinued. Kidney biopsy done 2 months after brentuximab and 5 months following ifosfamide therapies showed karyomegalic interstitial nephritis. Genetic evaluation showed no FAN1 gene mutations. The patient was started on pembrolizumab; no steroids were given due to concerns about interference with lymphoma immunotherapy. She remains with stable disease and stable chronic kidney disease.ConclusionsThis case presents a patient who developed KIN with a progressively rising serum creatinine after ifosfamide, carboplatin and brentuximab treatment. Although ifosfamide and carboplatin have known associations with the development of KIN, this case raises the possibility that brentuximab, which has a different mechanism of action, also may be associated with KIN. Additionally, the genetic findings demonstrate that drug-induced KIN can develop in the absence of FAN1 mutations, a finding not previously reported.

A systematic review of efficacy and safety of newer drugs approved from 2016 to 2023 for the treatment of complicated urinary tract infections

Background: Complicated urinary tract infections are a significant cause of morbidity, hospitalization, and elevated hospital costs associated with kidney transplantations. The treatment of complicated urinary tract infections is very challenging, due to varying severities of infection and lower cure rates. The available drug options for treating these infections are limited, each with different mechanisms of action, efficacy, and safety profiles, making drug selection more difficult for healthcare professionals. Objectives: A systematic review was conducted to evaluate the safety and efficacy of drugs approved by the United States Food and Drug Administration for the treatment of complicated urinary tract infections between 2016 and 2023. The primary endpoint for all drugs used in treating complicated urinary tract infections was the cure rate. Results: Among the drugs used for treating complicated urinary tract infections, meropenem had the highest cure rate at 91.4%, followed by plazomicin at 88% and cefiderocol at 73% when used as monotherapy. In combination therapy, meropenem-vaborbactam had the highest cure rate at 98.4%, followed by piperacillin-tazobactam at 94%, and ceftazidime-avibactam at 87.5%. The safety profiles of the drugs indicated that almost all drugs caused gastrointestinal symptoms, with imipenem-relebactam and colistin-imipenem combinations having the most serious adverse events. Cefiderocol had a low magnitude of adverse events, with most side effects being mild gastrointestinal symptoms. Conclusion: The study concludes that appropriate drug selection and treatment adherence are crucial for preventing complicated urinary tract infections and improving health outcomes.

How improvements in US FDA regulatory process and procedures led to the drug approval for first ever treatment of a common liver disease.

Metabolic-associated liver disease is a growing public health crisis, with phenotypes from fatty liver to steatohepatitis, previously known as NASH (Non-Alcoholic SteatoHepatitis) and currently rebranded as MASH (Metabolic dysfunction-Associated SteatoHepatitis). Dysfunction in liver metabolism can progress to liver fibrosis, end stage cirrhosis and death. MASH (NASH) is associated with an increased risk of cardiovascular disease, elevation in serum lipids and Type 2 Diabetes Mellitus. There is now a US-approved drug to treat patients with NASH (MASH) under the FDA Accelerated Approval Pathway, which requires follow-up outcome studies to confirm clinical benefit or risk drug withdrawal by the agency. Despite extra-hepatic factors that contribute to MASH and complicate clinical trial design, reorganization of the FDA drug premarket review divisions, improvements to agency policies and procedures, as well as updates to the US Food, Drug & Cosmetic Act (FD&C Act) upon which FDA regulation is based, have provided new agency tools that facilitated such a drug approval to address the profound unmet medical need for patients with this metabolic-based liver disease. There is reason for hope that continued evolution of the regulatory process will lead to additional drug approvals, as well as the ability for clinical trial endpoints studying MASH treatments to include both liver-based and traditional metabolic measures, independent of the specific FDA review division. This initial NASH/MASH FDA approval has also opened the door for initiation of Combination Clinical Trials, where the approved drug is paired with an experimental drug with a different mechanism of action, to increase overall efficacy and potentially minimize risks. It is envisioned that future treatment of NASH/MASH will mirror what is currently observed with Type 2 Diabetes Mellitus practice patterns, where multiple drugs with different mechanisms of actions are used to optimize treatment benefit/risk in the selected patient populations.

Evaluation of pilot-scale drinking water treatment trains using a panel of bioassays

ABSTRACT Chemical water quality monitoring is increasingly complemented with bioassays. The performance of drinking water treatment technologies was evaluated with bioassays. CALUX bioassays and the Ames fluctuation bioassay for mutagenicity were used to analyze the responses of raw feed water with and without a spiking mixture of organic contaminants in different pilot-scale water treatment trains applying advanced oxidation processes, reverse osmosis and filtration with activated carbon for the preparation of drinking water. In general, CALUX responses in the spiked feed water were in the same range as in the unspiked feed water, indicating that spiking did not significantly elevate the activity measured in the feed water. This observation was in line with a calculation of the combined additive behavior of the spiking mixture using bioactivities of the spiked chemicals in analog bioassays from ToxCast. This calculation gave no indication of a measurable response in the bioassays to be expected by the spiking, except for oxidative stress. Responses in the Ames fluctuation assay in most feed water were in some cases increased by advanced oxidation processes (AOPs) and mostly removed by active concentrations. The bioassay responses demonstrate the removal of emerging chemicals with different mechanisms of action by different water treatment technologies.

Trans, Trans-Farnesol Enhances the Anti-Bacterial and Anti-Biofilm Effect of Arachidonic Acid on the Cariogenic Bacteria Streptococcus mutans and Streptococcus sobrinus.

Streptococcus mutans and Streptococcus sobrinus are Gram-positive bacteria involved in the development of dental caries, as they are able to form biofilms on tooth enamel, ferment sugars into acids, and survive under acidic conditions. This ultimately leads to a local lowering of the pH value on the tooth surface, which causes enamel cavities. One measure to reduce caries is to limit the growth of cariogenic bacteria by using two anti-bacterial agents with different mechanisms of action. The hypothesis of this study was that the anti-bacterial activity of ω-6 polyunsaturated arachidonic acid (AA) against S. mutans and S. sobrinus can be enhanced by the sesquiterpene alcohol trans, trans-farnesol (t,t-farnesol). The anti-bacterial activity of single and combined treatment was determined by the checkerboard assay. Bacterial viability was assessed by live/dead SYTO 9/propidium iodide (PI) staining on flow cytometry. Anti-biofilm activity was determined by MTT metabolic assay, crystal violet staining of biofilm biomass, SYTO 9/PI staining by spinning disk confocal microscopy (SDCM) and high-resolution scanning electron microscopy (HR-SEM). t,t-Farnesol lowered the minimum inhibitory concentration (MIC) and the minimum biofilm inhibitory concentration (MBIC) of AA at sub-MICs. AA reduced the metabolic activity of preformed mature biofilms, while t,t-farnesol had no significant effect. The enhanced anti-bacterial effect of the combined t,t-farnesol/AA treatment was further evidenced by increased PI uptake, indicating membrane perforation. The enhanced anti-biofilm effect was further verified by SDCM and HR-SEM. Gene expression studies showed reduced expression of some biofilm-related genes. Altogether, our study suggests a potential use of the two naturally occurring compounds arachidonic acid and t,t-farnesol for preventing biofilm formation by the cariogenic bacteria S. mutans and S. sobrinus. These findings have implications for caries prevention.