Different Mechanisms Of Action Research Articles

Delivery of Neuroregenerative Proteins to the Brain for Treatments of Neurodegenerative Brain Diseases

Neurodegenerative brain diseases such as Alzheimer’s disease (AD), multiple sclerosis (MS), and Parkinson’s disease (PD) are difficult to treat. Unfortunately, many therapeutic agents for neurodegenerative disease only halt the progression of these diseases and do not reverse neuronal damage. There is a demand for finding solutions to reverse neuronal damage in the central nervous system (CNS) of patients with neurodegenerative brain diseases. Therefore, the purpose of this review is to discuss the potential for therapeutic agents like specific neurotrophic and growth factors in promoting CNS neuroregeneration in brain diseases. We discuss how BDNF, NGF, IGF-1, and LIF could potentially be used for the treatment of brain diseases. The molecule’s different mechanisms of action in stimulating neuroregeneration and methods to analyze their efficacy are described. Methods that can be utilized to deliver these proteins to the brain are also discussed.

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. In this study, the performance of drinking water treatment technologies was evaluated with bioassays. CALUX reporter gene 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 five different pilot-scale water treatment trains applying advanced oxidation processes, reverse osmosis and filtration with (biological) 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 AOP 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.

Prefrontal cortex engagement during an fMRI task of emotion regulation as a potential predictor of treatment response in borderline personality disorder.

Borderline personality disorder (BPD) is a severe mental illness, with high rates of co-morbid depression and suicidality. Despite the importance of optimizing treatment in BPD, little is known about how neural processes relate to individual treatment response. This study examines how baseline regional brain blood oxygen level dependent (BOLD) activation during a functional magnetic resonance imaging (fMRI) task of emotion regulation is related to treatment response following a six-month randomized clinical trial of Dialectical Behavior Therapy (DBT) or Selective Serotonin Reuptake Inhibitor (SSRI) treatment. Unmedicated females with BPD (N = 37), with recent suicidal behavior or self-injury, underwent an fMRI task in which negative personal memories were presented and they were asked to distance (i.e., downregulate their emotional response) or immerse (i.e., experience emotions freely). Patients were then randomized to DBT (N = 16) or SSRI (N = 21) treatment, with baseline and post-treatment depression and BPD severity assessed. BOLD activity in prefrontal cortex, anterior cingulate, and insula was associated with distancing. Baseline BOLD during distancing in dorsolateral, ventrolateral, and orbital prefrontal cortex (dlPFC, vlPFC, OFC) differentially predicted depression response across treatment groups, with higher activity predicting better response in the SSRI group, and lower activity predicting better response in the DBT group. All female samples. Findings indicate that greater prefrontal engagement during emotion regulation may predict more antidepressant benefit from SSRIs, whereas lower engagement may predict better response to DBT. These results suggest different mechanisms of action for SSRI and DBT treatment, and this may allow fMRI to guide individualized treatment selection.

The Utility of Electroencephalograhy in Guiding General Anesthesia in Children.

Traditional pediatric anesthetic dosing using pharmacokinetic estimates based on age and weight is often imprecise, frequently leading to oversedation. Intraoperative electroencephalography (EEG) allows visualization of the brain's response to anesthetic agents in real time, facilitating precise titration of anesthetic drug doses optimized for the individual child. The goal of EEG-guided anesthesia management is to maintain an optimal state of hypnosis during various stages of the procedure while minimizing hemodynamic instability and other adverse effects of anesthesia. This is especially important in children with less predictable anesthetic requirements, such as children with atypical neurodevelopment, altered levels of consciousness before anesthesia, or those receiving total intravenous anesthesia, neuromuscular blockers, or a combination of anesthetic agents with different mechanisms of actions. Children with limited cardiorespiratory reserves and those undergoing high-risk procedures such as cardiopulmonary bypass also benefit from EEG guidance as they have a narrower therapeutic window for optimal anesthetic dosing. Various processed EEG (pEEG) monitors are available for intraoperative monitoring in children. These monitors display a pEEG index based on the manufacturer's algorithm, purportedly indicating the patient's hypnotic state. Due to differences in developmental neurophysiology and EEG dynamics in children, pEEG indices may not always reliably indicate the hypnotic state, especially in neonates and infants. Learning to interpret nonproprietary EEG parameters including the raw EEG, spectral-edge frequency 95% (SEF95), and density spectral array can prevent overreliance on pEEG indices. This review provides an overview of the advantages of EEG guidance during clinical anesthesia, including potential reduction in anesthetic dosage, prevention of EEG suppression, and reduction in peri-operative adverse events. We describe the use of nonproprietary EEG parameters in guiding anesthesia in children for various clinical end points including laryngoscopy, surgical incision, and maintenance of anesthesia, as well as sedation. We illustrate these principles with various case examples commonly encountered during pediatric anesthesia. Lastly, we discuss strategies to expand intraoperative EEG monitoring in children through education and training programs, as well as advocate for further research to assess clinical outcomes associated with EEG guidance to support its routine use in clinical care.

Chemical and Biological Prospection of Marine Sponges Belonging to the Class Demospongiae: A Review.

Marine sponges belonging to the class Demospongiae have shown to be promising sources of bioactive compounds. This review aimed to compile studies on the biological activities and chemical components of sponge species from this class, highlighting the structure/activity relationship. Data collection was conducted using the Science Direct, PubMed, Scielo, Web of Science and Google Scholar databases, employing the following descriptors: antimicrobial marine sponges, antioxidant marine sponges, and biological activity of marine sponges. The inclusion criteria were: (1) publications from the year 2022 onwards; (2) written in English or Portuguese; and (3) that evaluated biological activities. Exclusion criteria included: (1) duplicate studies; (2) studies that were not within the scope; and (3) studies that did not evaluate biological activities. As a result of this survey, it was possible to isolate and identify 262 compounds from different metabolic classes, with terpenes, lipids, and alkaloids being highlighted. The extracts, fractions, and isolates were investigated for their antioxidant, antimicrobial, anti-inflammatory, and cytotoxic properties. The sponges demonstrated broad-spectrum antimicrobial potential and cytotoxic potential against various cancer cell lines. Based on data analysis, it is concluded that the studied compounds show promise for the development of drugs for microorganism control and cancer treatment, acting through different mechanisms of action.

NeuropsychopharmARCology: Shaping Neuroplasticity through Arc/Arg3.1 Modulation

Activity-regulated cytoskeletal associated protein (aka activity-regulated gene Arg3.1) belongs to the effector gene family of the immediate early genes. This family encodes effector proteins, which act directly on cellular homeostasis and function. Arc/Arg3.1 is localized at dendritic processes, allowing the protein local synthesis on demand, and it is considered a reliable index of activitydependent synaptic changes. Evidence also exists showing the critical role of Arc/Arg3.1 in memory processes. The high sensitivity to changes in neuronal activity, its specific localization as well as its involvement in long-term synaptic plasticity indeed make this effector gene a potential, critical target of the action of psychotropic drugs. In this review, we focus on antipsychotic and antidepressant drugs as well as on psychostimulants, which belong to the category of drugs of abuse but can also be used as drugs for specific disorders of the central nervous system (i.e., Attention Deficit Hyperactivity Disorder). It is demonstrated that psychotropic drugs with different mechanisms of action converge on Arc/Arg3.1, providing a means whereby Arc/Arg3.1 synaptic modulation may contribute to their therapeutic activity. The potential translational implications for different neuropsychiatric conditions are also discussed, recognizing that the treatment of these disorders is indeed complex and involves the simultaneous regulation of several dysfunctional mechanisms.

Beneficial effects of resveratrol on diabetes mellitus and its complications: focus on mechanisms of action.

Diabetes mellitus (DM) is a significant global health issue, associated with various microvascular and macrovascular complications that significantly impair patients' quality of lifeas well as healthspan and lifespan. Despite the availability of several anti-diabetic medications with different mechanisms of action, there remains no definite curative treatment. Hence, discovering new efficient complementarytherapies is essential. Natural products have received significant attention due to their advantages in various pathological conditions. Resveratrol is a natural polyphenol that possesses antioxidant and anti-inflammatory properties, and its efficacy has been previously investigated in several diseases, including DM. Herein, we aimed to provide a holistic view of the signaling pathways and mechanisms of action through which resveratrol exerts its effects against DM and its complications.

Cycling versus swapping strategies with TNF-α inhibitors and IL-17 inhibitors in psoriatic arthritis in clinical practice

The availability of a number of bDMARDs with different mechanism of action increases potential treatment pathways in psoriatic arthritis (PsA). In clinical practice, following the failure of one bDMARD, it is normal to consider which options are the best for switching strategy. In most cases this choice involves IL17i and TNFi. The main aim of this study was to compare the effectiveness of cycling (from TNFi to another TNFi) and swapping (from TNFi to IL17i or vice versa) strategies. In this monocentric retrospective observational study, all PsA patients treated with TNFi or IL17i between January 2016 and January 2022 were enrolled. The prescriptions were clustered in one cycling group (CG), and two swap groups: from TNFi to IL17i (SG1) and from IL17i to TNFi (SG2). The Kaplan–Meier method and Cox regression models were applied to compare the drug retention rates and to identify factors affecting treatment persistence. A total of 122 patients were enrolled. The CG, SG1 and SG2 2-years retention rates were 51%, 58% and 34% (p = 0.1), respectively. SG1 strategy (HR 0.53; CI 0.31–0.89; p = 0.02), age (HR 0.98; CI 0.96–0.99; p = 0.003), Disease Activity PsA (HR 1.11; CI 1.08–1.13; p < 0.0001), year of switch (HR 1.78; CI 1.39–2.22; p < 0.0001) influenced the retention rate. The findings of this real-world study, even if burdened by bias related to its observational nature, support the hypothesis that in PsA patients swapping from TNFi to IL17i might be more effective than cycling TNFis.

Formulation of Thermo-Sensitive In Situ Gels Loaded with Dual Spectrum Antibiotics of Azithromycin and Ofloxacin.

In situ gels have been developed as an innovative strategy to prolong corneal residence time and enhance drug absorption compared to traditional eye drops. Our study aimed to formulate an ophthalmic in situ gel with a combination of two thermosensitive poloxamers, P407 and P188, in an optimal ratio not only to increase the time of action but also to increase the solubility of selected antibiotics for the treatment of ophthalmic infections. Two BSC II class substances, Azithromycin and Ofloxacin, with different mechanisms of action, have been incorporated into the in situ gel system after determining their solubility. The antibiotics-loaded in situ gel formulation was evaluated for its clarity, pH, rheological properties, and gel characteristics of gelling time, temperature, and capacity. The formulation demonstrated satisfactory clarity, appropriate pH, effective gelation properties in simulated tear fluid, and suitable rheological characteristics. In addition, APIs release insight has been studied through a dissolution test, and the effectivity against sensitive and resistant bacterial strains has been proved through the antimicrobial study. Therefore, our in situ gel system based on thermosensitive poloxamers, with two hydrophobic antibiotics, AZM and OFX, can be considered a valuable approach for ophthalmic drug delivery with an enhancement of the antibiotics bioavailability through increasing the contact time with the ocular surface and enhancing patient compliance.

Complex therapy of musculoskeletal pain: the role of centrally acting muscle relaxants

Chronic pain is the main manifestation of musculoskeletal diseases (MSDs), leading to deterioration of quality of life and loss of ability to work. The importance of this problem is determined by the widespread prevalence of MSDs, osteoarthritis (OA), acute and chronic non-specific back pain (NBP), periarticular soft tissues lesions. Introduction of effective methods of treatment of musculoskeletal pain (MSP) into medical practice is one of the fundamental tasks of modern medicine.The pathogenesis of MSP includes mechanisms such as injury, inflammation, peripheral sensitization, biomechanical disorders, dysfunction of the nociceptive system and psychoemotional disorders. Painful muscle tension plays an important role in the development of MSP, especially in NBP. Given the complex pathogenesis of MSP, its treatment is based on the combined use of drugs with different mechanisms of action and nonpharmacological methods. Non-steroidal anti-inflammatory drugs (NSAIDs) have a central place in this context. However, they can cause serious adverse reactions (ARs), so when choosing NSAIDs, it is necessary to consider comorbid pathology and risk factors. One of the most acceptable NSAIDs with a pronounced analgesic effect and low incidence of ARs is aceclofenac, which is available in various dosage forms (tablets, sachets, topical cream for external use). This medication is characterized by proven efficacy and good tolerability.Centrally acting muscle relaxants (CM) play an important role in the treatment of MSP. They eliminate muscle spasm, enhance the effect of analgesics and reduce the need for NSAIDs. The effect of CM has been demonstrated in spasticity and NBP. However, the use of many drugs of this group can be associated with serious ARs, which limits their use.Tolperisone has the best combination of efficacy and favorable safety profile among CM. Its positive effect in the complex treatment of NBP has been confirmed in several well-organized, placebo-controlled trials. There are also studies demonstrating the efficacy of tolperisone in OA. An important advantage of this drug is virtually no sedative effect, and no negative impact on hemodynamics and on the ability to perform concentration-intensive work. Emergence of a new form of tolperisone – extended-release tablets (Mydocalm® Long 450 mg) – increases patient compliance with CM therapy and facilitates the physician's work.

Impact of saflufenacil and glyphosate-based herbicides on the morphoanatomical and development of Enterolobium contortisiliquum (Vell.) Morong (Fabaceae): new insights into a non-target tropical tree species.

The unregulated use and improper management of herbicides can cause negative effects on non-target species and promote changes in biological communities. Therefore, the current study is aimed at understanding morphoanatomical responses and effects on seedling development induced by the herbicides glyphosate and saflufenacil in Enterolobium contortisiliquum, a non-target tropical species. The plants were cultivated in a greenhouse and subjected to herbicides at doses of 0, 160, 480, and 1440g a.e ha-1 for glyphosate, and 0, 25, 50, and 100g a.i ha-1 for saflufenacil. We conducted visual and morphological assessments over 90days post-application. Leaf samples were collected 12days after the application for anatomical analysis, and we also performed a micromorphometric analysis of the leaf tissues. Biomarkers of phytotoxicity were identified in plants exposed to both herbicides, even at the lowest doses, including in leaves without visual symptoms. The main morphological alterations were the decrease in growth, stem diameter, and dry mass. Furthermore, the leaves and stems visually exhibited chlorosis and necrosis. Both herbicides triggered anatomical modifications such as significant changes (p < 0.05) in the thickness of leaf tissues, hypertrophy, cell collapse, and changes in epicuticular waxes. However, the alterations induced by glyphosate were more widespread compared to saflufenacil, encompassing alterations in the root system. We confirmed that the different mechanisms of action of each herbicide and the existence of an underground reserve system in this species are intrinsically linked to the morphological and developmental responses described. Our findings suggest that E. contortisiliquum could be a potential bioindicator species for these herbicides in the environment, even at concentrations lower than those typically recommended for field application.

Co-delivery of Doxorubicin and VEGF siRNA using carcinoembryonic antigen-targeted chitosan nanoparticles for colorectal cancer

Developing a targeted nanocarrier-based therapeutic approach is highly effective in delivering therapeutics to specific cancer cells. Combining two or more therapeutic approaches with different mechanisms of action can effectively maintain their unique benefits while considerably improving cancer treatment. Doxorubicin (DOX) binds to DNA by intercalation and triggers a cascade of biochemical processes in tumor cells leading to death. Anti-VEGF medicines may sensitize cancer cells to chemotherapeutics by limiting blood supply and increasing penetration by disrupting tumor vasculature. In this study, DOX and vascular endothelial growth factor siRNA (VEGF siRNA) loaded chitosan nanoparticles (ChNPs) were prepared by using the ionic gelation method. The DOX-siRNA-ChNPs surface was then functionalized with carcinoembryonic antigen (CEA) targeted monoclonal antibody (DOX-siRNA-ChNPs-CMAb), thereby delivering therapeutic moieties into the cancer milieu. The cytotoxicity and cellular uptake of the developed nanocarrier were tested in-vitro on HT-29, which revealed that DOX-siRNA-ChNPs-CMAb possessed the highest cytotoxicity when compared with other prepared formulations and free DOX. The cellular uptake using fluorescence microscopy displayed a significantly higher uptake of DOX-siRNA-ChNPs-CMAb (targeted) than free DOX and DOX-siRNA-ChNPs (non-targeted). Apoptosis analysis in flow cytometry using annexin-V/PI staining demonstrated a substantially higher apoptosis rate of HT-29 cells using DOX-siRNA-ChNPs-CMAb than DOX-siRNA-ChNPs. Moreover, DOX-siRNA-ChNPs-CMAb were studied in CRC induced animal models, showing that DOX-siRNA-ChNPs-CMAb specifically targets CRC cells without showing organ toxicity. Thus, the novel approach of simultaneous delivery of DOX and siRNA using CMAb conjugated ChNPs demonstrated significant targeting in both in-vitro and in-vivo with minimal organ toxicity.

TREATMENT OF PULMONARY ARTERIAL HYPERTENSION ASSOCIATED WITH CONGENITAL HEART DEFECTS

Patients with pulmonary arterial hypertension, associated with congenital heart disease (PAH-CHD) are a heterogeneous population with a varied course of PH. Improvements in pediatric cardiac surgery have changed the epidemiology and survival rate of patients with CHD, of which 90% reach adulthood. Progress in terms of prognosis has also been observed among patients with PAH-CHD. Better survival was observed in ES compared with PAH after defect correction. Advances in surgical treatment of CHD and an increase in life expectancy have led to the study of PAH-CHD and the need to create recommendations for drug treatment of this category of patients. In most of studies, the evaluation of drug treatment of group 1 PAH was carried out without identifying its subgroups. And thus, according to existing recommendations, treatment algorhithms for patients with PAH-CHD are similar to approaches to other forms of PAH. However, various clinical, functional, physical and hemodynamic characteristics of patients with PAH-CHD call into question of correct risk stratification approaches development. Multicenter randomized clinical trials included predominantly a small number of patients with corrected defects, which does not allow the results to be interpreted for the entire population of patients with PAH-CHD. Data from single-center observational studies, expert opinion, and several randomized trials primarily involving patients with Eisenmenger syndrome (ES) indicate the effectiveness and safety of PAH-specific therapy in patients with PAH-CHD. In this literature review, we examined and showed the results of studies involving patients with PAH-CHD and their response to specific therapy. The results obtained significantly expanded the possibilities of using bosentan, sildenafil, epoprostenol, riociguat, ralinepag, sotatercept as they lead to improvement of functional capacity and hemodynamic parameters in patients with PAH-CHD, and only epoprostenol demonstrated an effect on prognosis. Combination PAH-specific therapy, initial or sequential administration of two or more drugs with different mechanisms of action, is an important treatment strategy for patients with PAH. The role of such therapy has increased in recent years. Based on the results of the AMBITION, SERAPHIN, GRIPHON, COMPASS-2 studies, initial or sequential oral combination PAH-specific therapy is recommended for patients with WHO FC II or III. At the same time, there is little evidence to support the effectiveness of this approach in ES patients. The use of anticoagulants in PAH-CHD remains controversial. Low-flow oxygen therapy should be considered individually and continued when there is a significant predominance of subjective or objective benefit. Iron deficiency is associated with poor survival in ES. It is important to note that microcytosis is rare in patients with iron deficiency cyanosis and a normal mean red cell volume does not indicate the absence of anemia. In cases of intolerance to oral iron, intravenous drugs should be used. Currently, based on existing guidelines, most centers follow a consistent symptom-based approach in the treatment of patients with PAH-CHD. Therapy begins with oral ERAs or PDE-5 inhibitors and is escalated if symptoms persist or clinical worsening occurs. If there is no effect of oral PAH-specific therapy, it is recommended to consider parenteral drugs.

Proteome Aggregation in Cells Derived from Amyotrophic Lateral Sclerosis Patients for Personalized Drug Evaluation.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder that currently lacks effective therapy. Given the heterogeneity of clinical and molecular profiles of ALS patients, personalized diagnostics and pathological characterization represent a powerful strategy to optimize patient stratification, thereby enabling personalized treatment. Immortalized lymphocytes from sporadic and genetic ALS patients recapitulate some pathological hallmarks of the disease, facilitating the fundamental task of drug screening. However, the molecular aggregation of ALS has not been characterized in this patient-derived cellular model. Indeed, protein aggregation is one of the most prominent features of neurodegenerative diseases, and therefore, models to test drugs against personalized pathological aggregation could help discover improved therapies. With this work, we aimed to characterize the aggregation profile of ALS immortalized lymphocytes and test several drug candidates with different mechanisms of action. In addition, we have evaluated the molecular aggregation in motor neurons derived from two hiPSC cell lines corresponding to ALS patients with different mutations in TARDBP. The results provide valuable insight into the different characterization of sporadic and genetic ALS patients' immortalized lymphocytes, their differential response to drug treatment, and the usefulness of proteome homeostasis characterization in patients' cells.

Second messenger c-di-AMP regulates multiple antibiotic sensitivity pathways in Mycobacterium smegmatis by discrete mechanisms.

One of the debilitating causes of high mortality in the case of tuberculosis and other bacterial infections is the resistance development against standard drugs. There are limited studies so far to describe how a bacterial second messenger molecule can directly participate in distinctive antibiotic tolerance characteristics of a cell in a mechanism-dependent manner. Here we show that intracellular cyclic di-AMP (c-di-AMP) concentration can modulate drug sensitivity of Mycobacterium smegmatis by interacting with an effector protein or interfering with the 5'-UTR regions in mRNA of the genes and thus causing transcriptional downregulation of important genes in the pathways. We studied four antibiotics with different mechanisms of action: rifampicin, ciprofloxacin, erythromycin, and tobramycin and subsequently found that the level of drug sensitivity of the bacteria is directly proportional to the c-di-AMP concentration inside the cell. Further, we unraveled the underlying molecular mechanisms to delineate the specific genes and pathways regulated by c-di-AMP and hence result in differential drug sensitivity in M. smegmatis.

Perception of the Capixaba population regarding the use and benefits of antidepressants and anxiolytics

Depression is a routine disorder characterized by at least two weeks of loss of pleasure, mood, and interest in basic daily activities. Treatment involves psychotherapy, lifestyle changes, and medication therapy with antidepressants. These medications increase the availability of neurotransmitters in the central nervous system through different mechanisms of action, such as Monoamine Oxidase Inhibitors, Tricyclic Antidepressants, Selective Serotonin Reuptake Inhibitors, and Atypicals. Studies indicate that, after the pandemic, mental health issues such as anxiety and depression became more frequent in society, leading to greater use of antidepressants, especially clonazepam, sertraline, and amitriptyline. This project aims to investigate this usage, focusing on the benefits and drawbacks from the user’s perspective. To this end, it was submitted to the Ethics and Human Research Council of UNESC, with a bibliographic review conducted in the PubMed, Lilacs, and Scielo databases during the approval period. After approval, the research was conducted through structured questionnaires, made available online to the Capixaba society. The study evaluated the rate of use of these psychotropic drugs in the region, the benefits, risks, and behaviors regarding the use of antidepressants and anxiolytics from the perspective of patients. The use of psychotropic drugs by the population can be satisfactory for treating mental disorders, but it is essential that these medications are used with caution and under the guidance of a healthcare professional. Regular monitoring helps to manage adverse effects, ensure the medication is working properly, and prevent long-term medication-related problems.

Improved survival among elderly patients with aggressive adult T-cell leukemia/lymphoma: Impact of mogamulizumab-containing chemotherapy.

Due to the poor prognosis of adult T-cell leukemia/lymphoma (ATL), new treatments are urgently needed, especially for elderly patients with aggressive ATL. The anti-CCR4 antibody drug mogamulizumab (MOG) has been approved for the treatment of untreated ATL. To analyze the impact of MOG on elderly patients, we conducted a retrospective analysis of patients aged 70years and older with aggressive ATL diagnosed at our institution between 2015 and 2021. Among 32 patients, including those who received best supportive care, the median survival time (MST) and 2-year overall survival (OS) rate were 14.6months (range, 0.0-83.7), and 34.7% [95% confidence interval (CI), 18.2-51.9], respectively, which were better than outcomes in our previous study. The MST and 2-year OS for patients treated with MOG-containing chemotherapy were 18.1months (range, 4.0-83.7) and 45.0% (95%CI, 23.1-64.7), respectively, demonstrating clear improvement. Adverse events observed with MOG-containing treatment, such as myelosuppression and skin rash, were similar to those reported previously. Univariate analysis identified comorbidity as a predictor of poor outcomes, but not intensity of MOG-containing treatment, suggesting a different mechanism of action than that of classical chemotherapy. Our study suggests that MOG-containing treatments are an option for elderly patients with ATL.

Single turnover transient state kinetics reveals processive protein unfolding catalyzed by Escherichia coli ClpB

Escherichia coli ClpB and Saccharomyces cerevisiae Hsp104 are AAA+ motor proteins essential for proteome maintenance and thermal tolerance. ClpB and Hsp104 have been proposed to extract a polypeptide from an aggregate and processively translocate the chain through the axial channel of its hexameric ring structure. However, the mechanism of translocation and if this reaction is processive remains disputed. We reported that Hsp104 and ClpB are non-processive on unfolded model substrates. Others have reported that ClpB is able to processively translocate a mechanically unfolded polypeptide chain at rates over 240 amino acids (aa) per second. Here, we report the development of a single turnover stopped-flow fluorescence strategy that reports on processive protein unfolding catalyzed by ClpB. We show that when translocation catalyzed by ClpB is challenged by stably folded protein structure, the motor enzymatically unfolds the substrate at a rate of ~0.9 aa s−1 with a kinetic step-size of ~60 amino acids at sub-saturating [ATP]. We reconcile the apparent controversy by defining enzyme catalyzed protein unfolding and translocation as two distinct reactions with different mechanisms of action. We propose a model where slow unfolding followed by fast translocation represents an important mechanistic feature that allows the motor to rapidly translocate up to the next folded region or rapidly dissociate if no additional fold is encountered.