First-line Drug For Treatment Research Articles

The anthraquinone derivative KA-4s reduces energy metabolism and enhances the sensitivity of ovarian cancer cells to cisplatin.

Ovarian cancer is the leading cause of death from female gynecological cancers. Cisplatin (DDP)is a first-line drug for ovarian cancer treatment. Due to DDP resistance, there is an urgent need for novel therapeutic drugs with improved antitumor activity. AMPK-mediated metabolic regulatory pathways are related to tumor drug resistance. Our study aimed to determine the relationship between reversing DDP resistance with the anthraquinone derivative KA-4s and regulating AMPK energy metabolism in ovarian cancer. The results showed that KA-4s inhibited the proliferation of ovarian cancer cells. The combination of KA-4s with DDP effectively promoted drug-resistant ovarian cancer cell apoptosis and inhibited cell migration and invasion. Moreover, KA-4s decreased the intracellular ATP level and increased the calcium ion level, leading to AMPK phosphorylation. Further studies suggested that the AMPK signaling pathway may be involved in the mechanism through which KA-4s reduce drug resistance. KA-4s inhibited mitochondrial respiration and glycolysis; downregulated the glucose metabolism-related proteins GLUT1 and GLUT4; the lipid metabolism-related proteins SREBP1 and SCD1; and the drug resistance-related proteins P-gp, MRP1, and LRP. The inhibitory effect of KA-4s on GLUT1 was confirmed by the application of the GLUT1 inhibitor BAY-876. KA-4s combined with DDP significantly increased the expression of p-AMPKand reduced the expression of P-gp. In a xenograft model of ovarian cancer, treatment with KA-4s combined with DDP reduced energy metabolism and drug resistance, inducing tumor apoptosis. Consequently, KA-4s might be evaluated as a new agent for enhancing the chemotherapeutic efficacy of treatment for ovarian cancer.

The potential effects of methotrexate on cardiovascular outcomes in rheumatoid arthritis patients: a multi-institutional analysis

Abstract Introduction and Purpose The association between rheumatoid arthritis (RA) and increased risk of developing cardiovascular disease has been previously described. Recent studies have also shown that methotrexate may reduce the risk of cardiovascular events in patients with RA but have been limited by small sample size and/or demographic constraints. Methotrexate is a first-line drug treatment for RA and works by suppressing multiple anti-inflammatory and immune reactions, thereby reducing the inflammation that promotes progression of cardiovascular disease in these patients. The goal of this study is to evaluate the potential benefit of methotrexate use on cardiovascular outcomes in patients with RA on a larger scale by utilizing a large international medical record database. Methods The TriNetX Diamond network was used for this study. Two cohorts were generated for comparison by using International Classification of Disease 10 (ICD-10) codes. Both cohorts included adult patients with a diagnosis of rheumatoid arthritis (M06) and both were excluded from being treated with the following biologic therapies: etanercept, infliximab, adalimumab, golimumab, and certolizumab pegol. One cohort was on active treatment with methotrexate while the other was excluded from being on it. The cohorts were then balanced for age, gender, race, ethnicity, presence of known coronary artery disease (I20-I25) and history of prior cardiovascular diseases (Z86.7) by propensity score matching and use of the greedy nearest neighbor algorithm. This resulted in 471,054 patients in each arm. They were then compared for the outcomes of acute myocardial infarction, chronic ischemic heart disease, congestive heart failure, and death at 5 years. Results Untreated RA patients were 11% more likely to develop myocardial infarction (RR 1.11, 95% CI (1.09,1.14), P value <0.0001) and 14% more likely to develop chronic ischemic heart disease (RR 1.14, 95% CI (1.13,1.15), P value <0.0001). CHF incidence was 21% higher (RR 1.21, 95% CI (1.19,1.22), P value <0.0001) in the untreated group, but 5-year mortality in the two groups was comparable at around 8.2% (RR 0.98, 95% CI (0.97,0.997), P value 0.016). Conclusion This study confirms that methotrexate is associated with fewer cardiovascular events in RA patients, especially congestive heart failure. Although the use of methotrexate in patients with RA did not result in a mortality benefit, treatment may offer substantial improvements in patient morbidity and healthcare system cost. These benefits were seen in a sample of greater than 900,000 patients representing every adult demographic. These data reaffirm the previously described association between RA and cardiovascular disease and support the initiation of treatment with methotrexate for any adult patient with RA. Watchful waiting is associated with a higher incidence of adverse events in this population.

Medical Professionals and Pharmacological Intervention for the Treatment of Insomnia: A Cross-Sectional Study

Abstract Objective To explore the preferences of medical practitioners concerning various medications and other remedies to manage insomnia, and to ascertain whether these preferences are associated with their respective medical specialties. Materials and Methods Employing the snowball sampling technique, we administered two versions of a questionnaire to an international group of medical professionals, including trainees and specialists from diverse medical backgrounds. Results Zopiclone, zolpidem, and mirtazapine were evaluated as the most effective treatments for insomnia, while physicians would typically avoid using other tricyclic antidepressants, dual orexin receptor antagonists, and tryptophan for insomnia treatment. Noteworthy statistical correlations between physicians' specialty and preferred drug therapy, were observed in three out of five cases: 1) first-line drug treatment for short-term intervention against insomnia; (2) second-line treatment for long-term intervention; and 3) cases involving the elderly. Discussion Psychiatrists demonstrated a greater preference for antipsychotics and antidepressants for the treatment of insomnia compared with other physicians. Conversely, other medical professionals exhibited a preference for benzodiazepines and Z-drugs (zopiclone and zolpidem). Although Z-drugs were evaluated as the most effective in the treatment of insomnia, in the clinical practice, physicians administer or would administer antidepressant or antipsychotic drugs more often (mirtazapine and quetiapine respectively). Regarding Dual Orexin Receptor Antagonists (DORAs), the high prevalence of “Do not know/No opinion” answers implies that our sample was not familiar with this innovative treatment.

Evaluation of the efficacy of preventive therapy in chronic migraine with or without medication overuse headache: data from a prospective study

Chronic migraine (CM) affects three out of every hundred people. As the frequency of attacks increases, so does the frequency of painkillers usage, and 85% of patients with CM are also diagnosed with medication overuse headache (MOH).Objective: to investigate the efficacy of preventive therapy of CM with or without MOH.Material and methods. The study involved 117 patients with CM and MOH (group 1) and 23 patients with CM without MOH (group 2), patients were examined at the initial visit and after 3 and 9 months of follow-up. All patients in the 1st group (CM+MOH) received a 7-day "detoxification" therapy. Patients in both groups were given an educational and information session on the type of their diagnosis, treatment methods and lifestyle correction. The choice of a preventive treatment in both groups was based on the current clinical recommendations, algorithms of modern international guidelines, concomitant pathology, the presence of contraindications in a particular patient, tolerability, as well as territorial and economic factors.Results. A positive effect was found in both groups, regardless of the presence of MOH. The lack of significant differences between the groups of CM with/without MOH is probably due to the use of "detoxification" therapy and the cessation/restriction of the use of the drug of abuse in all patients with CM and MOH, although a more pronounced positive dynamics is observed in patients of the 2nd group (CM without MOH), which in turn emphasizes the severity of the disease, the greater disability and the poorer prognosis for response to preventive treatment in the presence of MOH. It was found that one third of patients in the study favored monoclonal antibodies (mAbs) due to convenience, rapid onset of action and tolerability. In the group of patients with MOH, the best results were obtained when using injection methods of treatment (anti-CGRP mAbs, botulinum therapy) or when using combined therapy compared to monotherapy with venlafaxine or topiramate.Conclusion. All first-line drugs for the CM prophylactic treatment according to the clinical guidelines of the Ministry of Health of Russia are clearly effective, including cases with both CM and MOH. The use of combined therapy in CM with/without MOH can be effective even with a low initial response to one of the monotherapies.

Disturbing microtubule-endoplasmic reticulum dynamics by gold nanoclusters for improved triple-negative breast cancer treatment.

Microtubules are highly dynamic structures, and their dynamic instability is indispensable for not only cell growth and movement, but also stress responses, such as endoplasmic reticulum (ER) stress. Docetaxel, a microtubule targeting agent (MTA), is the first-line drug for cancer treatment by simultaneously promoting microtubule dysregulation- and ER stress-induced cell death. However, it also causes adverse effects and drug resistance, especially in triple-negative breast cancer (TNBC) with a poor prognosis and high mortality rate. In this study, we developed a peptide-templated gold nanocluster, namely GA. GA significantly sensitizes TNBC cells to docetaxel, causing severe cell death. This effect is further validated by a 3D tumor spheroid model. Mechanistically, GA disrupted microtubule dynamic instability, meanwhile promoting PERK-mediated ER stress. Interestingly, ER stress inhibitors profoundly suppressed microtubule dysregulation, suggesting a retrograde regulation of ER stress on microtubules. In vivo, the combined administration of docetaxel and GA significantly suppresses tumor growth while docetaxel alone cannot. GA similarly elevated the level of caspases and PERK within tumors as in vitro. Importantly, GA treatment also profoundly promoted the production of anti-tumor inflammatory cytokines. Collectively, we developed an ER-microtubule regulatory nanomaterial that enhanced the therapeutic effect of docetaxel by elevating tumor cell death and anti-tumor cytokine production, providing a potential supplemental strategy for TNBC treatment.

Safety and Tolerability of Antihypertensive Agents in Long-term: A Literature Review

Hypertension is known to affect more than one billion people globally and is estimated to increase to 1.5 billion by 2025. It is considered one of the leading causes of death and cardiovascular disease worldwide. The safety of long-term antihypertensive use is also a concern. Through a narrative or literature review, this study evaluated antihypertensive agents based on the results of various literature searches. Researchers reviewed the safety and tolerability of five classes of antihypertensive agents such as Diuretics, Angiotensin-Converting Enzyme Inhibitors (ACEI), Angiotensin Receptor Blockers (ARB), Beta-Blockers, and Calcium Channel Blockers (CCB). The use of ARB antihypertensive drugs like valsartan is well tolerated and safe. Moreover, the mortality rate associated with enalapril was 16% lower (95% CI 0.76-0.93; P < 0.001). Captopril and lisinopril of Angiotensin-converting Enzyme Inhibitors (ACEIs) have significant side effects (SEs) compared to any antihypertensive drug. Therefore, this study recommends using the ACEIs group, especially captopril and lisinopril, due to the minimal side effects produced compared to other antihypertensive drugs. In addition, the CCBs or Ca antagonists class like amlodipine is potentially well tolerated and safe as a first-line drug for hypertension treatment. Keywords: antihypertensive drugs, hypertension, safety, side effect, tolerability

Initial Experience of Long-Term Prophylaxis with Lanadelumab for Hereditary Angioedema in China: A Clinical Observation Study on Six Patients

Plain Language SummaryHereditary angioedema (HAE) is a rare genetic disease characterized by recurring episodes of painful swelling of the subcutaneous and submucosal tissue, and its pathogenesis is due to the deficiency or dysfunction C1-esterase inhibitors. HAE attacks can affect many areas of the body, but most frequently involve the extremities, gastrointestinal tract, genitals, face, and upper airway. Swelling of the larynx can occur, with potentially fatal consequences owing to asphyxiation. Since 2020, China has had the only first-line treatment drug that can prevent HAE attacks – lanadelumab. Our study evaluated the efficacy and safety of lanadelumab by observing the 6 patients in China mainland who were the first to use it. Our research showed that lanadelumab can prevent the attack of HAE, greatly improve the quality of life of patients, and has good safety. A reasonable dosage plan can ensure stable therapeutic effects of lanadelumab. In addition, the efficacy of lanadelumab remained stable during COVID-19 vaccination and infection.

Alpha-asarone alleviates cutaneous hyperalgesia by inhibiting hyperexcitability and neurogenic inflammation via TLR4/NF-κB/NLRP3 signaling pathway in a female chronic migraine rat model

Migraine is a highly prevalent neurological disorder. Alpha-asarone (ASA), a major active component found in Acorus tatarinowii, plays a crucial role in analgesia and anti-inflammation for neuropathic pain. This study aimed to assess the efficacy of ASA against migraine and elucidate its potential mechanisms using a well-established inflammatory soup (IS) migraine female rat model. Mechanical pain thresholds were assessed daily before IS infusion, followed by post-infusion administration of ASA. Subsequently, spontaneous locomotor activities, exploratory behavior, short-term spatial memory, and photophobia were blindly evaluated after the final drug administration. The rats were then sacrificed for investigation into the underlying mechanisms of action. Network pharmacology was also employed to predict potential targets and pathways of ASA against migraine. The anti-inflammatory activity of ASA and pathway-related proteins were examined in BV2 cells stimulated with lipopolysaccharides (LPS). The results demonstrated that ASA ameliorated cutaneous hyperalgesia and photophobia while improving spatial memory and increasing exploratory behavior in IS rats. ASA attenuated central sensitization-related indicators and excessive glutamate levels while enhancing GABA synthesis. ASA rescued neuronal loss in the cortex and hippocampus of IS rats. Notably, the ability of ASA to improve spatial memory performance in the Y maze test was not observed with sumatriptan, a first-line treatment drug, suggesting the potential involvement of the TLR4 pathway. Moreover, ASA suppressed microglial activation, reduced pro-inflammatory factors, and downregulated TLR4, MyD88, p–NF–κB/NF-κB, NLRP3, caspase-1, IL-1β, and IL-18. Overall, ASA demonstrated its potential to alleviate hyperalgesia and improve behavioral performance in migraine rats by inhibiting hyperexcitability and microglia-related inflammation.

Andrographolide sensitizes glioma to temozolomide by inhibiting DKK1 expression.

Temozolomide (TMZ) is the first-line chemotherapeutic drug for gliomas treatment. However, the clinical efficacy of TMZ in glioma patients was very limited. Therefore, it is urgently needed to discover a novel approach to increase the sensitivity of glioma cells to TMZ. Western blot, immunohistochemical staining, and qRT-PCR assays were used to explore the mechanisms underlying TMZ promoting DKK1 expression and andrographolide (AND) inhibiting DKK1 expression. HPLC was used to detect the ability of andrographolide (AND) to penetrate the blood-brain barrier. MTT assay, bioluminescence images, magnetic resonance imaging (MRI) and H&E staining were employed to measure the proliferative activity of glioma cells and the growth of intracranial tumors. TMZ can promote DKK1 expression in glioma cells and brain tumors of an orthotopic model of glioma. DKK1 could promote glioma cell proliferation and tumor growth in an orthotopic model of glioma. Mechanistically, TMZ increased EGFR expression and subsequently induced the activation of its downstream MEK-ERK and PI3K-Akt pathways, thereby promoting DKK1 expression in glioma cells. Andrographolide inhibited TMZ-induced DKK1 expression through inactivating MEK-ERK and PI3K-Akt pathways. Andrographolide can cross the blood-brain barrier, the combination of TMZ and andrographolide not only improved the anti-tumor effects of TMZ but also showed a survival benefit in an orthotopic model of glioma. Andrographolide can enhance anti-tumor activity of TMZ against glioma by inhibiting DKK1 expression.

The impact of oxygen content on Staphylococcus epidermidis pathogenesis in ocular infection based on clinical characteristics, transcriptome and metabolome analysis.

This study aims to delineate the etiology and prevalence of isolated pathogens, along with the clinical characteristics of endophthalmitis patients over a 9-year period at hospital in Southwest of China. Additionally, we investigating the metabolic and cellular processes related to environmental factors may offer novel insights into endophthalmitis. We analyzed data pertaining to endophthalmitis patients treated at the Affiliated Hospital of Yunnan University from 2015 to 2023. According to our clinical data, we conducted an experiment based on transcriptomics and metabolomics analysis to verify whether environmental factors affect behavior of S. epidermidis by culturating S. epidermidis under oxic and microoxic condition. In this study, 2,712 fungi or bacteria strains have been analyzed, gram-positive bacteria constituted 65.08%, with S. epidermidis being the most predominant species (25.55%). Ophthalmic trauma was the primary pathogenic factor for S. epidermidis ocular infections. Regarding fluoroquinolones, S. epidermidis exhibited the higher resistance rate to levofloxacin than moxifloxacin. Moreover, our investigation revealed that S. epidermidis in microoxic environment increase in energy metabolism, amino acid metabolism, and membrane transport. Our findings underscore the significance of S. epidermidis as a crucial pathogen responsible for infectious endophthalmitis. It is crucial to exercise vigilance when considering Levofloxacin as the first-line drug for empiric endophthalmitis treatment. The metabolites alteration observed during the commensal-to-pathogen conversion under microoxic condition serve as a pivotal environmental signal contributing to S. epidermidis metabolism remodeling, toward more pathogenic state.

Identification and Validation of Tumor Microenvironment-Associated Signature in Clear-Cell Renal Cell Carcinoma through Integration of DNA Methylation and Gene Expression.

The tumor microenvironment (TME) is crucial in tumor development, metastasis, and response to immunotherapy. DNA methylation can regulate the TME without altering the DNA sequence. However, research on the methylation-driven TME in clear-cell renal cell carcinoma (ccRCC) is still lacking. In this study, integrated DNA methylation and RNA-seq data were used to explore methylation-driven genes (MDGs). Immune scores were calculated using the ESTIMATE, which was employed to identify TME-related genes. A new signature connected with methylation-regulated TME using univariate, multivariate Cox regression and LASSO regression analyses was developed. This signature consists of four TME-MDGs, including AJAP1, HOXB9, MYH14, and SLC6A19, which exhibit high methylation and low expression in tumors. Validation was performed using qRT-PCR which confirmed their downregulation in ccRCC clinical samples. Additionally, the signature demonstrated stable predictive performance in different subtypes of ccRCC. Risk scores are positively correlated with TMN stages, immune cell infiltration, tumor mutation burden, and adverse outcomes of immunotherapy. Interestingly, the expression of four TME-MDGs are highly correlated with the sensitivity of first-line drugs in ccRCC treatment, especially pazopanib. Molecular docking indicates a high affinity binding between the proteins and pazopanib. In summary, our study elucidates the comprehensive role of methylation-driven TME in ccRCC, aiding in identifying patients sensitive to immunotherapy and targeted therapy, and providing new therapeutic targets for ccRCC treatment.

Similarities and differences of bone marrow and peripheral blood samples from acute myeloid leukemia patients in terms of cellular heterogeneity and ex-vivo drug sensitivity.

Bone marrow (BM) evaluation is the de facto standard for diagnosis, molecular analysis, risk stratification, and therapy response assessment in acute myeloid leukemia (AML), but in patients with a high number of circulating blast cells, the peripheral blood (PB) sample could provide similar information as BM. However, there is no large-scale molecular study comparing the two specimens in terms of their gene expression profiles, cellular heterogeneities, and ex-vivo drug sensitivity. We used (i) the BEAT-AML cohort each with detailed molecular data; (ii) cell-type deconvolution to estimate leukemic and immune cell proportions between specimen types; (iii) differential expression (DE) and drug-cell type association analysis; and (iv) logistic regression models to assess the association between induction therapy response, cell-type composition and first-line drug treatment. Results: We identified 207 patients having BM and 116 patients having PB samples. There was a total of 1271 DE genes (false discovery rate<0.05) between BM and PB; the top enriched pathways in terms of DE genes belong to the immune system pathways. Aggregated ex-vivo drug response profiles from the two specimens were largely similar, as were the cellular components, except for the GMP-like cell type (17% in BM vs. 5% in PB, p-value=2×10-7). Among the specimen-specific results, the GMP-like subtype was associated with multiple drug resistance in BM and the ProMono-like subtype in PB. Several cell types were associated with the response to induction therapy, but the impact of specimen type on the interaction of cell type and cytarabine-associated induction therapy was not statistically significant for most cell types. Conclusions: Even though there are molecular and cellular differences between BM and PB samples, they show many similarities in ex-vivo drug response profiles, indicating the clinical utility of the substantially less-invasive PB samples.

Dual-targeted delivery of temozolomide by multi-responsive nanoplatform via tumor microenvironment modulation for overcoming drug resistance to treat glioblastoma.

Glioblastoma (GBM) is the most aggressive primary brain tumor with low survival rate. Currently, temozolomide (TMZ) is the first-line drug for GBM treatment of which efficacy is unfortunately hindered by short circulation time and drug resistance associated to hypoxia and redox tumor microenvironment. Herein, a dual-targeted and multi-responsive nanoplatform is developed by loading TMZ in hollow manganese dioxide nanoparticles functionalized by polydopamine and targeting ligands RAP12 for photothermal and receptor-mediated dual-targeted delivery, respectively. After accumulated in GBM tumor site, the nanoplatform could respond to tumor microenvironment and simultaneously release manganese ion (Mn2+), oxygen (O2) and TMZ. The hypoxia alleviation via O2 production, the redox balance disruption via glutathione consumption and the reactive oxygen species generation, together would down-regulate the expression of O6-methylguanine-DNA methyltransferase under TMZ medication, which is considered as the key to drug resistance. These strategies could synergistically alleviate hypoxia microenvironment and overcome TMZ resistance, further enhancing the anti-tumor effect of chemotherapy/chemodynamic therapy against GBM. Additionally, the released Mn2+ could also be utilized as a magnetic resonance imaging contrast agent for monitoring treatment efficiency. Our study demonstrated that this nanoplatform provides an alternative approach to the challenges including low delivery efficiency and drug resistance of chemotherapeutics, which eventually appears to be a potential avenue in GBM treatment.

Temporal trend of first-line drug choice and treatment continuity for hypertension among citizens 75 years or over - a register-based, cohort study

BackgroundLimited knowledge of antihypertensive treatment of the elderly potentially impedes effective strategies for hypertension management in this growing patient group. We aimed to investigate temporal trends for first-line drug choice for antihypertensive treatment and treatment continuity among patients ≥75 years from 2000 to 2021. MethodsUsing nationwide Danish registers, patients ≥75 years initiated for the first time on antihypertensive drugs: Angiotensin converting enzyme inhibitors (ACEi), angiotensin II receptor blockers (ARB), beta blockers (BB), calcium channel blockers (CCB), thiazides, or combinations, were identified. Patients with other indications than hypertension were excluded. Treatment continuity was described using claimed prescriptions the first 180 days following study entry. ResultsFrom 2000 to 2021, 170,769 patients (median age 80 years [interquartile range:77–84], 60.3% female) were included. From 2000 to 2003 to 2015–2021 the proportion of first-line drug choice increased for ACEi (8.7% to 14.9%), ARB (4.1% to 23.9%), and CCB (10.7% to 27.6%), decreased for thiazides (60.6% to 15.9%) and remained stable for BB (12.9% to 14.1%) and combinations (2.9% to 3.6%). For 157,457 patients alive after 180 days, discontinuation was highest among patients initiated on thiazides (28.3%) whereas most patients continued the same single drug regimen if they started on ACEi (55.2%), ARB (65.0%), BB (57.2%) or CCB (59.3%). ConclusionsFrom 2000 to 2021 thiazides have been replaced by ACEi, ARB and CCB. Thiazides had the lowest treatment continuity while ARB appeared preferred slightly over ACEi. Differences in adherence in relation to first-line drug choice may warrant scrutiny regarding recommendations for the elderly.

Adjunctive repetitive transcranial magnetic stimulation therapy’s effectiveness in treating a sample of patients with major depressive disorder refractory to first-line drug treatment

BackgroundThe usefulness of repetitious transcranial magnetic stimulation (rTMS) and its protocols in the treatment of major depressive disorder (MDD) remains controversial. This study aimed to evaluate the efficacy of rTMS in treating a sample of patients with MDD who did not respond to conventional treatment.ResultsThe Hamilton Depression Rating Scale (HDRS) scores for the active rTMS group were 19.66 ± 6.70 at baseline, 12.50 ± 6.69 at 2 weeks, and 11.23 ± 6.59 at 4 weeks. The average HDRS scores for the sham rTMS group were 20.03 ± 7.40 at baseline, 19.36 ± 6.86 at 2 weeks, and 18.53 ± 7.10 at 4 weeks (F = 5.98; p < 0.01). The Clinical Global Impression-Severity Scale (CGI-S) scores were significantly lower in the second and fourth weeks than the baseline due to the significant interaction between time effects and the groups (F = 9.95, p = 0.002). This condition was also similar to the CGI-Improvement Scale and Brief Illness Perception Questionnaire (Brief IPQ), and the intervention group showed a significantly lower score than the control group (p < 0.05).ConclusionsThis study showed that rTMS using the employed protocol was promising for patients with MDD resistant to first-line drug therapy. Further studies are required to ensure our observation.Trial registrationTrial registration number: IRCT20190612043877N1Trial registry Record URL: https://irct.behdasht.gov.ir/trial/63919

Nanoparticles Partially Restore Bacterial Susceptibility to Antibiotics.

The growing resistance of bacteria to antibiotics is one of the main public health problems nowadays. The influence of silver nanoparticle (AgNP) pretreatment of 220 cows with mastitis on the susceptibility of Staphylococcus epidermidis bacteria to 31 antibiotics was studied. The obtained results were compared with the previous results for Escherichia coli, Streptococcus dysgalactiae, and Staphylococcus aureus. For all four bacteria, an increase in susceptibility (9.5-21.2%) to 31 antibiotics after cow treatment with AgNPs was revealed, while after first-line antibiotic drug treatment as expected, the susceptibility decreased (11.3-27.3%). These effects were explained by (1) the increase in the contribution of isolates with efflux effect after antibiotic treatments and its decrease after AgNP treatment and (2) the changes in bacteria adhesion and anti-lysozyme activity after these treatments. The effect of the increasing antibacterial activity of antibiotics after AgNP treatment was the most pronounced in the case of E. coli and was minimal in the case of S. epidermidis. With AgNP treatment, the time of recovery decreased by 26.8-48.4% compared to the time of recovery after treatment with the first-line antibiotic drugs. The AgNP treatment allows for achieving the partial restoration of the activity of antibiotics.

Exposure to resistant fungi across working environments and time

Antifungal resistance has emerged as a significant health concern with increasing reports of resistant variants in previously susceptible species. At present, little is known about occupational exposure to antifungal-resistant fungi. This study aimed to investigate Danish workers' occupational exposure to airborne fungi resistant to first-line treatment drugs. A retrospective study was performed on a unique collection of personal exposure samples gathered over a twenty-year period from Danish working environments, in sectors including agriculture, animal handling, waste management, and healthcare. A total of 669 samples were cultivated at 37 °C and fungal colonies were identified using MALDI-TOF MS. Subsequently, identification was confirmed by amplicon sequencing the genes of calmodulin and beta-tubulin to unveil potential cryptic species.Infectious fungi (495 isolates from 23 species) were tested for resistance against Itraconazole, Voriconazole, Posaconazole, and Amphotericin B. Working environments were highly variable in the overall fungal exposure, and showed vastly different species compositions. Resistance was found in 30 isolates of the species Aspergillus fumigatus (4 of 251 isolates), A. nidulans (2 of 13), A. niger complex (19 of 131), A. versicolor (3 of 18), and A. lentulus (2 of 2). Sequence analysis revealed several cryptic species within the A. niger complex including A. tubingensis, A. luchuensis, and A. phoenicis. Among the resistant A. fumigatus isolates, two contained the well-described TR34/L98H mutation in the cyp51A gene and promoter region, while the remainder harbored silent mutations.The results indicate that the working environment significantly contributes to exposure to resistant fungi, with particularly biofuel plant workers experiencing high exposure. Differences in the prevalence of resistance across working environments may be linked to the underlying species composition.

Evaluation of the Modulatory Effects of Capsicum Chinensis Methanol Extract in Streptozotocin-Induced Diabetic Neuropathic Pain in Mice

Diabetes is one of the common causes of neuropathic pain. The first-line treatment drugs used in alleviating neuropathic pain can cause adverse effects. Therefore, the aim of this study is to evaluate the analgesic property of Capsicum chinensis, since the plant was reported to be used against chronic pain in traditional medicine. Streptozotocin-induced diabetes was adopted to model neuropathy in mice and the antihyperalgesic effect of the extract was evaluated using a hot plate test, cold allodynia test, and Randall- Selitto paw pressure test. The plasma level of pain-associated inflammatory biomarkers like interleukin-6 (IL-6) and tissue necrotic factor-α (TNF-α) was also measured. Treatment with varying doses of extract (1, 2.5, and 5 mg/kg) significantly (p &lt; 0.05) increased the mean reaction time to thermal pain during hot and cold plate tests. During the Paw pressure test, reaction time was significantly prolonged in the treatment groups and the plasma level of TNF-α and IL-6 were reduced (p &lt; 0.05). The extract showed a better antihyperalgesic effect than the positive control drug (gabapentin). The result obtained showed that Capsicum chinensis extract can alleviate diabetes neuropathic pain in mice models with a better analgesic effect thanthe control drug (gabapentin).

NQO1 Mediates Lenvatinib Resistance by Regulating ROS-induced Apoptosis in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-associated death worldwide. As a first-line drug for advanced HCC treatment, lenvatinib faces a significant hurdle due to the development of both intrinsic and acquired resistance among patients, and the underlying mechanism remains largely unknown. The present study aims to identify the pivotal gene responsible for lenvatinib resistance in HCC, explore the potential molecular mechanism, and propose combinatorial therapeutic targets for HCC management. Cell viability and colony formation assays were conducted to evaluate the sensitivity of cells to lenvatinib and dicoumarol. RNA-Seq was used to determine the differences in transcriptome between parental cells and lenvatinib-resistant (LR) cells. The upregulated genes were analyzed by GO and KEGG analyses. Then, qPCR and Western blotting were employed to determine the relative gene expression levels. Afterwards, the intracellular reactive oxygen species (ROS) and apoptosis were detected by flow cytometry. PLC-LR and Hep3B-LR were established. There was a total of 116 significantly upregulated genes common to both LR cell lines. The GO and KEGG analyses indicated that these genes were involved in oxidoreductase and dehydrogenase activities, and reactive oxygen species pathways. Notably, NAD(P)H:quinone oxidoreductase 1 (NQO1) was highly expressed in LR cells, and was involved in the lenvatinib resistance. The high expression of NQO1 decreased the production of ROS induced by lenvatinib, and subsequently suppressed the apoptosis. The combination of lenvatinib and NQO1 inhibitor, dicoumarol, reversed the resistance of LR cells. The high NQO1 expression in HCC cells impedes the lenvatinib-induced apoptosis by regulating the ROS levels, thereby promoting lenvatinib resistance in HCC cells.

In vitro activity of ceftazidime/avibactam, cefiderocol, meropenem/vaborbactam and imipenem/relebactam against clinical strains of the Stenotrophomonas maltophilia complex.

Infections caused by Stenotrophomonas maltophilia and related species are increasing worldwide. Unfortunately, treatment options are limited, whereas the antimicrobial resistance is increasing. We included clinical isolates identified as S. maltophilia by VITEK 2 Compact. Ceftazidime/avibactam, meropenem/vaborbactam, imipenem/relebactam, cefiderocol, quinolones, and tetracycline family members were evaluated by broth microdilution method and compared with first-line treatment drugs. Minimum inhibitory concentrations (MICs) were reported for all antibiotics. We sequenced the Whole Genome of cefiderocol resistant strains (CRSs) and annotated their genes associated with cefiderocol resistance (GACR). Presumptive phylogenetic identification employing the 16S marker was performed. One hundred and one clinical strains were evaluated, sulfamethoxazole and trimethoprim, levofloxacin and minocycline showed susceptibilities of 99.01%, 95.04% and 100% respectively. Ceftazidime was the antibiotic with the highest percentage of resistance in all samples (77.22%). Five strains were resistant to cefiderocol exhibiting MIC values ≥ 2 μg/mL (4.95%). The β-lactamase inhibitors meropenem/vaborbactam and imipenem/relebactam, failed to inhibit S. maltophilia, preserving both MIC50 and MIC90 ≥64 μg/mL. Ceftazidime/avibactam restored the activity of ceftazidime decreasing the MIC range. Tigecycline had the lowest MIC range, MIC50 and MIC90. Phylogeny based on 16S rRNA allowed to identify to cefiderocol resistant strains as putative species clustered into Stenotrophomonas maltophilia complex (Smc). In these strains, we detected GARCs such as Mutiple Drug Resistance (MDR) efflux pumps, L1-type β-lactamases, iron transporters and type-1 fimbriae. Antimicrobial resistance to first-line treatment is low. The in vitro activity of new β-lactamase inhibitors against S. maltophilia is poor, but avibactam may be a potential option. Cefiderocol could be considered as a potential new option for multidrug resistant infections. Tetracyclines had the best in vitro activity of all antibiotics evaluated.