Low-dose Treatment Research Articles

Effect of integrated soil fertility management on water retention, productivity and physiological parameters of Alfalfa (Medicago sativa) without and under deficit irrigation

The use of subpar agricultural techniques in arid regions is causing depletion of fresh water reservoirs and soil fertility, which has serious implications for the environment and food productivity. Although numerous studies have examined the effects and benefits of biochar as a soil supplement, particularly on soil water holding capacity, plant productivity, and soil fertility, limited information exists on the effects of biochar at different doses with biocompost on the productivity and physiological parameters of alfalfa compared to conventional agricultural practices under water stress in the field. This field study at three repetitions aimed to investigate how biochar made from tomato waste and date seeds pyrolyzed at a temperature around 540 °C affects soil chemical composition, water retention capacity, photosynthesis, protein levels, enzymatic activity, productivity, maturity, and stomatal traits in alfalfa under and without deficit water compared to conventional agricultural practices based on manure and chemical fertilizer. The results showed that biochar significantly increased the water retention capacity, especially when mixed with biocompost. The highest water retention capacity was observed in the 6 % biochar 3 % biocompost and 6 % biochar 6 % biocompost treatments, which exceeded 0.7 g H2O/g dw. The high productivity and maturity were observed with manure at medium doses combined with chemical fertilizers and at high doses of munure alone, but these results were unstable with time and with the irrigation regime. On the other hand, the fluctuation of these data was minimal for the 3 % biochar 0 % biocompost treatment under and without water stress. In addition, the low dose treatment of manure with chemical fertilizers resulted in high levels of proteins, photosynthetic activities, and low enzymatic activities, indicating that this treatment is better adapted to stress conditions. The treatments with biocompost alone yielded low results on all the parameters studied. To conclude, incorporating biochar and biocompost, especially in synergistic combinations, enhances water retention capacity and sustains alfalfa productivity under both stressed and unstressed conditions. These findings suggest a promising alternative to traditional manure and chemical fertilizers, showcasing the potential of biochar-based strategies for resilient and sustainable agricultural practices.

Assessing the Impacts of Cu and Mo Engineered Nanomaterials on Crop Plant Growth Using a Targeted Proteomics Approach.

In this study, we investigated the effects of molybdenum (Mo)-based nanofertilizer and copper (Cu)-based nanopesticide exposure on wheat through a multifaceted approach, including physiological measurements, metal uptake and translocation analysis, and targeted proteomics analysis. Wheat plants were grown under a 16 h photoperiod (light intensity 150 μmol·m-2·s-1) for 4 weeks at 22 °C and 60% humidity with 6 different treatments, including control, Mo, and Cu exposure through root and leaf. The exposure dose was 6.25 mg of element per plant through either root or leaf. An additional low-dose (0.6 mg Mo/plant) treatment of Mo through root was added after phytotoxicity was observed. Using targeted proteomics approach, 24 proteins involved in 12 metabolomic pathways were quantitated to understand the regulation at the protein level. Mo exposure, particularly through root uptake, induced significant upregulation of 16 proteins associated with 11 metabolic pathways, with the fold change (FC) ranging from 1.28 to 2.81. Notably, a dose-dependent response of Mo exposure through the roots highlighted the delicate balance between nutrient stimulation and toxicity as a high Mo dose led to robust protein upregulation but also resulted in depressed physiological measurements, while a low Mo dose resulted in no depression of physiological measurements but downregulations of proteins, especially in the first leaf (0.23 < FC < 0.68) and stem (0.13 < FC < 0.68) tissues. Conversely, Cu exposure exhibited tissue-specific effects, with pronounced downregulation (18 proteins involved in 11 metabolic pathways) particularly in the first leaf tissues (root exposure: 0.35 < FC < 0.74; leaf exposure: 0.49 < FC < 0.72), which indicated the quick response of plants to Cu-induced stress in the early stage of exposure. By revealing the complexities of plants' response to engineered nanomaterials at both physiological and molecular levels, this study provides insights for optimizing nutrient management practices in crop production and advancing toward sustainable agriculture.

Outcome of Low Dose of Tamoxifen for Ocular Manifestations in Breast Cancer Patients

Background: Tamoxifen, a non-steroidal triphenylethylene estrogen antagonist, serves as a crucial therapy, both alone and in conjunction with other treatments, for disseminated breast carcinomas due to its proven efficacy and minimal adverse effects in oncology. Despite its extensive use, ocular toxicity reports linked to tamoxifen remain relatively scarce in available literature. Given the limited studies in the Bangladeshi context, this investigation aims to explore ocular manifestations in breast cancer patients undergoing prolonged low-dose tamoxifen therapy for over two years. Methods: This longitudinal study was conducted at Dhaka Medical College Hospital between October 2019 and July 2020, involving 45 patients undergoing low-dose tamoxifen treatment for more than two years post-surgical intervention for breast carcinoma. Detailed patient histories were obtained, and thorough ophthalmic examinations were performed for each participant. Data were meticulously recorded in separate case files and analyzed using SPSS 22 to ensure accuracy and reliability. Observations and Results: The average age of the patients was 51.16 (±8.82) years, and 11.10% of the respondents exhibited ocular manifestations. These manifestations primarily comprised cataracts (6.70%), retinitis (2.20%), and optic neuritis (2.20%). Regarding eye-related conditions, cataracts are evident in patients 01, 02, and 03, while retinitis is observed in patients 04 and 05. Optic neuritis is specifically noted in patient 05. The data highlights occurrences of these conditions in relation to the duration of Tamoxifen treatment and the patients' ages, potentially suggesting associations worthy of further exploration regarding the impact of Tamoxifen on eye health in this demographic. Conclusion: This study revealed that approximately one-tenth of the patient cohort undergoing tamoxifen therapy for over two years experienced ocular manifestations. However, further in-depth investigations are strongly ...

Applying Lessons Learned from Developing Exon Skipping for Duchenne to Developing Individualized Exon Skipping Therapy for Patients with Neurodegenerative Diseases

AbstractAntisense oligonucleotides (ASOs) are short, modified pieces of DNA that are chemically modified. They can be used to induce exon skipping and treat Duchenne muscular dystrophy (DMD) patients by interfering with the splicing process so mutated dystrophin transcripts become readable allowing production of partially functional dystrophin proteins, rather than nonfunctional dystrophins. After over 2 decades of research, 4 ASOs are FDA approved for DMD, but clinical effects are suboptimal due to limited delivery to skeletal muscle. At the same time, ASOs for brain diseases result in much more functional impact, because local delivery allows higher exposure to the target tissue at a low dose and infrequent treatment regimen. This has opened the way to develop ASOs in an individualized setting, as was exemplified by the development of Milasen to treat a patient with CLN7 Batten disease.In this perspective paper I will share my personal journey as one of the pioneers of ASO-mediated exon skipping development for DMD, currently applying expertise gained and lessons learned along the way to develop exon skipping ASOs for eligible patients with genetic brain diseases in a national and international setting.1 Duchenne and Antisense-Mediated Exon Skipping2 Opportunities for Treating Central Nervous System Diseases and Developing Individualized ASOs for Central Nervous System Diseases3 Collaborative Spirit to Develop Individualized Treatments Globally4 Global Implementation5 Concluding Remarks

Measuring herbicide (73.3 % glyphosate) exposure response in Halophila ovalis (previously johnsonii) and Halodule wrightii seagrass

We evaluated the effects of Roundup QuikPRO™ (73.3 % glyphosate) using real-world herbicide application treatments: (1) overspray (low-dose), (2) powder spill (high-dose), and (3) controls (no-dose). Seagrass and water quality were monitored to observe responses to acute herbicide application. Seagrass shoot densities significantly declined over time in high-dose treatments, whereas seagrass shoot densities in low-dose treatments were comparable to controls. In high-dose treatments, seagrass mortality increased over time, 100 % Halophila ovalis and 81 % Halodule wrightii mortality from day zero to 53. Collectively, glyphosate concentrations were negatively correlated with seagrass shoot densities, and positively correlated with water column nutrients (TN and TP). Based on these results we do not attribute local seagrass declines to low-dose glyphosate exposure, i.e., herbicide overspray events. However, we advise caution against improper herbicide handling, since glyphosate remained detectable in relatively high concentrations (<88 mg/L) after 53 days, resulting in seagrass mortality and increased water column nutrients.

Sex and interspecies differences in ESR2-expressing cell distributions in mouse and rat brains

BackgroundESR2, a nuclear estrogen receptor also known as estrogen receptor β, is expressed in the brain and contributes to the actions of estrogen in various physiological phenomena. However, its expression profiles in the brain have long been debated because of difficulties in detecting ESR2-expressing cells. In the present study, we aimed to determine the distribution of ESR2 in rodent brains, as well as its sex and interspecies differences, using immunohistochemical detection with a well-validated anti-ESR2 antibody (PPZ0506).MethodsTo determine the expression profiles of ESR2 protein in rodent brains, whole brain sections from mice and rats of both sexes were subjected to immunostaining for ESR2. In addition, to evaluate the effects of circulating estrogen on ESR2 expression profiles, ovariectomized female mice and rats were treated with low or high doses of estrogen, and the resulting numbers of ESR2-immunopositive cells were analyzed. Welch’s t-test was used for comparisons between two groups for sex differences, and one-way analysis of variance followed by the Tukey–Kramer test were used for comparisons among multiple groups with different estrogen treatments.ResultsESR2-immunopositive cells were observed in several subregions of mouse and rat brains, including the preoptic area, extended amygdala, hypothalamus, mesencephalon, and cerebral cortex. Their distribution profiles exhibited sex and interspecies differences. In addition, low-dose estrogen treatment in ovariectomized female mice and rats tended to increase the numbers of ESR2-immunopositive cells, whereas high-dose estrogen treatment tended to decrease these numbers.ConclusionsImmunohistochemistry using the well-validated PPZ0506 antibody revealed a more localized expression of ESR2 protein in rodent brains than has previously been reported. Furthermore, there were marked sex and interspecies differences in its distribution. Our histological analyses also revealed estrogen-dependent changes in ESR2 expression levels in female brains. These findings will be helpful for understanding the ESR2-mediated actions of estrogen in the brain.

Th1-related transcription factors and cytokines in systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is an inflammatory disorder related to immunity dysfunction. The Th1 cell family including Th1 cells, transcription factor T-bet, and related cytokines IFNγ, TNFα, IL-2, IL-18, TGF-β, and IL-12 have been widely discussed in autoimmunity, such as SLE. In this review, we will comprehensively discuss the expression profile of the Th1 cell family in both SLE patients and animal models and clarify how the family members are involved in lupus development. Interestingly, T-bet-related age-associated B cells (ABCs) and low-dose IL-2 treatment in lupus were emergently discussed as well. Collection of the evidence will better understand the roles of the Th1 cell family in lupus pathogenesis, especially targeting IL-2 in lupus.

Low-dose buprenorphine initiation and treatment continuation among hospitalized patients with opioid dependence: A retrospective cohort study

BackgroundBuprenorphine is an effective treatment for both opioid use disorder (OUD) and chronic pain, but buprenorphine's pharmacology complicates treatment initiation for some patients. Low-dose buprenorphine initiation is a novel strategy that may reduce precipitated withdrawal. Few studies describe what patient populations benefit most from low-dose initiations and the clinical parameters that impact treatment continuation. This study aimed to 1) describe experiences with low-dose buprenorphine initiation, including both successes and failures among hospitalized patients in an urban underserved community; 2) identify patient- and treatment-related characteristics associated with unsuccessful initiation and treatment discontinuation; and 3) assess buprenorphine treatment continuation after discharge. MethodsThis is a retrospective cohort study with opioid-dependent (meaning OUD or receiving long-term opioid therapy for chronic pain) patients who underwent low-dose buprenorphine initiation during hospital admission from October 2021 through April 2022. The primary outcome was successful completion of low-dose initiation. Bivariate analysis identified patient- and treatment-related factors associated with unsuccessful initiation. Secondary outcomes were buprenorphine treatment discontinuation at post-discharge follow-up, 30- and 90-days. ResultsOf 28 patients who underwent low-dose buprenorphine initiation, 68 % successfully completed initiation. Unsuccessful initiation was associated with receipt of methadone during admission and higher morphine milligram equivalents (MME) of supplemental opioids. Of 22 patients with OUD, the percent receiving a buprenorphine prescription at a follow-up visit, 30 days, and 90 days, respectively, was 46 %, 36 %, and 36 %. Of 6 patients with chronic pain, the percent receiving a buprenorphine prescription at a follow-up visit, 30 days, and 90 days, respectively, was 100 %, 100 %, and 83 %. ConclusionLow-dose buprenorphine initiation can be successful in opioid-dependent hospitalized patients. Patients taking methadone or requiring higher MME of supplemental opioids may have more difficulty with the low-dose buprenorphine initiation approach, but these findings should be replicated in larger studies. This study suggests patient- and treatment-related factors that clinicians could consider when determining the optimal treatment strategy for patients wishing to transition to buprenorphine.

Essential oil from Fructus Alpiniae zerumbet ameliorates vascular endothelial cell senescence in diabetes by regulating PPAR-γ signalling: A 4D label-free quantitative proteomics and network pharmacology study

Ethnopharmacological relevanceVascular endothelial cell senescence is associated with cardiovascular complications in diabetes. Essential oil from Fructus Alpiniae zerumbet (Pers.) B.L.Burtt & R.M.Sm. (EOFAZ) has potentially beneficial and promising diabetes-related vascular endothelial cell senescence-mitigating effects; however, the underlying molecular mechanisms remain unclear. Aim of the studyTo investigate the molecular effects of EOFAZ on vascular endothelial cell senescence in diabetes. Materials and methodsA diabetes mouse model was developed using a high-fat and high-glucose diet (HFD) combined with intraperitoneal injection of low-dose streptozotocin (STZ, 30 mg/kg) and oral treatment with EOFAZ. 4D label-free quantitative proteomics, network pharmacology, and molecular docking techniques were employed to explore the molecular mechanisms via which EOFAZ alleviates diabetes-related vascular endothelial cell senescence. A human aortic endothelial cells (HAECs) senescence model was developed using high palmitic acid and high glucose (PA/HG) concentrations in vitro. Western blotting, immunofluorescence, SA-β-galactosidase staining, cell cycle, reactive oxygen species (ROS), cell migration, and enzyme linked immunosorbent assays were performed to determine the protective role of EOFAZ against vascular endothelial cell senescence in diabetes. Moreover, the PPAR-γ agonist rosiglitazone, inhibitor GW9662, and siRNA were used to verify the underlying mechanism by which EOFAZ combats vascular endothelial cell senescence in diabetes. ResultsEOFAZ treatment ameliorated abnormal lipid metabolism, vascular histopathological damage, and vascular endothelial aging in diabetic mice. Proteomics and network pharmacology analysis revealed that the differentially expressed proteins (DEPs) and drug-disease targets were associated with the peroxisome proliferator-activated receptor gamma (PPAR-γ) signalling pathway, a key player in vascular endothelial cell senescence. Molecular docking indicated that the small-molecule compounds in EOFAZ had a high affinity for the PPAR-γ protein. Western blotting and immunofluorescence analyses confirmed the significance of DEPs and the involvement of the PPAR-γ signalling pathway. In vitro, EOFAZ and rosiglitazone treatment reversed the effects of PA/HG on the number of senescent endothelial cells, expression of senescence-related proteins, the proportion of cells in the G0/G1 phase, ROS levels, cell migration rate, and expression of pro-inflammatory factors. The protective effects of EOFAZ against vascular endothelial cell senescence in diabetes were aborted following treatment with GW9662 or PPAR-γ siRNA. ConclusionsEOFAZ ameliorates vascular endothelial cell senescence in diabetes by activating PPAR-γ signalling. The results of the present study highlight the potential beneficial and promising therapeutic effects of EOFAZ and provide a basis for its clinical application in diabetes-related vascular endothelial cell senescence.

Doxorubicin induced epigenetic regulation of dendritic cell maturation in association with T cell activation facilitates tumor protective immune response in non-small cell lung cancer (NSCLC)

BackgroundNSCLC is one of the leading causes of death and is often diagnosed at late stages with no alternative therapeutic approach. DCs are professional antigen-presenting cells and DC-based immunotherapy has been under the spotlight for its anti-cancer properties. Epigenetic modifications including DNA methylation and histone modification in DCs play a crucial role in regulating their functions such as maturation and activation,innate immune responses, T cell priming, antigen presentation, and cytokine production. In the current study, we investigated the anti-cancer properties of Doxorubicin at a noncytotoxic concentration that could be extrapolated as an epigenetic regulator for DC maturation to elicit anti-tumor activity. MethodologiesPBMCs from normal and NSCLC blood samples were isolated and treated with growth factors. DCs were matured with low dose Doxorubicin and the DC maturation markers were checked by using flow-cytometry. Further, ELISA was performed and low dose Doxorubicin-induced DCs were pulsed with LCA (Lung Cancer Antigen) and primed with CD4 +T helper (Th) cells for cytotoxicity assessment. Further, epigenetic markers of T: DC conjugation were immunofluorescently visualized under a microscope. ChIP-qPCR and Invitro assays such as histone methylation, DNA methylation, and m6A methylation were performed to study the epigenetic changes under low dose Dox treatment. IL-12 neutralization assay was performed to check for the IL-12 dependency of DCs and their effect under Dox at low dose treatment. This was further followed by a Western Blotting analysis for histone and non-histone proteins. ResultsLow dose Doxorubicin induces epigenetic changes in DCs to elicit an anti-tumor response in NSCLC through the generation of CTLs with a concomitant increase in the extracellular secretions of anti-inflammatory cytokines. We also found that low dosage of Doxorubicin matured DCs when pulsed with LCA and primed with CD4 +T helper cells, secrete IFN-γ which is important in orchestrating adaptive immunity by activating CD8 + cytotoxic T-lymphocytes. Also, the secretions of IL-12 help us infer that protective immunity is also induced via Th1 response which triggered selectively the translocation of PKCθ to immunological synapse in between DC and Th. Further, methylation and acetylation markers H3K4me3 and H3K14Ac respectively upregulated whereas levels of STAT5, NFkB, NOTCH1, and DNAPKcs were downregulated. DNA and RNA methylation assays then lead to confirmations about the epigenetic changes caused by low dose Dox treatment. DNA methylation was reduced which resulted in the activation of tumor suppressor gene p53 and Th1-associated transcription factor TBX21. On the other hand, both absolute and relative RNA methylation quantification increased in the presence of Dox at a low dose. ConclusionFrom this study, we understand that non-cytotoxic concentration of Doxorubicin increases the Ag-presenting ability of DCs via an IL-12-dependent mechanism and causes epigenetic modifications in NSCLC.

A new strategy for Alzheimer’s disease: low‐dose combination of radiotherapy and pharmacological epigenetic perturbation

AbstractBackgroundMost Alzheimer’s disease (AD) drug discovery studies focus exclusively on one specific target. This approach has to date shown limited success in AD, mainly because this complex disease is multifactorial and involves numerous pathways. In light of the large number of disappointing clinical trials, the National Institute on Aging (NIA) and the Alzheimer’s Association (AA) published, in 2018, new guidelines recommending focusing on biomarkers of the AD continuum. These guidelines advise targeting Amyloid‐β (A), neurofibrillary tangles (T) and neurodegeneration markers (N), designated “ATN”, to advance AD research. Using 2 different approaches, we have been able to both reverse and prevent ATN burden in mouse models of AD. Indeed, our group has previously demonstrated that histone deacetylase inhibition (HDACi) and cranial radiotherapy (RT) independently improve (AD)‐like pathogenesis in cell and animal models. In the present study, we investigate the synergistic potential of using both RT and HDACi as a low‐dose combination therapy (LDCT) to further improve molecular and behavioral AD‐like phenotypes in AD models.MethodLDCT consisted of daily administration of the HDAC3 inhibitor RGFP‐966 and/or bi‐weekly cranial x‐irradiation. Behavioral analyses, real‐time qPCR, NanoString technology, ELISAs and Western blots were used to assess the effects of RT, RGFP‐966 and LDCT on AD‐like pathogenesis in AD models. Additionally, innate immune response to LDCT was also assessed in vitro and in vivo using human and murine cell models and 3xTg‐AD mice.ResultLDCT induced a tolerant, anti‐inflammatory innate immune response in microglia and increased non‐amyloidogenic APP processing. Both RT and LDCT improved spatial learning and memory in the Barnes maze test. No sensorimotor deficits were observed. LDCT induced a unique anti‐AD gene expression profile in the brain, that included upregulation of neurotrophic genes and downregulation of inflammation‐related genes. Brain region specific observations included lowered Aβ42/40 ratio, decreased Bace1, and reduced p‐tau181 levels.ConclusionThis work shows that it is possible to attenuate AD‐related pathologies through the synergy of low doses of RT and HDACi treatment. This project supports a paradigm shift to a multipronged approach to AD therapeutics.

Low-dose PLX5622 treatment prevents neuroinflammatory and neurocognitive sequelae after sepsis

BackgroundSepsis-associated encephalopathy (SAE) is characterized by symptoms of delirium including hallucinations, impaired concentration, agitation, or coma and is associated with poor outcome in the early phase of sepsis. In addition, sepsis survivors often suffer from persisting memory deficits and impaired executive functions. Recent studies provide evidence that microglia are involved in the pathophysiology of SAE.MethodsHere, we investigated whether pharmacological depletion of microglia using PLX5622 (1200 ppm or 300 ppm) in the acute phase of sepsis is able to prevent long-term neurocognitive decline in a male mouse model of polymicrobial sepsis or lipopolysaccharide-induced sterile neuroinflammation. Therefore, we performed the novel object recognition test at different time points after sepsis to address hippocampus-dependent learning. To further assess synapse engulfment in microglia, colocalization analysis was performed using high-resolution 3D Airyscan imaging of Iba1 and Homer1. We also investigated the effect of PLX5622 on acute astrocyte and chronic microglia proliferation in the hippocampus after sepsis induction using immunofluorescence staining.ResultsHigh-dose application of the colony stimulating factor 1 receptor (CSF1R) inhibitor PLX5622 (1200 ppm) seven days prior to sepsis induction lead to 70–80% microglia reduction but resulted in fatal outcome of bacterial sepsis or LPS induced inflammation. This is likely caused by severely compromised host immune response upon PLX5622-induced depletion of peripheral monocytes and macrophages. We therefore tested partial microglia depletion using a low-dose of PLX5622 (300 ppm) for seven days prior to sepsis which resulted in an increased survival in comparison to littermates subjected to high-dose CSF1R inhibiton and to a stable microglia reduction of ~ 40%. This partial microglia depletion in the acute stage of sepsis largely prevented the engulfment and microglia-induced stripping of postsynaptic terminals. In addition, PLX5622 low-dose microglia depletion attenuated acute astrogliosis as well as long-term microgliosis and prevented long-term neurocognitive decline after experimental sepsis.ConclusionsWe conclude that partial microglia depletion before the induction of sepsis may be sufficient to attenuate long-term neurocognitive dysfunction. Application of PLX5622 (300 ppm) acts by reducing microglia-induced synaptic attachement/engulfment and preventing chronic microgliosis.

Cardioprotective and Antifibrotic Effects of Low-Dose Renin-Angiotensin-Aldosterone System Inhibitors in Type 1 Diabetic Rat Model.

Diabetic cardiovascular complications are associated with up to 50% mortality, and current therapies are not effective enough. Renin-angiotensin-aldosterone system inhibitors (RAASis) are the standard of care for diabetic patients with hypertension and albuminuria. Based on our previous studies reporting the renoprotective effects of low-dose RAASis, here, we hypothesized that low-dose RAASi treatment has cardioprotective and antifibrotic benefits in type 1 diabetes mellitus (T1DM). After five weeks of T1DM, adult male Wistar rats received low doses of ramipril, losartan, or eplerenone for two weeks. Heart rate, blood pressure, and pulse wave velocity (PWV) were recorded. Aortic intima-media thickness (IMT), collagen accumulation, and myocardial fibrosis were assessed. All RAASis reduced PWV elevation, prevented the progression of myocardial fibrosis, and normalized B-type natriuretic peptide, troponin I, and fibroblast growth factor 23 levels without affecting blood pressure. Interestingly, only eplerenone reversed the decline in Klotho levels and reduced IMT and fibrosis in the media of the aorta. Our comparative analysis suggests that mineralocorticoid receptor antagonists, particularly eplerenone, may offer superior efficacy in halting both the arterial and the myocardial injuries in T1DM compared to angiotensin-converting enzyme inhibitors or angiotensin II type 1 receptor blockers.

Acute Myeloid Leukemia in Elderly, Unfit Patients: Analysis of Turkish AML Prospective Registry Database, on Behalf of Acute Leukemia Working Group of Turkish Society of Hematology

Objective: Low dose Ara-C and hypomethylating agents (HMAs) - decitabine (DEC) and azacitidine (AZA) - have made it possible to treat more elderly patients with acute myeloid leukemia (AML). Both HMAs demonstrated efficacy in monotherapy and in combination with targeted therapies. We analyzed the outcomes of elderly and unfit patients with newly diagnosed AML in our population. Methods: Analyses of our database revealed 222 eligible AML patients from diagnosed between January 2013 to December 2020. All patients were received low intensity treatments including AZA +/- venetoclax, DEC and low dose Ara-C. The effects of cytogenetic risk group, response rate, treatment type on overall survival (OS) and PFS (progression-free survival) were evaluated. Survival analyses were performed with the Kaplan-Meier method and log-rank test. A p-value of &amp;lt;0.05 was considered statistically significant. Results: Median age was 73 years (51-89). Eastern Cooperative Oncology Group (ECOG) performance score was &amp;lt;2 and ≥2 for 75 patients (36.8%) and 147 patients (63.2%), respectively. Of the patients 8.2% had favorable, 76.9% intermediate and 15.0% adverse risk according to European Leukemia Network (ELN) risk classification. Extramedullary involvement was present in 4.5%. Low dose treatment regimens included AZA in 119 patients (53.6%), DEC in 38 (17.6%), low dose ARA-C in 26 (11.7%) and AZA + venetoclax in 39 (17.1%). Complete remission was achieved in 61 patients (27.5%), whereas 39 patients (17.6%) had partial remission (PR) and 64 (28.8%) had stable/progressive disease (SD/PD). Overall response rate was 48.1%. CR rate was higher with AZA + venetoclax (44.7%, p=0,005) and other regimens had similar outcomes. Median OS was 10.3 months. No significant difference difference in PFS was observed between the regimens. However, the lowest PFS was observed with low-dose Ara-C (p=0.33). ELN risk groups revealed no significant effect on PFS and OS (p=0.77 and p=0.82, respectively). Infections were the most common cause of death (42.7%). Conclusions: The prognosis of AML in the elderly remains poor. HMA monotherapy is effective among elderly and unfit patients. However, combination therapies may be more effective and safe. The incorporation of targeted therapies may provide additional benefit in this patient group. However, the accessibility of several novel targeted drugs is still very limited in many countries.

Low-dose Esketamine suppresses NLRP3-mediated apoptotic and pyroptotic cell death in microglial cells to ameliorate LPS-induced depression via ablating GSK-3β

Esketamine is verified as a potential therapeutic drug for the treatment of depression, but it is still unclear the detailed underlying mechanisms by which Esketamine ameliorates depression-related symptoms, which seriously limits the utilization of this drug in clinical practices. In this study, the C57BL6/J mice and mouse primary microglial cells were subjected to lipopolysaccharide (LPS)-induced depressive models in vivo and in vitro, and our results confirmed that LPS-induced neuroinflammation, pyroptotic and apoptotic death contributed to the development of LPS-induced depressive symptoms. Then, the following experiments verified that low-dose Esketamine treatment decreased the expression levels of IL-6, TNF-α and IL-18 to restrain cellular inflammation, downregulated NLRP3, cleaved Caspase-1, IL-1β and GSDMD-N to hamper pyroptotic cell death, and inhibited cleaved caspase-3 and Bax, but upregulated Bcl-2 to restrict apoptotic cell death in the LPS-treated mice hippocampus tissues and mouse microglial cells, leading to the suppression of depression development. However, high-dose Esketamine did not have those effects. Next, by conducting mechanical experiments, we verified that low-dose Esketamine downregulated GSK-3β to inactivate NLRP3 inflammasome, and the effects of low-dose Esketamine on cell pyroptosis, neuroinflammation and apoptosis in the LPS-treated microglial cells were all abrogated by overexpressing GSK-3β and NLRP3. Taken together, low-dose Esketamine ameliorated LPS-induced depressive symptoms in mice through regulating the GSK-3β/NLRP3 pathway, and our work suggested that appropriate doses of Esketamine were essential for the treatment of depression in clinic.

Exogenous Oxytocin Administration Restores Memory in Female APP/PS1 Mice.

Current treatment options for Alzheimer's disease (AD) are limited, inefficient, and often have serious side effects. Oxytocin is a neuropeptide implicated in a variety of central processes, such as social and reproductive behaviors. Among others, it has garnered attention in various domains of psychiatric research, while its role in the development and course of neurodegenerative disorders like AD is rather unknown. This study aimed to investigate the role of exogenous oxytocin administration on memory, specifically in view of AD, as a potential novel treatment option. We describe a novel treatment approach by using a relatively low dose of long-term intranasal oxytocin treatment, to restore memory deficits in female APPswePS1dE9 mice. Female APPswePS1dE9 mice treated with oxytocin showed increased spatial memory performance in the object location task and improved working memory in the Y-Maze, while indicating decreased sociability. These results indicate that oxytocin is able to reverse acquired cognitive deficits in female APPswePS1dE9 mice.

The combination of tetracyclines effectively ameliorates liver fibrosis via inhibition of EphB1/2

Eph receptor tyrosine kinase EphB1/2 contributes to the development of liver fibrosis, suggesting the rationale that EphB1/2 inhibitors may be effective in liver fibrosis therapy. Since tetracycline antibiotics were recently demonstrated as EphB kinase inhibitors, in present study we investigated their therapeutic potential against liver fibrosis. Our results showed that the tetracycline combination of demeclocycline (D), chlortetracycline (C), and minocycline (M) inhibited the activation of hepatic stellate cells (HSCs) in vitro and alleviated CCl4-induced animal model of liver fibrosis in vivo. Mechanistically, DCM combination inhibited EphB1/2 phosphorylation and subsequent activation of the MAPK signaling. Moreover, we found that short-term and low-dose DCM combination treatment decreased tissue inflammation and improved liver fibrosis in mice. Thus, our study indicates that tetracyclines may be repurposed for the treatment of liver fibrosis.

Biomarkers and the Risk of Preeclampsia

(JAMA. 2023;329:539–541) Though maternal and fetal deaths due to preeclampsia and other hypertensive disorders of pregnancy have decreased in recent years, the incidence of preeclampsia has risen. Current clinical practice for preventing preeclampsia includes initiating a low-dose aspirin treatment at the end of the first trimester of pregnancy; it has been shown to largely mitigate the effects of preeclampsia and reduce incidence. One recent study by Mendoza et al examined the effect of discontinuation of aspirin treatment between 24 and 28 weeks of gestation and found discontinuation is non-inferior to continuation of treatment to 36 weeks. This study had some important findings and implications, but is hard to generalize to the United States, as there are some fundamental differences in the aspirin treatment regimen; the dosage in the United States is 81 mg rather than 150 mg, and there is no recommendation to stop treatment at 36 weeks of gestation. Diagnostically, the United States also does not use molecular biomarkers (the sFlt-1:PlGF ratio) but rather clinical factors to determine risk of preeclampsia. Implementing the methods proposed in this recent study would be a major overhaul of current clinical practice in the United States.

Promising efficacy of Low-Dose rituximab in Muscle specific kinase antibody positive Myasthenia Gravis

AimsThe study aims to evaluate the efficacy of low dose rituximab (RTX) in patients with muscle-specific kinase antibody positive myasthenia gravis (MuSK-MG). MethodsThis is a single-center, retrospective study. A total of 10 patients with MuSK-MG were admitted to the Department of Neurology, First Hospital, Shanxi Medical University, between April 2021 to April 2023. Of them, 9 patients had been treated with low dose RTX (500 mg every 6 month) and recruited in this study. The clinical information, including the severity before and after RTX treatment, were collected from the medical records. Clinical effectiveness was assessed by Myasthenia Gravis Foundation of America (MGFA)-postintervention status (PIS), MG-related activities of daily living (MG-ADL), Quantitative Myasthenia Gravis (QMG) scores, Myasthenia Gravis Quality of Life 15-item revised (MG-QOL15r), dosage of steroid at the end of follow up. ResultsAll nine patients showed clinical improvement at the final follow-up after low-dose RTX treatment. The mean dose of prednisolone decreased significantly from 50 mg at baseline to 18.33 mg at the last follow-up (z = -3.417, p = 0.001). The administration of low-dose RTX treatment led to significant improvements in ADL levels (Z = -2.675, P < 0.01), QMG score levels (Z = -2.371, P < 0.05) and QOL-15r levels (Z = -2.547, P < 0.01) at last visit. ConclusionLow-dose RTX is effective for treating MuSK-MG patients. Longer-term follow-up and larger-scale studies are needed to provide further evidence.

Sub-inhibitory concentrations of ceftriaxone induce morphological alterations and PIA-independent biofilm formation in Staphylococcus aureus

The exposure of bacteria to sub-inhibitory concentrations of antibiotics is of biological significance since it can occur in vivo under many circumstances, including low-dose treatment, poor adherence to a regimen, poor drug penetration, drug-drug interactions, and antibiotic resistance of the pathogen. In this study, we investigated the effects of subinhibitory concentrations of four antibiotics: ampicillin, ceftriaxone, gentamicin, and norfloxacin, which are commonly used in clinical settings and on cell morphology and biofilm formation in Staphylococcus aureus as one of the leading causes of nosocomial and biofilm-associated infections. Nine clinical S. aureus biofilm-producing isolates and two known biofilm-producing reference strains, S. aureus ATCC 29213 and S. aureus ATCC 6538, were used in this study. Sub-MICs of beta-lactam antibiotics (ampicillin and ceftriaxone) significantly induced biofilm formation in S. aureus ATCC 29213 and S. aureus ATCC 6538 and in six clinical isolates out of the nine selected isolates when compared with the antibiotic-free control group (P < 0.05), with an approximately 2- to 2.5-fold increase. Gentamicin and norfloxacin induced biofilms in S. aureus ATCC 29213 and S. aureus ATCC 6538, while gentamicin and norfloxacin induced biofilms only in three and two of the nine tested isolates, respectively (P < 0.05). The chemical nature of the biofilm matrix produced by half the MIC of ceftriaxone in the six isolates that showed increased biofilm was all non-polysaccharide in composition (PIA-independent). Gene expression of biofilm-encoding genes atl and sarA in biofilms of the two tested strains (S. aureus ATCC 6538) and clinical strain (S. aureus 16) showed a significant upregulation after exposure to half MIC of ceftriaxone. Additionally, the bacterial cell morphological changes in planktonic cells caused by half MIC of ceftriaxone were evaluated by scanning electron microscopy, which demonstrated a significant cell enlargement when compared with the antibiotic-free control (P < 0.05), and some deformed cells were also noticed. In S. aureus clinical isolates, sub-MICs of ampicillin, ceftriaxone, gentamicin, and norfloxacin may stimulate substantial production of biofilm, which could have important clinical significance and make infection treatment challenges. Further, in vivo research is needed to fully comprehend how sub-MIC of antibiotics can affect biofilm formation in clinical settings. Additionally, more research is required to reveal the clinical implications of the morphological alterations in S. aureus brought on by exposure to ceftriaxone at concentrations below its MIC.Graphical