High Dose Research Articles

Diagnosis, management, and outcomes of drug-induced erythrocytosis: A systematic review.

Secondary erythrocytosis refers to an elevation in hemoglobin or hematocrit due to elevated serum erythropoietin levels. Medications including testosterone and sodium-glucose cotransporter-2 (SGLT-2) inhibitors are increasingly recognized causes of secondary erythrocytosis. We conducted a systematic review to inform the clinical management of drug-induced erythrocytosis. Following PRISMA guidelines, we performed a systematic literature search in MEDLINE, EMBASE, CENTRAL (all via Ovid), and Google Scholar. Of the 2,036 articles screened for eligibility, 45 studies were included in our review, with 35 studies on testosterone and other androgen use, 5 studies on SGLT-2 inhibitors, 3 studies on anti-angiogenic tyrosine kinase inhibitors (TKIs), 1 study on erythropoiesis-stimulating agents (ESAs), and 1 study on a treatment regimen for multidrug-resistant tuberculosis (MDR-TB). Cisgender and transgender men on prescription testosterone had rates of erythrocytosis up to 66.7%, with intramuscular formulations, higher doses, and older age associated with increased risk of erythrocytosis. Up to 2.7% of men on testosterone therapy developed thromboembolic events. In individuals on SGLT-2 inhibitors, rates of erythrocytosis ranged from 2.1-22%, with those who discontinued therapy demonstrating improvement or resolution of erythrocytosis. Thromboembolic events were reported in up to 10% of these individuals. Anti-angiogenic TKIs were studied in patients with cancer, with erythrocytosis developing in up to 43.5% of patients. Drug-induced erythrocytosis is a heterogeneous condition for which there is no clear consensus among clinicians about its diagnosis and management. We offer recommendations for clinical practice within the scope of this systematic review, though further research is required.

Deferiprone ameliorates cisplatin induced peripheral neurotoxicity via ferritinophagy adjustment

Abstract Cisplatin-induced neurotoxicity is one of the limiting factors to its use especially in tumors that demand high drug dosage. One of the Cisplatin pathways is ferritinophagy which may end up in ferroptosis. So, we aimed to use iron chelator as a new strategy based on an anti-ferroptotic mechanism and to evaluate its neuroprotective effect against polyneuropathy in Cisplatin-treated rats. Twenty-four male Wistar albino rats were arranged into four groups: (I) Control group, rats were given vehicle; (II) Def group, rats received deferiprone (200 mg/kg orally once daily for 10 days); (III) Cis group, rats were injected by Cis 2 mg/Kg once daily for 3 consecutive days i.p.; and (IV) Cis + Def group, rats received deferiprone (200 mg/kg orally once daily for 10 days, rats were injected with Cis in the 4th, 5th, and 6th days). Cis increased and upregulated ferritinophagy inducers significantly including MDA, NCOA4, and IREB1 as compared to the control group. On the other hand, GSH, GPX4, SLCA11 and FTH1 were decreased and down regulated significantly compared to the control group. In addition to significant deterioration in the histopathological and immunological nerve tissue assessment using silver stain and PNCA. Embracing the cisplatin dosage with deferiprone reversed cisplatin-induced neuropathy, in which the physiological function significantly improved along with the immune and histopathology of nerve tissue. This was accompanied by down regulation of ferritinophagy inducers and enhancing ferritinophagy inhibitors. The current results concluded that rapping cisplatin with deferiprone can mitigate neurotoxicity induced by cisplatin in experimental animals through ferritinophagy pathway adjustment.

The effect of Ga-ion irradiation on sub-micron-wavelength spin waves in yttrium-iron-garnet films

We investigate the effect of focused-ion-beam (FIB) irradiation on spin waves with sub-micron wavelengths in yttrium-iron-garnet films. Time-resolved scanning transmission x-ray microscopy was used to image the spin waves in irradiated regions and deduce corresponding changes in the magnetic parameters of the film. We find that the changes of Ga+irradiation can be understood by assuming a few percent change in the effective magnetizationMeffof the film due to a trade-off between changes in anisotropy and effective film thickness. Our results demonstrate that FIB irradiation can be used to locally alter the dispersion relation and the effective refractive indexneffof the film, even for submicron wavelengths. To achieve the same change innefffor shorter wavelengths, a higher dose is required, but no significant deterioration of spin wave propagation length in the irradiated regions was observed, even at the highest applied doses.

Pharmacological Evaluation of (Piliostigma thonningi) Root Extract: Antioxidant and Anti-inflammatory Properties

Medicinal plants have been widely explored for their therapeutic potential due to their rich phytochemical composition. Piliostigma thonningii, a widely used plant in traditional medicine, is known for its diverse bioactive compounds with potential health benefits. This study aims to evaluate the phytochemical composition, antioxidant activity, and anti-inflammatory properties of the methanol root extract of Piliostigma thonningii. Standard qualitative methods revealed the presence of anthraquinones, alkaloids, phenols, tannins, phytosterols, and saponins, while cardiac glycosides, glycosides, flavonoids, and steroids were absent. Antioxidant potential was assessed using DPPH radical-scavenging, ferric reducing antioxidant potential (FRAP), and hydrogen peroxide scavenging assays, revealing dose-dependent radical inhibition. The root crude extract of Piliostigma thonningii exhibits dose-dependent antioxidant activity across DPPH, FRAP, and hydrogen peroxide scavenging assays, with higher concentrations showing increased efficacy. The presence of bioactive phytochemicals, including flavonoids and phenolic compounds, contributes to its ability to reduce oxidative stress and inhibit free radicals. Anti-inflammatory activity was evaluated in vitro via albumin denaturation inhibition and in vivo using the carrageenan-induced paw edema model in rats. At 100 mg/kg, the extract exhibited moderate anti-inflammatory effects, with paw edema peaking at 4 hours (9.093 ± 0.071) and declining at 5 hours (7.362 ± 0.089). However, higher concentrations (200 and 400 mg/kg) showed increased inflammation, peaking at 4 hours (19.621 ± 0.033) and 5 hours (20.001 ± 0.056), respectively. Diclofenac (negative control) demonstrated controlled inflammatory responses, with edema peaking at 4 hours (10.585 ± 0.066) and declining by 5 hours (9.207 ± 0.022). These findings suggest that while the extract has notable anti-inflammatory effects at lower doses, higher doses may exhibit pro-inflammatory tendencies. This study highlights the potential of Piliostigma thonningii root extract as a natural source of anti-inflammatory agents, warranting further investigation for therapeutic applications.

Impact of nitroglycerin-induced vasodilation on stroke volume and diuretic response in acute heart failure: A protocol for a mechanistic trial.

Acute heart failure is a clinical syndrome characterized by cardiac dysfunction and neurohumoral activation, encompassing complex underlying pathophysiology which may vary across phenotypes. Nitroglycerine is a nitrate donor with vasodilatory effects on both venous capacitance vessels and arterial resistance vessels in higher doses, typically used with the aim of reducing congestion, preload, and afterload. A limited number of studies have proposed that nitroglycerin could promote diuresis and natriuresis. However, the exact hemodynamic effects of nitroglycerin remain uncertain in the clinical setting of acute decompensated heart failure. We hypothesize that intravenous nitroglycerin induces a significant increase in stroke volume and urinary output while lowering cardiac filling pressures. This will be a prospective single-center interventional clinical study of 21 patients hospitalized with a diagnosis of AHF. Patients are examined before and after administration of intravenous nitroglycerin. To characterize hemodynamic phenotypes of AHF, continuous estimates of stroke volume will be obtained, and total blood volume estimated. Vital signs and estimates of peripheral perfusion will be recorded continuously. Measures of cardiac function, renal function, volume status, and autonomic function will be assessed sequentially. This study will assess the acute effects of vasodilation on stroke volume and urinary output in hospitalized patients with AHF. Furthermore, characterizing the hemodynamic profile of the patient prior to vasodilation may help explore which patients will benefit from vasodilation.

Single inhaler with beclometasone, formoterol, and glycopyrronium versus triple therapies in adults with uncontrolled asthma: a systematic review and meta-analysis

Recent literature has shown that triple therapy is more effective than dual therapy for individuals with uncontrolled asthma. However, the comparative efficacy between different triple therapies remains unclear. The objective of this study was to determine the comparative efficacy of extra-fine single-inhaler medium-dose (MD) or high-dose (HD) of beclometasone/formoterol/glycopyrronium bromide (BDP/FOR/GLY) compared to other triple therapies in patients whose asthma remains uncontrolled with MD or HD inhaled corticosteroids and long-acting β2-agonists. A systematic literature review identified randomized control trials on adult patients with uncontrolled asthma. Two separate networks were constructed according to patients’ previous inhaled-corticosteroid dosage. Network meta-analyses evaluated severe and moderate-to-severe exacerbations, pre-dose forced expiratory volume, and asthma control questionnaire responses at 52 (± 3) weeks. Among single-inhaler triple therapies, MD BDP/FOR/GLY significantly reduced the risk of severe exacerbations (RR [95% CrI] compared to MD fluticasone/umeclidinium/vilanterol: 0.65 [0.49, 0.89]), while HD BDP/FOR/GLY demonstrated an improved trend in reducing severe and moderate-to-severe exacerbations versus HD indacaterol acetate/glycopyrronium bromide/mometasone, fluticasone/umeclidinium/vilanterol, and salmeterol/fluticasone + tiotropium. HD BDP/FOR/GLY and HD BDP/FOR + tiotropium did not differ significantly. Compared to relevant single-inhaler triple therapies, MD and HD BDP/FOR/GLY are associated with a significant benefit or trend for improvement in terms of reducing the rate of severe and moderate-to-severe exacerbations.

Oviposition Deterrents from Extracts of Eryngium foetidum Against Potato Tuber Moth Phthorimaea operculella Zeller (Lepidoptera: Gelechiidae)

The potato tuber moth Phthorimaea operculella is a serious boring pest of potato. An integrated ecological approach to sustainable pest management is necessary for the control of this species. This study investigated the effects of minced leaves and plant extracts of Eryngium foetidum on the oviposition behavior of PTM females. The behavioral regulatory components of PTM females in response to the extracts were determined using chemical analyses and electrophysiological tests. Individual electroantennographic detection (EAD)-active compounds and mixtures were evaluated using oviposition choice bioassays. The results indicate that minced leaves had a deterrent effect on oviposition. The extracts at low dosages had an attraction effect, while high dosages had a repellent effect on the oviposition of PTM adult females. The dominant compounds of the extracts were trans-2-dodecenal and trans-2-tridecenal and showed EAD activity. trans-2-dodecenal, trans-2-tridecenal and their mixtures showed significant oviposition-repellent effects toward the PTM. The oviposition stimulation indices (OSIs) of trans-2-dodecenal and trans-2-tridecenal were −100% and −94.03% at 10 mg/mL, respectively. The OSIs of mixtures at natural ratios of 10 mg/mL and 5 mg/mL were −95.11% and −90.96%, respectively. The results can be used for the further development of ecological control strategies for this pest species.

Recycling Water Hyacinth as Supplementary Cementitious Material, Admixture, and Fiber in Mortar and Concrete: Current Trends and Research Gaps

This review explores the potential of water hyacinth (WH) as a sustainable material in cement-based applications, focusing on its use as an addition, admixture, and fiber reinforcement. WH’s unique physical and chemical properties, such as high cellulose content and pozzolanic potential, make it suitable for bio-composites and eco-friendly concrete formulations. The present study highlights several promising findings, including the enhancement of the resulting mechanical properties and the reduction in their environmental impact when the WH is incorporated in controlled quantities. Challenges such as workability and durability issues at higher dosages are discussed. This review aims to bridge knowledge gaps and support WH’s adoption in sustainable construction practices.

Inhibition of soluble epoxide hydrolase ameliorates cerebral blood flow autoregulation and cognition in alzheimer's disease and diabetes-related dementia rat models.

Alzheimer's Disease and Alzheimer's Disease-related dementias (AD/ADRD) pose major global healthcare challenges, with diabetes mellitus (DM) being a key risk factor. Both AD and DM-related ADRD are characterized by reduced cerebral blood flow, although the exact mechanisms remain unclear. We previously identified compromised cerebral hemodynamics as early signs in TgF344-AD and type 2 DM-ADRD (T2DN) rat models. Genome-wide studies have linked AD/ADRD to SNPs in soluble epoxide hydrolase (sEH). This study explored the effects of sEH inhibition with TPPU on cerebral vascular function and cognition in AD and DM-ADRD models. Chronic TPPU treatment improved cognition in both AD and DM-ADRD rats without affecting body weight. In DM-ADRD rats, TPPU reduced plasma glucose and HbA1c levels. Transcriptomic analysis of primary cerebral vascular smooth muscle cells from AD rats treated with TPPU revealed enhanced pathways related to cell contraction, alongside decreased oxidative stress and inflammation. Both AD and DM-ADRD rats exhibited impaired myogenic responses and autoregulation in the cerebral circulation, which were normalized with chronic sEH inhibition. Additionally, TPPU improved acetylcholine-induced vasodilation in the middle cerebral arteries (MCA) of DM-ADRD rats. Acute TPPU administration unexpectedly caused vasoconstriction in the MCA of DM-ADRD rats at lower doses. In contrast, higher doses or longer durations were required to induce effective vasodilation at physiological perfusion pressure in both control and ADRD rats. Additionally, TPPU decreased reactive oxygen species production in cerebral vessels of AD and DM-ADRD rats. These findings provide novel evidence that chronic sEH inhibition can reverse cerebrovascular dysfunction and cognitive impairments in AD/ADRD, offering a promising avenue for therapeutic development.

Prophylactic Aspirin Dose and Preeclampsia.

It is unclear whether a higher dose (150-160 mg) or a lower dose (75 mg) of aspirin should be used to prevent preeclampsia. To compare the risk of preeclampsia and bleeding complications between women using 150 to 160 mg of aspirin and those using 75 mg of aspirin for preeclampsia prevention. This nationwide cohort study included 13 828 women giving birth at 22 weeks' gestation or later in Sweden between January 2017 and December 2020 who used low dose aspirin (75-160 mg) during pregnancy. Data were analyzed from October to November 2023. The use of 150 to 160 mg or 75 mg of aspirin in pregnancy. The main outcome was a preeclampsia diagnosis recorded in the maternal birth record at the time of hospital discharge. The main safety outcome was postpartum hemorrhage, defined as bleeding more than 1000 mL after delivery. Relative risks (RRs) and 95% CIs were estimated using a doubly robust inverse probability-weighted regression adjustment model controlling for background characteristics. In the total cohort of 13 828 women, the mean (SD) age was 33.0 (5.5) years and 3003 women (21.7%) were nulliparous. Of the women, 4687 (33.9%) were prescribed 150 to 160 mg of aspirin, and 9141 (66.1%) were prescribed 75 mg of aspirin. A total of 10 635 women (76.9%) had at least 2 dispensed prescriptions of low-dose aspirin. Among women using 150 to 160 mg of aspirin, 443 (9.5%) developed preeclampsia compared with 812 (8.9%) of those using 75 mg of aspirin (adjusted RR [aRR], 1.07; 95% CI, 0.93-1.24). Additionally, the risk of postpartum hemorrhage between the groups was similar, with 326 women (6.9%) using 150 to 160 mg of aspirin experiencing a postpartum hemorrhage compared with 581 (6.4%) in the 75-mg group (aRR, 1.08; 95% CI, 0.90-1.30). In this cohort study of 13 828 women, no difference was found in preeclampsia incidence or bleeding complications between those using 150 to 160 mg of aspirin vs 75 mg of aspirin during pregnancy for preeclampsia prevention. These findings suggest that either dose may be a reasonable choice when using aspirin to prevent preeclampsia. However, large randomized trials investigating aspirin dose in pregnancy are still needed.

Essential Oil of Bay Laurel (Laurus nobilis) Enhances Growth and Immunity in Cold-Stressed Nile Tilapia (Oreochromis Niloticus).

Bay laurel (Laurus nobilis) essential oil is known for its antimicrobial, anti-inflammatory, and antioxidant properties. This study examined the effects of L. nobilis oil (LN) on Nile tilapia (Oreochromis niloticus) under cold stress conditions (16°C). Tilapia (initial weight, 5.02 ± 0.02 g) were acclimatized to 16°C for 14 days before being fed diets containing 0, 0.5, 1.0, 1.5, 2.0, and 2.5 g/kg LN oil for 84 days. The 1.5 g/kg LN oil group exhibited the highest final body weight and weight gain (p ≤ 0.05), while survival rates peaked at 1 g/kg. Biometric indices and feed efficiency were significantly enhanced, particularly at 1.5 g/kg (p ≤ 0.05). Histological analysis revealed improved intestinal and hepatic structures in LN-supplemented groups, although mild alterations were observed at 2.0 and 2.5 g/kg. Blood biochemical analysis showed increased total protein and reduced cholesterol in supplemented groups. Immune responses, including serum lysozyme activity and bacterial inhibition, were significantly enhanced at 1.5 g/kg or higher (p ≤ 0.05). Antioxidant enzyme activities, including superoxide dismutase (SOD) and catalase (CAT), increased (p ≤ 0.05) with LN oil supplementation, while malondialdehyde (MDA) levels decreased, indicating reduced oxidative stress. Gene expression analysis demonstrated increased insulin-like growth factor 1 and glucose transporter 4 levels with 1.5 g/kg LN oil, and tumor necrosis factor-alpha expression decreased at higher dosages. Dietary LN oil, particularly at 1.5 g/kg, enhances growth, immunity, and antioxidant defense in Nile tilapia under cold stress. Future studies should optimize dosages and explore broader applications across species and conditions.

The role of statins in dementia or Alzheimer’s disease incidence: a systematic review and meta-analysis of cohort studies

BackgroundThe effect of statins on the risk of dementia and Alzheimer’s disease (AD) is unclear.MethodsWe systematically searched EMBASE, Web of Science, PubMed, CENTRAL and ClinicalTrail.gov for cohort studies comparing incidence of new-onset dementia and AD between statin users and non-users. We applied the DerSimonian–Laird random effects method to pool hazard ratio (HR) with 95% confidence intervals (CI).ResultsWe included forty-two studies comprising 6,325,740 patients. Thirty-five cohort studies involving 6,306,043 participants were pooled and indicated that statin use was associated with a reduced risk of dementia (HR: 0.79, 95% CI: 0.71–0.88). Similarly, an analysis of 19 studies comprising 1,237,341 participants demonstrated a 29% decrease in the risk of AD among statin users (HR: 0.71, 95% CI: 0.60–0.85). In sensitivity analyses, diagnostic criteria for dementia/AD significantly affected the combined risk estimates. In subgroup analyses, compared to studies enrolling participants with a mean/median age over 70 years, those younger than 70 years exhibited greater efficacy of statins in preventing dementia (HR: 0.67, 95% CI: 0.56–0.81 vs HR: 0.86, 95% CI: 0.78–0.95; P = 0.02) and AD (HR: 0.47, 95% CI: 0.44–0.50 vs. HR: 0.81, 95% CI: 0.71–0.92; P < 0.01). Due to significant heterogeneity in the definitions of statin dosage and exposure duration, pooling the results was abandoned and most studies suggested that higher dosages and longer exposure duration of statins further reduce the risk of dementia and AD.ConclusionStatin use is associated with a reduced incidence of dementia and AD, which might be modified by ages.

Mechanistic investigation and the optimal dose based on baicalin in the treatment of ulcerative colitis–A preclinical systematic review and meta-analysis

BackgroundUlcerative colitis (UC) is a type of inflammatory bowel disease, and current treatments often fall short, necessitating new therapeutic options. Baicalin shows therapeutic promise in UC animal models, but a systematic review is needed.MethodsA systematic search was conducted across databases including PubMed, EBSCO, Web of Science, and Science Direct, up to March 2024, identifying randomized controlled trials (RCTs) examining baicalin’s impact on UC in animal models. Seventeen studies were selected through manual screening. Meta-analyses and subgroup analyses utilized Rev Man 5.3 and Stata 15.0 software to assess symptom improvement.ResultsFrom 1304 citations, 17 were analyzed. Baicalin significantly modulated various biomarkers: HCS (SMD = -3.91), DAI (MD = -2.75), spleen index (MD = -12.76), MDA (SMD = -3.88), IL-6 (SMD = -10.59), IL-1β (SMD = -3.98), TNF-α (SMD = -8.05), NF-κB (SMD = -5.46), TLR4 (MD = -0.38), RORγ (MD = -0.89), MCP-1 (MD = -153.25), MPO (SMD = -7.34), Caspase-9 (MD = -0.93), Caspase-3 (MD = -0.45), FasL (MD = -1.20)) and enhanced BWC (MD = 0.06), CL (MD = 1.39), ZO-1 (MD = 0.44), SOD (SMD = 3.04), IL-10 mRNA (MD = 3.14), and FOXP3 (MD = 0.45) levels. Baicalin’s actions may involve the PI3K/AKT, TLR4/NF-κB, IKK/IKB, Bcl-2/Bax, Th17/Treg, and TLRs/MyD88 pathways. Optimal therapeutic outcomes were predicted at dosages of 60–150 mg/kg over 10–14 weeks.ConclusionBaicalin demonstrates a multifaceted therapeutic potential in UC, attributed to its anti-inflammatory, antioxidant, anti-apoptotic, and intestinal barrier repair properties. While higher doses and longer treatments appear beneficial, further research, particularly human clinical trials, is necessary to verify its effectiveness and safety in people.

Finger roots (Uvaria chemea) and African greenheart (Cylicodiscus gabunensis): Alternative Potent Therapy to Sildenafil in Erectile Dysfunction

Background and aimErectile dysfunction (ED) is a prevalent condition affecting men worldwide, characterized by the inability to achieve or maintain an erection sufficient for sexual intercourse. Traditional herbal remedies, rooted in cultural practices, have been explored as alternative therapies for ED, and this study focuses on Uvara chemea and Cylicodiscus gabunensis, two plants with reported medicinal properties, as potential alternatives to sildenafil, a standard pharmaceutical for ED. Experimental procedureForty male Wistar rats were randomly divided into five groups: control (treated with distilled water), low, medium, and high doses (treated with 61.23, 122.47, and 183.71 mg/kg each of Uvara chemea and Cylicodiscus gabunensis respectively), and a positive control group (treated with sildenafil citrate). The rats were treated for 21 days, and their erectile responses were estimated ResultsSignificant improvements in erectile responses were observed in rats treated with Uvara chemea and Cylicodiscus gabunensis extracts compared to the control group. When compared to sildenafil citrate, the extracts showed comparable effects in most parameters, with a significant disparity noted in intromission frequency at low and high dosages. Strikingly, there was no significant difference between the extracts treated animals and their counterparts treated with sildenafil citrate. ConclusionUvara chemea and Cylicodiscus gabunensis extracts demonstrated potential in ameliorating erectile dysfunction in rats, suggesting their viability as alternative or complementary therapeutic options to sildenafil citrate. Further investigations are necessary to elucidate the underlying mechanisms of action, determine optimal dosages, and evaluate the long-term safety profiles of these herbal extracts for potential human applications.

Assessment of sedative activity of Chrysin: Behavioral approach with pharmacokinetics, toxicological profile and molecular docking.

The purpose of this study was to investigate the sedative effects of Chrysin (CHR) along with modulatory effects on diazepam (DZP) and flumazenil (FLU) in an animal sleep model produced by thiopental sodium (TS). Additionally, we explored the pharmacokinetics and potential GABAA receptor interactions of CHR through computational studies. Swiss albino mice were treated with intraperitoneal administration of CHR (5 and 10mg/kg), DZP (2mg/kg), and FLU (0.1mg/kg) either alone or in combination. Sleeping onset and duration were measured following TS administration. Molecular docking was performed to investigate CHR's binding affinity with GABAA (PDB: 6X3X) receptors. Results found that CHR significantly (p<0.05) reduced sleep latency and increased sleep duration in a dose-dependent manner compared to the control group. The highest dose (CHR-10) exhibited the most potent significant sedative effect with onset (11.57±1.74min) and duration (172.86±7.37min). Combination therapy of CHR-10 with DZP resulted in synergistic effects, further enhancing sleep duration. In molecular docking, CHR demonstrated a higher binding affinity (-8.9kcal/mol) for GABAA receptors compared to DZP (-8.7kcal/mol) and FLU (-6.6kcal/mol). CHR also showed favorable pharmacokinetic properties with high intestinal absorption and low toxicity. CHR exhibits promising sedative activity, with the potential to enhance the effects of traditional sedatives like DZP. However, further research, including clinical trials and detailed mechanistic studies, is warranted to explore its full therapeutic potential.

CB1 Receptor Signaling: Linking Neuroplasticity, Neuronal Types, and Mental Health Outcomes.

The endocannabinoid system (ECS) is crucial in the pathophysiology of mental disorders. Historically, cannabis has been utilized for centuries to mitigate symptoms of anxiety and depression; however, the precise role of cannabinoids in these conditions has only recently garnered extensive research attention. Despite the growing body of literature on the ECS and its association with mental health, several critical questions remain unresolved. This review primarily focuses on cannabinoid CB1 receptors (CB1R), providing an examination of their regulatory roles in states related to mental disorders. Evidence suggests that CB1R distribution occurs among various neuronal types, astrocytes, and subcellular membranes across multiple brain regions, potentially exhibiting both analogous and antagonistic effects. Additionally, various forms of stress have been shown to produce divergent impacts on CB1R signaling pathways. Furthermore, numerous CB1R agonists demonstrate biphasic, dose-dependent effects on anxiety and depression; specifically, low doses may exert anxiolytic effects, while higher doses can induce anxiogenic responses, a phenomenon observed in both rodent models and human studies. We also discuss the diverse underlying mechanisms that mediate these effects. We anticipate that this review will yield valuable insights into the role of CB1R in mental disorders and provide a framework for future research endeavors on CB1R and the ECS. This knowledge may ultimately inform therapeutic strategies aimed at alleviating symptoms associated with mental health conditions.

Synthesis and Characterization of Sodium Alginate Spheres Functionalized with Dicarboxylic Acids for Copper Removal in Aqueous Media

AbstractNew polymeric spheres of sodium alginate (AlgNa) containing dicarboxylic acids—maleic acid (MA) and oxalic acid (OA)—were developed for adsorption of copper metal from water. Water adsorption capacity, elementary composition, structural, morphological, vibrational, and thermal properties were characterized by scanning electron microscopy (SEM), intumescence degree (IG), X‐ray diffraction (XRD), Fourier transform infrared (FT‐IR) spectroscopy, and differential scanning calorimetry. SEM data revealed that functionalization with dicarboxylic acids affects the morphology and surface of the AlgNa matrix. Sample containing MA (0.35 ± 0.004 g) absorbs more water than the OA sphere (0.28 ± 0.007 g). XRD patterns showed that the AlgNa–MA and AlgNa samples exhibit an amorphous nature, whereas the AlgNa–OA sample has a partially crystalline phase. Adsorption experiments were conducted to analyze whether the synthesized spheres could be optimized to reach the best performance in copper adsorption. The adsorbents were most efficient at the highest dosage used (250 mg), corresponding to removal percentages of 84.54 ± 3.97% (AlgNa), 94.21 ± 3.04% (AlgNa–MA), and 84.22 ± 3.39% (AlgNa–OA). The energy‐dispersive X‐ray spectroscopy maps validated the incorporation of Cu2+ ions on the surface of the adsorbents. Kinetic and isotherm assays confirmed the highest efficiency of AlgNa–MA spheres.

Preclinical toxicity evaluation of the novel anti-hypertensive compound KSD179019.

The Secretin receptor (SCTR) presents a promising path for hypertension management, with KSD179019 as identified as a Positive Allosteric Modulator (PAM) of SCTR, demonstrating anti-hypertensive effects in animal models. Our objective was to comprehensively evaluate the potential toxicity of KSD179019 through in vitro and in vivo investigations. Initial in vitro studies showed minimal toxicity in liver and kidney cells and non-mutagenicity in bacterial assays. A 14-day acute toxicity test indicated an LD50 over 5000mg/kg body weight, suggesting a safe profile, yet necessitating further in vivo analysis before progressing to human trials. Following OECD protocols, we conducted sub-chronic (90 days) and chronic (180 days) toxicity studies in male and female C57 mice at various dosages. These included comprehensive hematological, biochemical, macroscopic, urinalysis, and histopathological examinations. The sub-chronic study reported minimal toxicity except at the highest doses (700 and 1000mg/kg), while the chronic study suggested a no-observed-adverse-effect-level (NOAEL) at 250mg/kg with limitations. QSAR analysis supported the non-mutagenic nature of KSD179019. KSD179019 demonstrated a favorable general toxicity profile at a dose of 250mg/kg in a 180-day chronic testing study. However, further preclinical investigations, including assessments of in vivo mutagenicity, reproductive and developmental toxicity, and carcinogenicity, are required to comprehensively establish its safety profile.

Preclinical and in silico studies of 3-benzothioyl-1-(3-hydroxy-3-phenyl-3-propyl)-1-methylthiourea: A promising agent for depression and anxiety.

The study investigated the anxiolytic, antidepressant, sedative/hypnotic and in silico molecular docking properties of the synthetic ephedrine-based derivative of thiourea, 3-benzothioyl-1-(3-hydroxy-3-phenyl-3-propyl)-1-methylthiourea. Safety profile of the compound at various doses was determined in an acute toxicity test. Results showed significant anti-anxiety effects of the compound in all mice studies. In the elevated plus maze (EPM), the time spent and entries into open arms were significantly increased upon treatment with the test compound. In the light-dark (LD) box test the drug increased the time spent in the light compartment. In hole board (HB) assay, exploration of hole and rearing significantly increased. For anxiolytic activity, 20mg/kg was determined to represent the optimal dose, while at a higher dose (i.e., 40mg/kg), it caused significant sedation and increased sleep duration in thiopental-induced sleep test. Escape latency in the tail suspension test (TST) and in the forced swim test (FST) increased and immobility was significantly reduced upon 3-benzothioyl-1-(3-hydroxy-3-phenyl-3-propyl)-1-methylthiourea administration. The molecular docking analysis was performed against the various protein target involved in the pathogenesis of anxiety. The molecular docking, molecular dynamic (MD) simulation and free energy calculation showed high binding affinity and stability of ligand with the 7VOD and 2C65 protein. Taken together, it is concluded from both the in vivo assays and molecular modeling studies that 3-benzothioyl-1-(3-hydroxy-3-phenyl-3-propyl)-1-methylthiourea possesses significant anxiolytic and antidepressant activity in concomitant with a high safety profile.

The prognostic value of HER2 gene dosage and heterogeneity at a single-cell resolution in gastroesophageal adenocarcinoma.

473 Background: HER2 gene dosage (i.e. level of amplification) and heterogeneity are key prognostic variables for HER2+ gastroesophageal adenocarcinoma (GEA), yet no standardized approach to test these in routine clinical use exists. Here we modify the analytical pipeline for HER2 FISH to quantitatively estimate these prognostic variables and correlate them with clinical outcomes. Methods: Patients with metastatic HER2+ GEA who received trastuzumab-based therapy between 2011-2024 at Dana-Farber Cancer Institute and had available pre-treatment tissue for FISH analysis were included. HER2 FISH was conducted in a CLIA approved clinical pathology laboratory. Standard HER2/CEP17 ratio (an average of 50 cells) and individual cell HER2/CEP17 ratio were calculated. Kaplan-Meier method was used to estimate progression free (PFS) on trastuzumab-based therapy and overall survival (OS). Survival outcomes were adjusted for age, gender, tumor site, grade, prior resection, number of metastatic sites, and HER2 IHC using cox proportional hazard regression models. Results: A total of 77 patients were included. Median age was 60 years, 88% were male, and 92% had HER2 3+ tumors. Individual cells with HER2/CEP17 ratio ≥ 2.0 were defined as amplified (same cutoff as current bulk standard) and those with HER2/CEP17 ratio ≥ 4.95 (population median) were labeled highly HER2 amplified providing objective metrics to assess heterogeneity and gene dosage. Using these metrics we defined three subgroups: 1. Heterogenous (Het, n = 15): &lt;75% cells HER2+; 2. Homogenous, low gene dosage (HL, n = 30): &gt;75% cells HER2+, &lt;50% cells with high HER2 amplification; 3. Homogenous, high gene dosage (HH, n = 32): &gt;75% cells HER2+, &gt;50% cells with high HER2 amplification. Cutoffs for both metrics were determined using data distribution patterns. The subgroups were prognostically relevant and PFS and OS were significantly lower for heterogenous tumors and numerically lower for homogenous tumors with low gene dosage after multivariable adjustment (Table). Conclusions: HER2 gene dosage and heterogeneity significantly impact outcomes in HER2+ GEA. More importantly by deconvoluting clinical HER2 FISH data at single cell level, we demonstrate an objective metric with prognostic value that could be adopted for routine clinical use and for patient stratification. Further insights into differing biology of these molecular subtypes are needed. Outcomes of patients by HER2 heterogeneity and gene dosage. Hazards ratio (HR) and p values are adjusted using multivariable cox proportional hazard regression model. PFS OS Patients, No. Median, mo HR (95%CI) P Value Median, mo HR (95%CI) P Value HH 32 16.2 1 16.4 1 HL 30 12.1 1.70 (0.79-3.66) 0.173 15.7 1.71 (0.93-3.14) 0.085 Het 15 6.7 3.12 (1.35-7.2) 0.008 12.4 2.72 (1.28-5.75) 0.009