Dose-effect relationship of copolymer on enhancing aqueous lubrication of a hybrid osteoarthritis drug delivery nanocarrier.

Developing stimulus-responsive properties of drug delivery nanocarriers combined with enhanced joint lubrication is an effective synergistic strategy for treating osteoarthritis. Poly(N-isopropylacrylamide) (PNIPAm) is a typical thermo-responsive polymer, which can achieve drug delivery by transition from swollen state to collapsed state. However, undesired transition temperature, limited drug loading capacity, and weakened mechanical properties in joint present obstacles to use as drug delivery nanocarriers. In this work, we demonstrate dose-effect relationship between the PNIPAm-based copolymer and nanoscale metal-organic frameworks on enhancing both aqueous lubrication and drug delivery performance of a hybrid osteoarthritis (OA) nanocarrier. A series of NIPAm and poly(ethylene glycol)methacrylate (PEGMa) copolymer microgels with different feeding content are optimized to grow on the surface of MIL-101(Cr) nanoparticles via one-pot soap-free emulsion copolymerization method. By changing the feeding mass ratio of NIPAm and PEGMa, MIL-101(Cr)@P(NIPAm-g-PEGMax) (x = 0, 1, 2, 3, and 4, named MPNPx) hybrids can ameliorate the lower critical solution temperature to match with OA and enhance the aqueous lubrication performance. Among the as-synthesized hybrids, MPNP3 hybrids manifested the notable enhanced thermo-responsive tribological performance due to the synergistic effect of "hydration lubrication" and "ball-bearing" function of the optimized copolymer microgel layer on the surface of metal-organic frameworks (MOFs). Anti-inflammatory drug loading is enabled by the high surface area and porosity of the MOFs, and the MPNP3 drug delivery nanocarriers achieve thermo-responsive release in vitro. Our work establishes the dose-effect relationship between thermo-responsive NIPAm and hydrophilic PEGMa of the copolymer grown on the surface of MOFs, providing valuable insights for improving the versatility of stimuli-responsive for biomedical application.

Acupuncture for Aromatase Inhibitor-Induced Arthralgia in Breast Cancer: An Umbrella Review.

Background: Acupuncture therapy shows promise in managing aromatase inhibitor-induced arthralgia (AIA) among breast cancer patients. An umbrella review synthesizes findings from systematic reviews and meta-analyses (SRs/MAs) to assess its effectiveness. Summary: This umbrella review aimed to evaluate the effectiveness of acupuncture therapy in treating AIA among breast cancer patients by analyzing existing evidence from SRs/MAs. Key Messages: Six SRs/MAs were analyzed, revealing shortcomings in reporting quality, methodological quality, and evidence quality assessment. Comprehensive searches across eight electronic databases were conducted. PRISMA, AMSTAR 2, and GRADE were utilized to assess reporting, methodological quality, and evidence quality, respectively. Despite methodological shortcomings, a recent meta-subgroup analysis suggests the efficacy of acupuncture therapy for AIA patients, recommending a 10-session treatment course. Conclusion: Acupuncture is identified as a secure and effective remedy for AIA sufferers, yet further high-quality research is needed to strengthen the evidence base and endorse acupuncture as a viable treatment option.

[Dose-effect relationship of moxibustion for rheumatoid arthritis of liver and kidney deficiency and its effect on fatigue: a randomized controlled trial].

OBJECTIVE: To observe the effects of moxibustion with different frequency on the disease activity and fatigue of rheumatoid arthritis (RA) with liver and kidney deficiency on the basis of western medication treatment. METHODS: A total of 135 RA patients with liver and kidney deficiency were randomly divided into a high-frequency moxibustion group (45 cases, 3 cases dropped out), a low-frequency moxibustion group (45 cases, 2 cases dropped out) and a western medication group (45 cases, 2 cases dropped out, 1 case discontinued). Leflunomide tablet was taken orally in the western medication group, once a day, 20 mg a time. On the basis of the treatment in the western medication group, moxibustion was applied at ashi points and bilateral Shenshu (BL 23) and Sanyinjiao (SP 6) in the two moxibustion groups, 15 min a time. The treatment was given once a day, 5 times a week in the high-frequency moxibustion group and once every other day, 3 times a week in the low-frequency moxibustion group. A total of 12-week treatment was required in the 3 groups. Before and after treatment, the 28 joint disease activity score (DAS28), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), rheumatoid factor (RF), TCM syndrome score, average grip strength (GS) of both hands, 30-second sit-to-stand (STS), timed up and go (TUG), 20-meter walk test (20MWT), self rating anxiety scale (SAS) score and self rating depression scale (SDS) score were observed; before treatment, after treatment and in follow-up of 1, 3 months after treatment completion, the scores of fatigue visual analogue scale (VAS), Bristol rheumatoid arthritis fatigue numerical rating scale (BRAF-NRS) and Bristol rheumatoid arthritis fatigue multi-dimensional questionnaire (BRAF-MDQ) were observed, and the relieving of disease was evaluated by American College of Rheumatology (ACR)20/50/70 standards in the 3 groups. RESULTS: After treatment, the DAS28 scores, ESR, CRP, RF, TCM syndrome scores, TUG, 20MWT, SAS scores and SDS scores were decreased compared with those before treatment (P<0.01, P<0.05), while the average GS of both hands and STS were increased compared with those before treatment (P<0.01, P<0.05) in the 3 groups. After treatment, in the high-frequency moxibustion group, the DAS28 score, ESR, CRP, TCM syndrome score, SAS score and SDS score were lower (P<0.01, P<0.05), while the average GS of both hands and STS were higher (P<0.01, P<0.05) than those in the low-frequency moxibustion group and the western medication group; the TUG and 20MWT were decreased compared with those in the western medication group (P<0.01, P<0.05). After treatment, in the low-frequency moxibustion group, the DAS28 score, ESR, CRP, TCM syndrome score, TUG, SAS score and SDS score were lower (P<0.05, P<0.01), while the average GS of both hands was higher (P<0.01) than those in the western medication group. In each time point after treatment, the scores of fatigue VAS and BRAF-NRS were decreased compared with those before treatment in the 3 groups (P<0.01), while the BRAF-MDQ scores were decreased compared with those before treatment in the high-frequency moxibustion group and the low-frequency moxibustion group (P<0.01). After treatment, the BRAF-MDQ score was decreased compared with that before treatment in the western medication group (P<0.01). In the high-frequency moxibustion group, the scores of fatigue VAS, BRAF-NRS and BRAF-MDQ of each time point after treatment were lower than those in the western medication group (P<0.01), the scores of fatigue VAS and BRAF-NRS in follow-up of 1 month after treatment completion as well as the BRAF-MDQ score after treatment were lower than those in the low-frequency moxibustion group (P<0.01, P<0.05). In the low-frequency moxibustion group, the scores of fatigue VAS, BRAF-NRS and BRAF-MDQ of each time point after treatment were lower than those in the western medication group (P<0.01, P<0.05). After treatment, the proportions of ACR20 and ACR50 in the high-frequency moxibustion group and the low-frequency moxibustion group were higher than those in the western medication group (P<0.01), the proportion of ACR70 in the high-frequency moxibustion group was higher than those in the low-frequency moxibustion group and the western medication group (P<0.05, P<0.01), and the proportion of ACR70 in the low-frequency moxibustion group was higher than that in the western medication group (P<0.05). CONCLUSION: On the basis of the western medication treatment, moxibustion can effectively reduce the disease activity and improve fatigue status in RA patients with liver and kidney deficiency, and its efficacy is positively correlated with treatment frequency.

Effects of hydrogen-rich water on blood uric acid in patients with hyperuricemia: A randomized placebo-controlled trial.

Background: Consumption of hydrogen-rich water (HRW) has been shown to have anti-inflammatory and metabolic-modulatory benefits. Objective: A randomized, placebo-controlled trial was conducted to assess the potential blood uric acid-lowering effects of HRW consumption with different doses (low and high doses) and duration (4 and 8 weeks) in patients with hyperuricemia. Methods: The Placebo group consumed three bottles of ordinary drinking water (330 mL per bottle), the Low-HRW group consumed two bottles of HRW (330 mL per bottle, H2 ≥ 4.66 mg/L) and a bottle of ordinary water, and the High-HRW group consumed three bottles of HRW daily for 8 weeks. The primary outcome was the blood uric acid levels following different time points (4 and 8 weeks) compared to baseline. Results: A total of 100 participants completed the entire trial (32 in Placebo, 35 in Low-HRW, and 33 in High-HRW groups). The high-dose of HRW was more effective than low-dose HRW in controlling blood uric acid. Following an 8-week period, the High-HRW group exhibited a significant reduction in blood uric acid levels compared to the baseline (488.2 ± 54.1 µmol/L to 446.8 ± 57.1 µmol/L, P < 0.05). Conclusion: As a rather safe agent, the prolonged consumption of HRW may be feasible in the management of hyperuricemia. Clinical trial registration: chictr.org.cn, identifier ChiCTR2200066369.

Genome-Wide Analysis Reveals Copy Number Variant Gene TGFBR3 Regulates Pig Back Fat Deposition.

BFT is closely related to meat quality and lean meat percentage in pigs. The BFT traits of European LW pigs significantly differ from those of Chinese indigenous fatty MZ pigs. CNV is a prevalent genetic variation that plays an important role in economically important traits in pigs. However, the potential contribution of CNV to BFT in LW and MZ pigs remains unclear. In this study, whole-genome CNV detection was performed using next-generation sequencing data from LW and MZ pigs, and transcriptome data from back fat tissue of 180-day-old LW and MZ pigs were integrated for expression quantitative trait loci (eQTL) analysis. We identified a copy number variation in the TGFBR3 gene associated with BFT, showing a dose effect between the genome and transcriptome levels of the TGFBR3 gene. In porcine preadipocytes, TGFBR3 expression continuously increased during differentiation. Knockdown of TGFBR3 using specific siRNA inhibited preadipocyte differentiation and proliferation. Our study provides insights into the genetic regulation of pork quality and offers a theoretical basis for improving carcass quality by modulating BFT in pigs.

Aged fragmented-polypropylene microplastics induced ageing statues-dependent bioenergetic imbalance and reductive stress: In vivo and liver organoids-based in vitro study.

Ageing is a nature process of microplastics that occurrs daily, and human beings are inevitably exposed to aged microplastics. However, a systematic understanding of ageing status and its toxic effect is currently still lacking. In this study, plastic cup lids-originated polypropylene (PP) microplastics were UV-photoaged until the carbonyl index (CI), a canonical indicator for plastic ageing, achieved 0.08, 0.17, 0.22 and 0.28. The adverse hepatic effect of these aged PPs (aPPs) was evaluated in Balb/c mice (75 ng/mL water, about 200 particles/day) and human-originated liver organoids (LOs, 50 particles/mL, ranged from 5.94 to 13.15 ng/mL) at low-dose equivalent to human exposure level. Low-dose of aged PP could induce hepatic reductive stress both in vitro and in vivo, by elevating the NADH/NAD+ratio in a CI-dependent manner, together with hepatoxicity (indicated by increased AST secretion and cytotoxicity), and disrupted the genes encoding the nutrients transporters and NADH subunits accompanied by the restricted ATP supply, declined mitochondrial membrane potential and mitochondrial complexI/IV activities, without significant increase in MDA levels in the liver. These changes in the liver disrupted systematic metabolism, representing a circulatory panel of increases in the lactate, triglyceride, Fgf21 levels, and decreases in the pyruvate level, linked the reductive stress to the declined body weight gain but elevated hepatic NADH contents following aPPs exposure. Additionally, assessing by the LOs, it was found that digestion drastically accelerated the ageing of aPPs and worsen the energy supply upon mitochondria, representing a "scattergun effect" induced by the formation of micro- and nano-plastics mixture toward NADH/NAD+imbalance.

RNA interference targeting WSSV ribonucleotide reductase 2 provides long-term protection against infection in Litopenaeus vannamei.

Many studies have demonstrated that long double-stranded RNAs (dsRNAs) targeting essential genes of white spot syndrome virus (WSSV) can induce a sequence-specific antiviral RNA interference (RNAi) response in shrimp, thereby offering protection against WSSV infection. However, further experimental data on the required dose of dsRNAs and the duration of protection from a single administration are necessary to establish RNAi-mediated methods as effective and practical antiviral measures. In this study, we evaluated the protective efficacy and the duration of protection provided by a single administration of various doses of long dsRNA targeting WSSV ribonucleotide reductase 2 (rr2) in white-leg shrimp Litopenaeus vannamei. The protective efficacy of long dsRNA targeting WSSV rr2 was not diminished by the reduction of the dose to 100 ng g-1 of body weight, suggesting that a relatively low dose can effectively induce an RNAi response in shrimp. Furthermore, shrimp were well-protected against WSSV challenges for up to 4 wk post-administration of the rr2-targeting long dsRNA, although the protective effect almost disappeared at 6 wk post-administration. These results suggest that long dsRNAs can provide protection against WSSV for at least 1 mo, and monthly administration of long dsRNAs could serve as a long-term protective strategy for shrimp against WSSV.

Effect of palliative radiation dose on symptom response in metastatic sarcomas.

Purpose: Palliative radiotherapy (RT) plays a crucial role in alleviating symptoms associated with metastatic sarcoma. However, there is a lack of consensus on the optimal palliative radiation dose and fractionation for metastatic sarcomas. We analyzed the association between biologically effective radiation dose and symptom response for patients who underwent palliative RT for metastatic sarcomas. Methods and materials: We retrospectively identified patients with metastatic sarcoma treated with palliative RT between 1999 and 2021 at our institution. We assessed the association between equivalent dose in 2 Gy fractions (EQD2) with an α/ß of three and symptom relief or overall survival (OS) using univariable and multivariable analyses. Results: Of the 198 metastatic sites treated, the most common indications for palliative radiation were pain (n = 181, 91 %) and compression of adjacent structures (n = 16, 8 %). In our analysis, an EQD2 of > 20 Gy was associated with greater rates of short-term symptom relief (n = 143, 85 %) at the RT site compared to an EQD2 of ≤ 20 Gy (n = 14, 54 %, P = 0.001) with no reports of grade 3 or higher toxicity. However, there was no significant improvement in short-term symptom relief for higher radiation doses. Patients treated with an EQD2 of ≤ 20 Gy had a significantly worse performance status, but there was no significant difference in overall survival based on EQD2 on multivariable analysis. Conclusions: An EQD2 ≤ 20 Gy (e.g., 8 Gy in 1 fraction) provided inadequate palliative benefit in this series. An EQD2 > 20 Gy resulted in greater rates of symptom palliation in metastatic sarcomas, but further dose escalation did not improve symptom response or durability. These findings suggest standard palliative regimens such as 20 Gy in 5 fractions (EQD2 of 28 Gy) are effective for patients with metastatic sarcomas.

Time-course and dose-effect of omalizumab in treating chronic idiopathic urticaria/chronic spontaneous urticaria.

PURPOSE: Several studies have shown that subcutaneous injections of omalizumab can treat chronic idiopathic/spontaneous urticaria (CIU/CSU) patients by only assessing the efficacy on specific endpoints. This study aimed to quantitatively analyze different doses of omalizumab in CIU/CSU and compare it with ligelizumab. METHODS: Literature searches were performed in PubMed, Embase, and Web of Science databases. A model-based meta-analysis (MBMA) was utilized to develop a model incorporating time since the initiation of treatment and dose for omalizumab, with the change from baseline in Urticaria Activity Score (CFB-UAS7) as the primary efficacy endpoint. The time-course and dose-effect relationship throughout the omalizumab treatment period was analyzed, and the findings were compared with those of the investigational ligelizumab. RESULTS: The model equation for the CFB-UAS7 was established as E = -Emax × time/(ET50 + time) × (b0 + b1 × dose). The estimated values of the model parameters E max , ET 50 , b 0 , and b 1 were -1.16, 1.26 weeks, -9.90, and -0.0361 mg-1, respectively. At week 12 after the first dose, the model-predicted CFB-UAS7 for 150 mg and 300 mg of omalizumab were -16.0 (95% CI, -17.2 to -14.8) and -21.7 (95% CI, -22.9 to -20.5), respectively. In the PEARL-1 trial, the CFB-UAS7 for 72 mg and 120 mg of ligelizumab were -19.4 (95% CI, -20.7 to -18.1) and -19.3 (95% CI, -20.6 to -18.0), respectively. In the PEARL-2 trial, these values were -19.2 (95% CI, -20.5 to -17.9) and -20.3 (95% CI, -21.6 to -19.0), respectively. CONCLUSION: Omalizumab showed a significant dose-dependent effect in the treatment of CSU. Both 72 mg and 120 mg ligelizumab might have the potential to outperform 150 mg (but not 300 mg) omalizumab.

A non-linear partial least squares based on monotonic inner relation.

A novel regression model, monotonic inner relation-based non-linear partial least squares (MIR-PLS), is proposed to address complex issues like limited observations, multicollinearity, and nonlinearity in Chinese Medicine (CM) dose-effect relationship experimental data. MIR-PLS uses a piecewise mapping function based on monotonic cubic splines to model the non-linear inner relations between input and output score vectors. Additionally, a new weight updating strategy (WUS) is developed by leveraging the properties of monotonic functions. The proposed MIR-PLS method was compared with five well-known PLS variants: standard PLS, quadratic PLS (QPLS), error-based QPLS (EB-QPLS), neural network PLS (NNPLS), and spline PLS (SPL-PLS), using CM dose-effect relationship datasets and near-infrared (NIR) spectroscopy datasets. Experimental results demonstrate that MIR-PLS exhibits general applicability, achieving excellent predictive performances in the presence or absence of significant non-linear relationships. Furthermore, the model is not limited to CM dose-effect relationship research and can be applied to other regression tasks.

Methamphetamine effects in zebrafish (Danio rerio) depend on behavioral endpoint, dose and test session duration.

Research using zebrafish (Danio rerio) has begun to provide novel information in many fields, including the behavioral pharmacology of drug use and misuse. There have been limited studies on the effects of methamphetamine in adult zebrafish and the parameters of exposure (dose, test session length) have not been well-documented. Behavior following drug exposure is generally measured during relatively short sessions (6-10 min is common) in a novel tank environment. Many procedural variables (isolation, netting, novel tank) elicit anxiety-like behavior that is most apparent during the initial portion of a test session. This anxiety-like behavior might mask the initial effects of methamphetamine. During longer test sessions, these anxiety-like responses would be expected to habituate and drug effects should become more apparent. To test this idea, we measured several locomotor activity responses for 50-min following a range of methamphetamine doses (0.1-3.0 mg/L via immersion in methamphetamine solution). Methamphetamine failed to alter swimming velocity, distance travelled, or freezing time. In contrast, methamphetamine produced a dose-dependent decrease in time spent in the bottom of the tank, an increase in the number of visits to the top of the tank, and an increase in the number of transitions along the sides of the tank. The effects of methamphetamine were apparent 10-20 min following exposure and generally persisted throughout the session. These findings indicate that longer test sessions are required to measure methamphetamine-induced changes in behavior in zebrafish, as has been shown in other laboratory animals. The results also suggest that anxiety-like responses associated with various procedural aspects (netting, isolation, novel test apparatus) likely interfere with the ability to observe many behavioral effects of methamphetamine in zebrafish. Based on the current results, habituation to testing procedures to reduce anxiety-like behaviors is recommended in determining the effects of methamphetamine in zebrafish.

Perspective of Dose-Response: New Chapter With New "Exposome" and "-omics".

This is an editorial from the new editor-in-chief, EIC, who starts his role in March 2024. Due to the remarkable advance of various research fields in terms of its concepts and technology, the emerging concepts of "Exposome" and associated "Exposomics" have been introduced into the toxicology research. Therefore, the mission of "Dose-Response" will remain adhered to the original goals but will incorporate with these new concepts as the next chapter's principle and strategies. Accordingly, although it remains with special interest in the biological response to low-dose (level) ranges of stresses. The types and contents of interested manuscripts will be extended with more diverse, newer concepts from a wide range of disciplines. We wish this journal can open a door for various discipline scientists and researchers to share their state-of-the-art discoveries to shed new insight to understand the impact of environmental and toxicological medicine and develop more specific and effective intervention strategies.

Exploring the association between dietary Inflammatory Index and chronic pain in US adults using NHANES 1999-2004.

Chronic pain, a substantial public health issue, may be influenced by dietary patterns through systemic inflammation. This cross-sectional study explored the association between Dietary Inflammatory Index (DII) and chronic pain among 2581 American adults from NHANES data. The DII, ranging from - 4.98 to 4.69, reflects the inflammatory potential of the diet, with higher scores indicating greater pro-inflammatory capacity. Our findings showed no significant association between the continuous DII score and chronic pain prevalence. However, a nonlinear relationship emerged. When the DII was categorized, a significant association between higher DII scores (DII ≥ 2.5) and chronic pain prevalence was observed. The analysis uncovered a U-shaped pattern, with an inflection point at a DII score of - 0.9, indicating an association between both low and high levels of dietary inflammation are associated with higher pain prevalence. This nuanced interaction between dietary inflammation and chronic pain indicates the possibility of incorporating dietary modification into pain management strategies and underscores the need for further research into the long-term effects of diet on chronic pain.

Effective dose of intranasal remimazolam for preoperative sedation in preschool children: a dose-finding study using Dixon's up-and-down method.

Background: Most preschool children are distressed during anesthesia induction. While current pharmacological methods are useful, there is a need for further optimization to an "ideal" standard. Remimazolam is an ultra-short-acting benzodiazepine, and intranasal remimazolam for pre-induction sedation may be promising. Methods: This study included 32 preschool children who underwent short and minor surgery between October 2022 and January 2023. After pretreatment with lidocaine, remimazolam was administered to both nostrils using a mucosal atomizer device. The University of Michigan Sedation Score (UMSS) was assessed for sedation 6, 9, 12, 15, and 20 min after intranasal atomization. We used Dixon's up-and-down method, and probit and isotonic regressions to determine the 50% effective dose (ED50) and 95% effective dose (ED95) of intranasal remimazolam for pre-induction sedation. Results: Twenty-nine pediatric patients were included in the final analysis. The ED50 and ED95 of intranasal remimazolam for successful pre-induction sedation, when processed via probit analysis, were 0.65 (95% confidence interval [CI], 0.59-0.71) and 0.78 mg/kg (95% CI, 0.72-1.07), respectively. In contrast, when processed by isotonic regression, they were 0.65 (95% CI: 0.58-0.72 mg/kg) and 0.78 mg/kg (95% CI: 0.69-1.08 mg/kg), respectively. At 6 min after intranasal remimazolam treatment, 81.2% (13/16) of "positive" participants were successfully sedated with a UMSS ≧ 1. All the "positive" participants were successfully sedated within 9 min. Conclusion: Intranasal remimazolam is feasible for preschool children with a short onset time. For successful pre-induction sedation, the ED50 and ED95 of intranasal remimazolam were 0.65 and 0.78 mg/kg, respectively.

Effectiveness of lapatinib for enhancing 5-aminolevulinic acid-mediated protoporphyrin IX fluorescence and photodynamic therapy in human cancer cell lines with varied ABCG2 activities.

5-Aminolevulinic acid (ALA) is a prodrug for protoporphyrin IX (PpIX)-mediated photodynamic therapy (PDT) and fluorescence-guided tumor surgery. We previously reported that lapatinib, a repurposed ABCG2 inhibitor, enhanced ALA-induced PpIX fluorescence and PDT by blocking ABCG2-mediated PpIX efflux. In the present study, we evaluated how the variation in ABCG2 activities/protein levels affected tumor cell response to the enhancement of PpIX/PDT by lapatinib and Ko143, an ABCG2 tool inhibitor. ABCG2 activities and protein levels were determined in a panel of human cancer cell lines. Effects of lapatinib and Ko143 on enhancing ALA-PpIX fluorescence and PDT were evaluated and correlated with tumor cell ABCG2 activities. We found that both lapatinib and Ko143 enhanced ALA-PpIX fluorescence and PDT in a dose-dependent manner, although lapatinib exhibited lower efficacy and potency than Ko143 in nearly all cancer cell lines. The EC50 of ABCG2 inhibitors for enhancing ALA-PpIX and PDT had a positive correlation with tumor cell ABCG2 activities, indicating that tumor cell lines with lower ABCG2 activities were more sensitive to ABCG2 inhibitors for PpIX/PDT enhancement. Our results suggest that, for optimal therapeutic enhancement, the dose of ABCG2 inhibitors needs to be tailored based on the ABCG2 expression/activity in tumors.

Molybdenum-mediated nitrogen accumulation and assimilation in legumes stepwise boosted by the coexistence of arbuscular mycorrhizal fungi and earthworms.

Molybdenum (Mo) is a critical micronutrient for nitrogen (N) metabolism in legumes, yet the impact of Mo on legume N metabolism in the context of natural coexistence with soil microorganisms remains poorly understood. This study investigated the dose-dependent effect of Mo on soil N biogeochemical cycling, N accumulation, and assimilation in alfalfa under conditions simulating the coexistence of arbuscular mycorrhizal fungi (AMF) and earthworms. The findings indicated that Mo exerted a hormetic effect on alfalfa N accumulation, facilitating it at low concentrations (below 29.98 mg/kg) and inhibiting it at higher levels. This inhibition was attributed to Mo-induced constraints on C supply for nitrogen fixation. Concurrently, AMF colonization enhanced C assimilation in Mo-treated alfalfas by promoting nutrients uptake, particularly Mg, which is crucial for chlorophyll synthesis. This effect was further amplified by earthworms, which improved AMF colonization (p < 0.05). In the soil N cycle, these organisms exerted opposing effects: AMF enhanced soil nitrification and earthworms reduced soil nitrate (NO3--N) reduction to jointly increase soil phyto-available N content (p < 0.05). Their combined action improved alfalfa N assimilation by restoring the protein synthesis pathway that is compromised by high Mo concentrations, specifically the activity of glutamine synthetase. These findings underscored the potential for soil microorganisms to mitigate N metabolic stress in legumes exposed to elevated Mo levels.

Correlations between bone metabolism biomarkers and fluoride exposure in adults and children.

Increased exposure to fluoride, which notably affects bone metabolism, is a global concern. However, the correlations and sensitivity of bone metabolism to fluoride remain controversial. In this cross-sectional study, 549 children (aged 7-12 years) and 504 adults (≥ 18 years old) were recruited in the high-fluoride areas of the Henan Province. Urinary fluoride (UF) level was determined using a fluoride electrode. Fasting venous blood serum was collected to measure bone metabolism biomarkers. The selected bone metabolism biomarkers for children included bone alkaline phosphatase (BALP), serum alkaline phosphatase (ALP), osteocalcin (OCN), calcitonin (CT), parathyroid hormone (PTH), phosphorus (P5+), and calcium (Ca2+). For adults, the biomarkers included ALP, CT, PTH, ß-CrossLaps (ß-CTX), P5+, and Ca2+. The correlations between UF and bone metabolism biomarkers were analyzed using binary logistic regression, a trend test, a generalized additive model, and threshold effect analysis. Regression analysis indicated a significant correlation between serum OCN, PTH, and UF levels in children aged 7-9 years. Serum OCN, PTH, and BALP contents were significantly correlated with UF in boys (P < 0.05). Furthermore, the interaction between age and UF affected serum P5+ and PTH (P < 0.05). The generalized additive model revealed nonlinear dose-response relationships between P5+, BALP, and UF contents in children (P < 0.05). Serum OCN level was linearly correlated with the UF concentration (P < 0.05). Similarly, a significant correlation was observed between ß-CTX and UF levels in adults. In addition, significant correlations were observed between UF-age and serum Ca2+, ß-CTX, and PTH contents. There was a non-linear correlation between serum Ca2+, P5+, and ß- CTX and UF levels (P < 0.05). Overall, serum OCN, BALP, and P5+ levels can serve as sensitive bone metabolism biomarkers in children, while ß-CTX, P5+, and Ca2+ can be considered fluoride-sensitive bone metabolism biomarkers in adults.

Exploration of the utility of different doses of Qingfei Dayuan granules: a multicenter, randomized, double-blind, placebo-controlled trial.

BACKGROUND: Clinical studies have confirmed that Qingfei Dayuan (QFDY) granules are effective in the treatment of influenza and upper respiratory tract infections (URTIs) caused by pulmonary heat-toxin syndrome (PHTS). Granules of Chinese medicine formulations have become a widely used dosage form in clinical practice. With the continuous optimization of extraction technology, the advantages of Chinese medicine granules have been gradually demonstrated, but the price of Chinese medicine granules is generally higher than that of traditional dosage forms of Chinese medicine, and we support the rational use of the appropriate dosage of QFDY for patients with these conditions. Therefore, we set up half of the conventional dose as the low dose group, and designed the three-arm study to rigorously compare the efficacy difference of low-dose QFDY, QFDY and the placebo group, with the expectation of providing scientific support for the rational selection of the dose and the safe and effective use of the medicine in clinical practice. METHODS: We recruited 108 patients with clinical diagnoses of influenza and URTIs caused by PHTS to receive treatment at six hospitals in Hubei, China. Using a centralized randomization system, patients were randomly assigned at a 1:1:1 ratio to the QFDY, low-dose QFDY, or placebo control groups to receive the corresponding drug, and the study physicians, subjects, outcome assessors, and statisticians were unaware of group assignments. The primary outcome was the time to complete fever relief. Secondary outcomes included the efficacy of Chinese medicine in alleviating signs and symptoms and the disappearance rate of individual symptoms. Adverse events were monitored throughout the trial. RESULTS: A total of 108 patients were recruited. A total of 106 patients were included in the full analysis set (FAS). In the FAS analysis, there was no statistically significant difference in baseline of the three groups before treatment (P > 0.05). 1. Regarding the median time to complete fever relief, the QFDY, low-dose QFDY and placebo groups had median times of 26 h, 40 h and 48 h, respectively. The QFDY group had a shorter time to complete fever relief than the placebo group, and the difference was statistically significant (P < 0.05), while the low-dose QFDY group had a shorter time than the placebo group, but the difference was not statistically significant (P > 0.05). 2. In terms of the total efficacy of Chinese medicine in alleviating symptoms at the end of three full days of treatment, as well as the cure rate of red and sore throat, stuffy and runny nose, and sneezing, QFDY and low-dose QFDY were superior to the placebo, and the differences were statistically significant (P < 0.01). There was no statistical significance in the comparison between the QFDY group and the low-dose QFDY group (P > 0.05). 3. In terms of the headache cure rate after three full days of treatment, QFDY was superior to the placebo, with a statistically significant difference (P < 0.05), and there was no significant efficacy of low-dose QFDY. 4. Safety comparisons showed no serious adverse events and 30 minor adverse events, which were not clinically considered to be related to the drug and were not statistically significant. CONCLUSIONS: In the treatment of patients with influenza and URTIs caused by PHTS, which are mainly characterized by clinical symptoms such as red and sore throat, stuffy and runny nose, and sneezing, when fever is not obvious or low-grade fever is present, the use of low-dose QFDY to simply alleviate the clinical symptoms is recommended and preferred. Moreover, with its good safety profile, QFDY can be used in the treatment of patients with influenza and URTIs caused by PHTS, which can effectively shorten the duration of fever, significantly increase the total efficacy of Chinese medicine in alleviating symptoms after 3 days of treatment, and accelerate the recovery of symptoms such as red and sore throat, stuffy and runny nose, sneezing, and headache, etc. Clinical Trial Registration: http://www.chictr.org.cn. TRIAL NUMBER: ChiCTR2100043449. Registered on 18 February 2021.

Effectiveness of Rhenium(I)-diselenoether Low Doses in a Triple-negative Breast Cancer Chicken Embryo Model.

BACKGROUND/AIM: Rhenium(I)-diselenoether (Re-diSe) is a promising anticancer agent composed of one rhenium and two selenium atoms. Its effectiveness was established in inhibiting cancer cells while maintaining low toxicity toward normal cells at a 5 µM dose for 120 hours in MDA-MB-231 cells. In MDA-MB-231 breast tumor-bearing mice, anti-tumor and anti-metastatic effects were observed at a 10 mg/kg dose. However, contradictory results were observed in the 4T1 breast cancer model, where a dose of 60 mg/kg had a pro-tumor effect. To address these discrepancies, the efficacy of Re-diSe at the effective 10 mg/kg dose was validated in a transplanted MDA-MB-231 breast tumor model using the chicken chorioallantoic membrane assay. MATERIALS AND METHODS: MDA-MB-231 cancer cells were xenografted onto the chicken chorioallantoic membrane (CAM), and daily drug administration was carried out for nine days at doses of 0.1, 1, and 10 mg/kg. At the study's conclusion, a standard histological analysis was conducted. RESULTS: The low dose of 0.1 mg/kg showed a significant reduction in tumor weights compared to controls. The 1 mg/kg dose resulted in an increased inflammation score but did not induce a significant difference in tumor weights compared to the 0.1 mg/kg dose. Notably, at the 10 mg/kg dose, six out of 11 treated embryos displayed no visible signs of tumors. These tumors exhibited extensive tumor necrosis and significant infiltration by inflammatory cells. CONCLUSION: In this particular model, the anticancer efficacy of Re-diSe was achieved at the low dose of 0.1 mg/kg. The higher dose of 10 mg/kg, while eliminating visible tumors, might have immune-mediated effects, as indicated by substantial tumor necrosis and infiltration by inflammatory cells. Overall, this study successfully demonstrated the effectiveness of Re-diSe as an anticancer agent.

The impact of sampling scale: A comparison of methods for estimating external contaminant exposure in free-ranging wildlife.

The impacts of contaminants on wildlife are dose dependent, and thus being able to track or predict exposure following contamination events is important for monitoring ecosystem health. However, the ability to track exposure in free-ranging wildlife is often severely limited. Consequently, researchers have predominantly relied on simple methods for estimating contaminant exposures in wildlife with little regard for spatial contaminant heterogeneity or an animal's use of diverse habitats. We evaluated the influence sampling scale (i.e., how finely contaminant distribution and organism's spatial use of the landscape is mapped) has on (1) realism and (2) conservativeness of exposure estimates. To do this, we monitored the actual exposure of wild boar (Sus scrofa) in Fukushima, Japan to radioactive contamination using GPS-coupled contaminant monitors placed on individual animals. We compared empirical exposures to estimates generated by combining varying amounts of information about an individual boar's location and/or movement, with the distribution of contamination on the landscape. We found that the most realistic exposure estimates were produced when finer-scale contaminant distribution surveys (e.g., airborne surveys) were combined with more accurate estimates of an individual's space use (e.g., home ranges or core areas). Importantly, estimates of exposure based on single point surveys at a trap site (a simple method commonly used in the literature), did not correlate with actual exposure rates, suggesting dose-effects studies using this method may result in spurious conclusions. These results suggest that researchers seeking realistic estimates of exposure, such as in dose-effect studies, should ensure they have adequately accounted for fine-scale contaminant distribution patterns and areas of higher use by study organisms. However, conservative estimates of exposure (i.e., intentionally over-predicting exposure as is done in initial tiers of ecological risk analyses) were not as scale sensitive and could be achieved with a single known location and coarse contaminant distribution maps.