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The article presents a study which reported a small molecule-catalyzed asymmetric rearrangement of cyclopropylcarbinyl cations, leading to a series of chiral homoallylic sulfide products with good to excellent yields and enantioselectivities. Topics discussed include reaction development and optimization, screening of substrate scopes, and mechanistic consideration.

The scope and limitations of dipolar cycloaddition reactions between nitrile oxides/nitrones and prop-1-ene-1,3-sultone have been investigated. A remarkably high degree of regioselectivity and stereoselectivity was observed. The homochiral sultam 8e was synthesized in a four-step reaction sequence starting from the substituted isoxazoline 4e obtained from the cycloaddition. The absolute stereochemistry of this material was assigned by an X-ray crystallographic investigation of the intermediate 7e. [Copyright &y& Elsevier]

We performed a series of toxicity studies on the safety of 6′-sialyllactose (6′-SL) sodium salt as a food ingredient. 6′-SL sodium salt, up to a maximum dose of 5000 μg/plate, did not increase the number of revertant colonies in five strains of Salmonella typhimurium in the presence or absence of S9 metabolic activation. A chromosomal aberration assay (using Chinese hamster lung cells) found no clastogenic effects at any concentration of 6′-SL sodium salt in the presence or absence of S9 metabolic activation. An in vivo bone marrow micronucleus test in Kunming mice showed no clastogenic activities with 6′-SL sodium salt doses up to 2000 mg/kg body weight (bw). In an acute toxicity study, the mean lethal dose of 6′-SL sodium salt was greater than 20 g/kg bw in rats. In a 13-week subchronic toxicity investigation, no effects were found at doses up to 5.0 g/kg bw of 6′-SL sodium salt in food consumption, body weight, clinical signs, blood biochemistry and hematology, urinalysis, or ophthalmic and histological macroscopic examination of organs. The no-observed-adverse-effect level (NOAEL) was 5.0 g/kg bw/day in rats. [ABSTRACT FROM AUTHOR]

The safety of 3′-sialyllactose (3′-SL) sodium salt was evaluated by testing for gene mutations, in vivo and in vitro clastogenic activity, and animal toxicity in beagle dogs and rats. The results of all mutagenicity and genotoxicity tests were negative, indicating that 3′-SL does not have any mutagenic or clastogenic potential. The mean lethal dose (LD 50 ) of 3′-SL sodium salt was well above 20 g/kg body weight (bw) in rats. A dose escalation acute toxicity study in Beagle dogs also indicated no treatment-related abnormalities. Subsequent 28-day and 90-day toxicity studies in Sprague- Dawley (SD) rats involved dietary exposure to 500, 1,000, and 2000 mg/kg bw of 3′-SL sodium salt and a water (vehicle) control. There were no treatment-related abnormalities on clinical observations, body weight, food consumption, behavior, hematology, clinical chemistry, organ weights, relative organ weights, urinalysis parameters, or necropsy and histopathological findings. The No Observed Adverse Effect Level (NOAEL) of 3′-SL sodium salt was determined to be higher than 2000 mg/kg bw/day in an oral subchronic toxicity study in rats, indicating that the substance is an ordinary carbohydrate with the lowest toxicity rating. Results confirm that 3′-SL sodium salt has a toxicity profile similar to other non-digestible carbohydrates and naturally occurring human milk oligosaccharides (HMOs) and support its safety for human consumption in foods. [ABSTRACT FROM AUTHOR]

Clinopodium chinense (Benth.) O. Ktze (Labiatae), known as ‘Duanxueliu’ in the Chinese Pharmacopoeia, has been widely used as a traditional Chinese medicine for the treatment of hemorrhagic disease. Total flavonoids from Clinopodium chinense (Benth.) O. Ktze (TFCC), the most active ingredient, possess a variety of properties, such as antioxygenation. Until now, evidence-based toxicity data on TFCC has been limited. This study evaluated the acute (in mice and rat) and the 28-day repeated-dose (in rat) toxicity study of TFCC, respectively. In acute study, oral administration of TFCC to rats and mice did not induce toxicity or mortality up to the maximum doses of 4000 and 5000 mg/kg, respectively. In subacute toxicity study, we administered TFCC at daily doses of 70, 210, and 630 mg/kg for 4 consecutive weeks to rats via gavage. We observed no changes in food consumption, water intake, body weight, chemistry and hematological parameters, organ weight, gross pathology or histopathology. No animals from any group died. These findings indicate that TFCC is relatively nontoxic, and provide practical guidance for selecting a safe dose for further investigation of TFCC in animal studies or clinical trials. [ABSTRACT FROM AUTHOR]

Astilbin is an active flavonoid compound isolated from Rhizoma Smilacis Glabrae . It has been widely used as an anti-hepatic, anti-arthritic, and anti-renal injury agent. However, its safety has not yet been established. The objective of this study was to evaluate 4-week repeated oral toxicity and genotoxicity of astilbin. We examined oral toxicity in Sprague-Dawley rats after daily oral administration of astilbin at 50, 150, and 500 mg/kg for 4 weeks. Negative control animals received the same volume of the solvent. Astilbin administration did not lead to death, body weight gain, food consumption, or adverse events. There were no significant differences in toxicity between the astilbin and control group; we observed no toxic effects on hematological or urinalysis parameters, biochemical values, organ weight, or histopathological findings. We assessed the genotoxicity of astilbin with the Ames test (TA97a, TA98, TA100, TA102, and TA1535), chromosomal aberration assay (using Chinese hamster ovary cells), and mammalian micronucleus test (in mice). We found no genotoxicity in any tested strains. The no-observed-adverse-effect level (NOAEL) for astilbin in the 4-week repeated oral toxicity study in rats was greater than 500 mg/kg body weight/day, regardless of gender. Results also suggested that astilbin does not have genotoxicity potential. [ABSTRACT FROM AUTHOR]

In this study, Beagle dogs were administered xylooligosaccharide (XOS, CAS # 87099-0) at doses of 0, 1250, 2500, and 5000 mg/kg/day by oral gavage for 26 weeks. A 4-week recovery period was added to observe delayed or reversible toxicity. Measurements included body weight, food consumption, clinical observations, temperature, electrocardiogram (ECG), urinalysis, blood chemistry, hematology, organ weight, gross necropsy, and histopathological examination. Except for transient diarrhea or vomiting, no treatment-related adverse effects were noted. In the mid-dose groups, transitional diarrhea was observed in the initial 1–2 weeks. In the high-dose groups, diarrhea and/or vomiting were observed episodically over the duration of treatment. However, they disappeared after XOS was withdrawn in the recovery period. Although there was a tendency toward less weight gain in the high-dose group animal group, this is typical in animals and humans fed non-digestible carbohydrates. This chronic toxicity study demonstrated that the no observed adverse effect level (NOAEL) of XOS is 2500 mg/kg body weight (BW)/day. Based on body surface area (conversion factor of 0.54 for dogs to human), this corresponds to daily doses of 1350 mg/kg BW or 81–108 g XOS in human adults weighing 60–80 kg. [ABSTRACT FROM AUTHOR]

To evaluate the potential toxicity of refined arachidonic acid-rich oil (RAO) derived from Mortierella alpina ( M. alpina ) XM027, we performed a 90-day subchronic study in F 1 Sprague Dawley (SD) rats. This study was preceded by a 4-week pretreatment period of parental (F 0 ) rats and exposure of the F 0 dams throughout mating, gestation, and lactation. The results indicated that RAO, at dose levels of 0.5%, 1.5%, and 5%, did not affect either reproductive performance of the parental rats, or any characteristics of the pups. In the subchronic study with the offspring (F 1 ) rats, no treatment related abnormalities were observed. In summary, no observable adverse effect level (NOAEL) in this study was placed at 5% RAO, the highest level tested. This level corresponds to approximately 3750 mg/kg in F 0 females, 2850 mg/kg in F 0 males, 4850 mg/kg in F 1 females, and 4480 mg/kg in F 1 males. [ABSTRACT FROM AUTHOR]

Benzynes (7, 16) generated from benzobisoxadisilole and benzotrisoxadisilole were trapped as the furan cycloaddition adducts. Naphthoxadisilole and naphthobisoxadisilole were also synthesized. [Copyright &y& Elsevier]

The syntheses, X-ray structures and characterization of a dibenzo macrocyclic acetylenic sulfide 4a and a comparable silane 4b are described. [Copyright &y& Elsevier]

In nature, cyclopropylcarbinyl cation is often involved in cationic cascade reactions catalyzed by natural enzymes to produce a great number of structurally diverse natural substances. However, mimicking this natural process with artificial organic catalysts remains a daunting challenge in synthetic chemistry. We report a small molecule-catalyzed asymmetric rearrangement of cyclopropylcarbinyl cations, leading to a series of chiral homoallylic sulfide products with good to excellent yields and enantioselectivities (up to 99% enantiomeric excess). In the presence of a chiral SPINOL-derived N -triflyl phosphoramide catalyst, the dehydration of prochiral cyclopropylcarbinols occurs rapidly to generate symmetrical cyclopropylcarbinyl cations, which are subsequently trapped by thione-containing nucleophiles. A subgram-scale experiment and multiple downstream transformations of the sulfide products are further pursued to demonstrate the synthetic utility. Notably, a few heteroaromatic sulfone derivatives could serve as "covalent warhead" in the enzymatic inhibition of severe acute respiratory syndrome coronavirus 2 main protease.

The objective of this study was to evaluate whether D-allulose has teratogenic effects on rats. A prenatal developmental toxicity test was conducted in SD rats in compliance with modified OECD guidelines test number 414, prenatal developmental toxicity study. Pregnant female rats received repeated doses of 1250, 2500, or 5000 mg/kg body weight D-allulose, or a vehicle control by gavage on GD 6-15. On GD 20, one day prior to the expected day of delivery, pregnant rats were weighed and anesthetized, and laparotomized to remove the uterine and its content were weighed. Fetuses were examined macroscopically for any soft tissue and skeletal changes. The evaluation indicators included general sign observation, body weight, food consumption, animal death, corpora lutea, numbers of embryonic or fetal deaths, and viable fetuses including live birth rate, fetal resorption rate, and stillbirth rate, as well as sex, body weights, and skeletal and soft tissue alterations of fetuses. No treatment-related abnormalities were observed in prenatal developmental toxicity and fetal malformation parameters, indicating that D-allulose had no teratogenic effects on pregnant rats and fetuses. From the findings of this prenatal developmental toxicity study, the NOAEL of D-allulose was estimated to be 5000 mg/kg/day in pregnant SD rats., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Authors.)

Background: 20(S)-ginsenoside-Rg3 (C 42 H 72 O 13 ), a natural triterpenoid saponin, is extracted from red ginseng. The increasing use of 20(S)-ginsenoside Rg3 has raised product safety concerns., Methods: In acute toxicity, 20(S)-ginsenoside Rg3 was singly and orally administrated to Kunming mice and Sprague-Dawley (SD) rats at the maximum doses of 1600 mg/kg and 800 mg/kg, respectively. In the 26-week toxicity study, we used repeated oral administration of 20(S)-ginsenoside Rg3 in SD rats over 26 weeks at doses of 0, 20, 60, or 180 mg/kg. Moreover, a 4-week recovery period was scheduled to observe the persistence, delayed occurrence, and reversibility of toxic effects., Results: The result of acute toxicity shows that oral administration of 20(S)-ginsenoside Rg3 to mice and rats did not induce mortality or toxicity up to 1600 and 800 mg/kg, respectively. During a 26-week administration period and a 4-week withdrawal period (recovery period), there were no significant differences in clinical signs, body weight, food consumption, urinalysis parameters, biochemical and hematological values, or histopathological findings., Conclusion: The mean oral lethal dose (LD 50 ) of 20(S)-ginsenoside Rg3, in acute toxicity, is above 1600 mg/kg and 800 mg/kg in mice and rats, respectively. In a repeated-dose 26-week oral toxicity study, the no-observed-adverse-effect level for female and male SD rats was 180 mg/kg., (© 2018 The Korean Society of Ginseng, Published by Elsevier Korea LLC.)

Background: Whole-brain radiotherapy (WBRT) in patients with brain metastases (BM) is associated with neurocognitive decline. Given its crucial role in learning and memory, efforts to mitigate this toxicity have mostly focused on sparing radiation to the hippocampus. We hypothesized that BM are not evenly distributed across the brain and that several additional areas may be avoided in WBRT based on a low risk of developing BM., Methods: We contoured 2757 lesions in a large, single-institution database of patients with newly diagnosed BM. BM centroids were mapped onto a standard brain atlas of 55 anatomic subunits and the observed percentage of BM was compared with what would be expected based on that region's volume. A region of interest (ROI) analysis was performed in a validation cohort of patients from 2 independent institutions using equivalence and one-sample hypothesis tests., Results: The brainstem and bilateral thalami, hippocampi, parahippocampal gyri, amygdala, and temporal poles had a cumulative risk of harboring a BM centroid of 4.83% in the initial cohort. This ROI was tested in 157 patients from the validation cohort and was found to have a 4.1% risk of developing BM, which was statistically equivalent between the 2 groups (P < 1 × 10-6, upper bound)., Conclusion: Several critical brain structures are at a low risk of developing BM. A risk-adapted approach to WBRT is worthy of further investigation and may mitigate the toxicities of conventional radiation., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Microbacterium foliorum is a naturally occurring bacteria in cruciferous vegetables and ripened cheese. The safety of M. foliorum SYG27B-MF has been assessed in both acute and subchronic studies and a battery of mutagenicity and clastogenicity tests. In a single dose acute study, the LD 50 of M. foliorum SYG27B-MF was greater than 3 g/kg bw or 5.1 × 10 16 colony forming unit (CFU)/kg bw, the highest dose tested. In a 90-day subchronic toxicity study in 80 Sprague-Dawley rats, no animals died and there were no treatment-related abnormalities at doses of 0, 500, 1000, or 2000 mg/kg bw. In a 90-day repeated toxicity test, the no-observed-adverse-effect level (NOAEL) M. foliorum SYG27B-MF was 2000 mg/kg/day or 3.4 × 10 16  CFU/kg bw/day, the highest level tested. A mutagenicity study using reverse bacterial mutation tests and a genotoxicity study employing cultured hamster ovarian fibroblasts (CHO-K1) cell showed that M. foliorum SYG27B-MF was not mutagenic or clastogenic in the presence or absence metabolic activation. In an in vivo mouse micronucleus assay, M. foliorum SYG27B-MF did not induce did not induce micronuclei formation in the bone marrow cells of mice, indicating that it is non-clastogenic. The results from these studies support the safety of M. foliorum SYG27B-MF for use as a production organism for human food ingredients., (Copyright © 2018. Published by Elsevier Inc.)

Background: Intakes of ready-to-eat cereal (RTEC) have been inversely associated with risk factors of chronic diseases such as cardiovascular disease (CVD), type 2 diabetes, and certain cancers; however, their relations with total and cause-specific mortality remain unclear., Objective: To prospectively assess the associations of RTEC intakes with all causes and disease-specific mortality risk., Design: The study included 367,442 participants from the prospective National Institutes of Health (NIH)-AARP Diet and Health Study. Intakes of RTEC were assessed at baseline., Results: Over an average of 14 years of follow-up, 46,067 deaths were documented. Consumption of RTEC was significantly associated with reduced risk of mortality from all-cause mortality and death from CVD, diabetes, all cancer, and digestive cancer (all p for trend < 0.05). In multivariate models, compared to nonconsumers of RTEC, those in the highest intake of RTEC had a 15% lower risk of all-cause mortality and 10%-30% lower risk of disease-specific mortality. Within RTEC consumers, total fiber intakes were associated with reduced risk of mortality from all-cause mortality and deaths from CVD, all cancer, digestive cancer, and respiratory disease (all p for trend < 0.005)., Conclusions: Consumption of RTEC was associated with reduced risk of all-cause mortality and mortality from specific diseases such as CVD, diabetes, and cancer. This association may be mediated via greater fiber intake.

The objective of this study was to estimate the independent associations between intake of phosphorus (P) and bone health parameters such as bone mineral content (BMC) and bone mineral density (BMD). It provides odds ratio (OR) of osteoporosis with quartiles of P intake adjusted for covariates (i.e., age, gender, BMI, and consumption of calcium (Ca), protein, total dairy foods, and vitamin D as well as intakes of supplemental Ca, vitamin D, and multivitamins/minerals). Data came from males and females aged 13-99 years who participated in the 2005-2010 National Health and Nutrition Examination Survey (NHANES). Analyses showed that higher P intake was associated with higher Ca intake, and that dietary Ca:P ratios (0.51-0.62, with a mean of 0.60 for adults) were adequate in all age/gender groups. High intake of P was positively associated with BMC in female teenagers (Q4 vs. Q1: BMC, 30.9 ± 1.1 vs. 29.0 ± 0.5 g, P = 0.001). It was also positively associated with BMC and BMD as well as reduced risk of osteoporosis in adults >20 years of age (Q4 vs. Q1: OR of osteoporosis, 0.55; 95% confidence interval [CI], 0.39- 0.79; P = 0.001; BMC, 37.5 ± 0.4 vs. 36.70 ± 0.3 g, P < 0.01; BMD, 0.986 ± 0.004 vs. 0.966 ± 0.005 g/cm(2), P < 0.05). The data suggest that high intake of P has no adverse effect on bone metabolism in populations with adequate Ca intake, and that it is also associated with positive bone parameters in some age/gender groups.

Binaphthyl-based chiral sulfonimide (CSI) is demonstrated for the first time to be an efficient, strong Brønsted acid in asymmetric organocatalysis. A series of CSIs were synthesized and screened in the asymmetric Friedel-Crafts alkylation of indoles with imines. Good to excellent yields and enantioselectivities have been achieved. It was proved that it was crucial to wash the CSI catalyst with HCl before use.

Anthracene capped isobenzofuran 5 (5,6-(9,10-dihydroanthracen-9,10-yl)isobenzofuran) was synthesized for the first time. It is a highly reactive and versatile synthon for the synthesis of iptycene derivatives via Diels-Alder reactions. Cycloadducts 10 could be readily deoxygenated to iptycenes 11. Two new reactions of PhI(OAc)(2)/TfOH have been explored. Endoxides 10 were directly oxidized to iptycene quinones 12, and isobenzofuran 5 was conveniently converted to triptycene dialdehyde 16. H-shaped centrally extended pentiptycene quinones 13 and 14 were also synthesized.

A ratiometric fluorescent probe based on a Cd(2+)-ACAQ complex was designed and demonstrated for the chemo- and enantioselective detection of cysteine in 99:1 buffered HEPES:ACN solutions. Under the measuring conditions, the sensor demonstrates high selectivity toward Cys against Hcy and GSH, and an enantioselectivity of 3.35 can be achieved for antipodal forms of Cys.

Cyclic sulfonyl hydrazine was demonstrated for the first time as a new functionality for organocatalysis. A series of six-membered cyclic hydrazines derived from camphor sulfonic acid were synthesized. With trichloroacetic acid as cocatalyst, they are efficient organocatalysts for enantioselective Diels-Alder reactions with good chemical yields and up to 96% ee. The reactions took place in brine at 0 degrees C to room temperature.