Oligodendrocyte-selective deletion of the eIF2α kinase Perk/Eif2ak3 limits functional recovery after spinal cord injury.

After spinal cord injury (SCI), re-establishing cellular homeostasis is critical to optimize functional recovery. Central to that response is PERK signaling, which ultimately initiates a pro-apoptotic response if cellular homeostasis cannot be restored. Oligodendrocyte (OL) loss and white matter damage drive functional consequences and determine recovery potential after thoracic contusive SCI. We examined acute (<48 h post-SCI) and chronic (6 weeks post-SCI) effects of conditionally deleting Perk from OLs prior to SCI. While Perk transcript is expressed in many types of cells in the adult spinal cord, its levels are disproportionately high in OL lineage cells. Deletion of OL-Perk prior to SCI resulted in: (1) enhanced acute phosphorylation of eIF2α, a major PERK substrate and the critical mediator of the integrated stress response (ISR), (2) enhanced acute expression of the downstream ISR genes Atf4, Ddit3/Chop, and Tnfrsf10b/Dr5, (3) reduced acute OL lineage-specific Olig2 mRNA, but not neuronal or astrocytic mRNAs, (4) chronically decreased OL content in the spared white matter at the injury epicenter, (5) impaired hindlimb locomotor recovery, and (6) reduced chronic epicenter white matter sparing. Cultured primary OL precursor cells with reduced PERK expression and activated ER stress response showed: (1) unaffected phosphorylation of eIF2α, (2) enhanced ISR gene induction, and (3) increased cytotoxicity. Therefore, OL-Perk deficiency exacerbates ISR signaling and potentiates white matter damage after SCI. The latter effect is likely mediated by increased loss of Perk-/- OLs.

Recent Advances in the Degradability and Applications of Tissue Adhesives Based on Biodegradable Polymers.

In clinical practice, tissue adhesives have emerged as an alternative tool for wound treatments due to their advantages in ease of use, rapid application, less pain, and minimal tissue damage. Since most tissue adhesives are designed for internal use or wound treatments, the biodegradation of adhesives is important. To endow tissue adhesives with biodegradability, in the past few decades, various biodegradable polymers, either natural polymers (such as chitosan, hyaluronic acid, gelatin, chondroitin sulfate, starch, sodium alginate, glucans, pectin, functional proteins, and peptides) or synthetic polymers (such as poly(lactic acid), polyurethanes, polycaprolactone, and poly(lactic-co-glycolic acid)), have been utilized to develop novel biodegradable tissue adhesives. Incorporated biodegradable polymers are degraded in vivo with time under specific conditions, leading to the destruction of the structure and the further degradation of tissue adhesives. In this review, we first summarize the strategies of utilizing biodegradable polymers to develop tissue adhesives. Furthermore, we provide a symmetric overview of the biodegradable polymers used for tissue adhesives, with a specific focus on the degradability and applications of these tissue adhesives. Additionally, the challenges and perspectives of biodegradable polymer-based tissue adhesives are discussed. We expect that this review can provide new inspirations for the design of novel biodegradable tissue adhesives for biomedical applications.

The tyrosine kinase inhibitor LPM4870108 impairs learning and memory and induces transcriptomic and gene­specific DNA methylation changes in rats.

Tyrosine kinase inhibitors (TKIs), which have been developed and approved for cancer treatment in the last few years, are involved in synaptic plasticity of learning and memory. Epigenetic modifications also play crucial roles in the process of learning and memory, but its relationship with TKI-induced learning and memory impairment has not been investigated. We hypothesized that LPM4870108, an effective anti-cancer Trk inhibitor, might affect the learning and memory via epigenetic modifications. In this study, rats were orally administered with LPM4870108 (0, 1.25, 2.5, or 5.0 mg/kg) twice daily for 28 days, after which animals were subjected to a Morris water maze test. LPM4870108 exposure caused learning and memory impairments in this test in a dose-dependent manner and reduced the spine densities. Whole-genome transcriptomic analysis revealed significant differences in the patterns of hippocampal gene expression in LPM4870108-treated rats. These transcriptomic data were combined with next-generation bisulfite sequencing analysis, after which RT-PCR and pyrosequencing were conducted, revealing epigenetic alterations associated with genes (Snx8, Fgfr1, Dusp4, Vav2, and Satb2) known to regulate learning and memory. Increased mRNA and protein expression levels of hippocampal Dnmt1 and Dnmt3a were also observed in these rats. Overall, these data suggest that gene-specific alterations in patterns of DNA methylation can potentially contribute to the incidence of learning and memory deficits associated with exposure to LPM4870108.

PCC-0105002, a novel small molecule inhibitor of PSD95-nNOS protein-protein interactions, attenuates neuropathic pain and corrects motor disorder associated with neuropathic pain model.

In view of postsynaptic density 95kDA (PSD95) tethers neuronal NO synthase (nNOS) to N-methyl-d-aspartate receptor (NMDAR), the PSD95-nNOS complex represents a therapeutic target of neuropathic pain. This study therefore sought to explore the ability of PCC-0105002, a novel PSD95-nNOS small molecule inhibitor, to alter pain sensitivity in rodent neuropathic pain models. Firstly, the IC50 of PCC-0105002 for PSD95 and NOS1 binding activity was determined using an Alpha Screen assay kit. Then, we examined the effects of PCC-0105002 in the mouse formalin test and in the rat spinal nerve ligation (SNL) model, and explored the ability of PCC-0105002 to mediate analgesia and to effect motor coordination in a rota-rod test. Moreover, the mechanisms whereby PCC-0105002 mediates analgesia was explored via western blotting, Golgi staining, and co-immunoprecipitation experiments in dorsal horn. The outcomes indicated that PCC-0105002 exhibited dose-dependent attenuation of phase II pain-associated behaviors in the formalin test. The result indicated that PCC-0105002 disrupted the PSD95-nNOS interaction with IC50 of 1.408 µM. In the SNL model, PCC-0105002 suppressed mechanical allodynia, thermal hyperalgesia, and abnormal dorsal horn wide dynamic range neuron discharge. PCC-0105002 mediated an analgesic effect comparable to that of MK-801, while it was better able to enhance motor coordination as compared with MK-801. Moreover, PCC-0105002 altered signaling downstream of NMDAR and thus functionally and structurally attenuating synaptic plasticity through respective regulation of the NR2B/GluR1/CaMKIIα and Rac1/RhoA pathways. These findings suggest that the novel PSD95-nNOS inhibitor PCC-0105002 is an effective agent for alleviating neuropathic pain, and that it produces fewer motor coordination-associated side effects than do NMDAR antagonists.

Inhaled loxapine for acute agitation in a psychiatric emergency service.

BACKGROUND: Rapid control of agitation in medical settings is necessary for safety and provision of care. Inhaled loxapine achieves peak plasma levels within 2 minutes of administration and is FDA-approved for managing acute agitation. METHODS: We examined the use of inhaled loxapine vs non-parenteral treatment as usual (TAU) in a psychiatric emergency service for consecutive patients with acute agitation or aggression. Data were collected retrospectively. T tests were used for continuous variables and Chi-square tests were used for categorical data. RESULTS: A total of 61 patients received inhaled loxapine and 29 received TAU. Time to outcome for patients receiving inhaled loxapine was 21 ± 21 minutes compared with 121 ± 206 minutes for TAU (t =-2.61; P = .014). At outcome, 89% of patients treated with loxapine experienced symptom resolution, compared with 69% of TAU (Chi-square = 17.4, P < .0001). Ten percent of patients receiving loxapine had no change in symptoms and 1% had worsening symptoms vs 14% in the TAU group who experienced no change in symptoms (z = 0.5, not significant), and 17% who described worsening symptoms (z = 6153.9, P < .0001). CONCLUSIONS: The rapid absorption of inhaled loxapine is associated with a 6-fold faster and more robust symptom control.

Toxicological evaluation of S. involucrata culture: Acute, 90-day subchronic and genotoxicity studies.

Saussurea involucrata is an endangered plant that is used in traditional Chinese medicine. Through the use of plant cell culture techniques, preparations of Saussurea involucrata (S. involucrata) cell cultures have been developed and used to generate medicinal preparations. There have been few evidence-based analyses of the toxicological effects of S. involucrata culture conducted to date. Here, we conducted the experiments designed to assess the acute, subchronic, and genotoxic toxicological effects of S. involucrata culture. The genotoxic study was assessed through Ames, marrow micronucleus, and sperm malformation assays. The acute toxicity was assessed by orally administering in rats and mice at dose of 7500 mg/kg. Subchronic toxicity studies were then conducted by administering rats at doses of 500, 1000, or 1500 mg/kg for 90 days. No genotoxicity was observed at any tested dose levels, nor was any evidence of acute toxicity detected in treated mice or rats. Similarly, subchronic study of S. involucrata culture administration was not associated with any changes in rat food intake, weight, hematological parameters, organ weight, or organ histology. Then, we determined that the no observed adverse effect level of S. involucrata culture was greater than 1500 mg/kg in our 90-day toxicity study.

Assessment of the toxicity and toxicokinetics of the novel potent tropomyosin receptor kinase (Trk) inhibitor LPM4870108 in rhesus monkeys.

LPM4870108 is a tropomyosin receptor kinase (Trk) inhibitor that is currently under consideration for human clinical trials. We characterized the toxicity and toxicokinetic properties of LPM4870108 following its oral administration to rhesus monkeys (5, 10, or 20 mg/kg/day for 4 weeks with a 4-week recovery period). No evidence of LPM4870108 toxicity was observed over this study as reflected by an absence of difference in body weight, ophthalmoscopy, urinalysis, gross, or histopathology findings. No significant differences in toxicity-related outcomes were detected when comparing LPM4870108 and control groups, and no significant treatment-related changes in food consumption, electrocardiogram results, blood pressure, hematological parameters, biochemical values, organ weight, or bone marrow parameters were observed. Treatment caused dose-dependent effects of gait disturbance, impaired balance, poor coordination, and decreased grip strength in all LPM4870108-treated animals, with these effects being attributable to excessive on-target Trk receptor inhibition. After the 4-week recovery period, all these abnormal treatment-related findings had fully or partially resolved. The toxicokinetic study of monkeys revealed that the LPM4870108 exposure increased with dose. Overall, LPM4870108 exhibited a safety profile in treated monkeys, indicating that the Highest Non-Severely Toxic Dose (HNSTD) for LPM4870108 in monkeys was 20 mg/kg/day.

WITHDRAWN: PCC-0105002, a novel small molecule inhibitor of PSD95-nNOS protein-protein interactions, attenuates neuropathic pain and corrects motor coordination-associated side effects in neuropathic pain model.

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Toxicological evaluation of, red rice yeast extract, Xuezhikang: Acute, 26-week chronic and genotoxicity studies.

Xuezhikang (XZK), an extract derived from red yeast rice, is commonly employed as a traditional Chinese medicine for treating coronary heart disease, improving endothelial function, decreasing blood lipids and preventing other cardiovascular events both within China and globally. However, there have not been studies of the toxicity associated with XZK. In this publication we hope to summarize and evaluate an acute study, a 26-week chronic toxicity study, and the genetic toxicity potential of XZK. Firstly, Sprague Dawley (SD) rats were treated with XZK at dose of 10 g/kg to observe the acute toxicity. Then, we sought to assess the toxicity of XZK (0, 500, 1000, and 2000 mg/kg) in SD rats for 26 weeks with a 4-week recovery period. Lastly, we assessed the genotoxicity of XZK utilizing an Ames test, chromosomal aberration assay, and mammalian micronucleus test. The results of the acute study, XZK did not induce toxicity up to the maximum doses of 10 g/kg in rats, so an LD50 could not be determined. In the chronic study, XZK administrated via gavage did not alter weight, food intake, urinalysis parameters, hematological analysis parameters, organ weight, organ to weight ratio, microscopic and macroscopic examination of organs. Also, we found no genotoxicity markers at any dose of XZK tested. The results revealed that the no observed adverse effect level (NOAEL) for XZK, based on the 26-week toxicity study, was 2000 mg/kg.

A 26-week toxicological study of Xuezhikang (XZK), red yeast rice extract, in Beagle dogs with a 4-week recovery period.

Xuezhikang (XZK) is an extract derived from red yeast rice that is commonly used to treat cardiovascular conditions as a traditional Chinese medicine, both within China and globally. Genotoxicity, acute toxicity, and a 26-week toxicity study in rat have been reported in our previous publication. The present study was designed to assess the long-term safety of XZK when administered orally to dogs. Dogs were treated with encapsulated XZK at a maximum dose of 2000 mg/kg followed by 1000 mg/kg and 500 mg/kg (n = 6/sex/group) for this 26-week oral toxicity study. Control animals were given an empty capsule. Treated animals were then monitored through measurements of body weight, body temperature, food intake, ophthalmic and electrocardiogram examinations, general clinical observations, mortality rates, and clinical and anatomic pathological findings. Additionally, blood samples were collected and used to conduct hematological and biochemical analysis. Several abnormalities were found in all groups including: fecal abnormalities (including mucoid, poorly formed, or liquid feces). Moreover, reduced CHOL and TRIG values were seen in all XZK groups (p < 0.05), increased WBC and NEUT levels in 500 mg/kg group (males only, p < 0.05), and elevated AST, ALT, and ALP activities in 2000 mg/kg group (p < 0.05). These changes were resolved in the recovery period. The results indicated that XZK may temporarily impact the liver enzyme levels, but were not considered adverse effects. These findings yielded a NOAEL for XZK in dogs of 2000 mg/kg.

A 26-week 20(S)-ginsenoside Rg3 oral toxicity study in Beagle dogs.

20(s)-ginsenoside Rg3 is a red ginseng-derived compound with the formula C42H72O13 that has been increasingly used by humans, leading to safety concerns regarding this use. In the current study, we conducted a 26-week study during which 20(S)-ginsenoside Rg3 (0, 7, 20, or 60 mg/kg) was continuously administered orally to Beagle dogs in order to explore its toxicity in these animals, with control dogs receiving a vehicle capsule. In total, 10 dogs received each dose of this compound (n = 5 male, n = 5 female per dose). Animals were continuously monitored for a 26-week administration period and a subsequent 4-week follow-up recovery period. At the end of study, we observed no evidence of 20(S)-ginsenoside Rg3 toxicity in clinical indications, body weight, food intake, ophthalmoscopy, electrocardiogram, urinalysis, hematology, serum biochemistry, gross and histopathology findings. However, the kidney relative weight of animals receiving 60 mg/kg of compound was significantly elevated relative to control animals (5.15 ±â€¯0.88‰ vs. 4.11 ±â€¯0.59‰. P < 0.05), and this effect was reversed after 4-week recovery period. Based on these results, the NOAEL value for orally administered 20(S)-ginsenoside Rg3 in dogs is 20 mg/kg.

Toxicological evaluation of 6'-sialyllactose (6'-SL) sodium salt.

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.

Acute, subchronic oral toxicity, and genotoxicity evaluations of LPM570065, a new potent triple reuptake inhibitor.

In the current study, to support the safety of LPM570065 as a new potent triple reuptake inhibitors (TRIs), LPM570065 was investigated through a single- and 13-week repeated-dose oral toxicity evaluation and mutagenicity assays. In an acute toxicity evaluation, Sprague-Dawley (SD) rats were single administration at dose of 500, 1000 and 2000 mg/kg. The results suggested that two (2/20) and seven (7/20) animals were died in the 1000 and 2000 mg/kg group, respectively. In contrast, there were no treatment-related effects at a dose of 500 mg/kg. In a 13-week toxicity evaluation, SD rats were given 30, 100, or 300 mg/kg LPM570065 for 13 successive weeks and then allowed a 4-week recovery period. Impermanent salivation was found at each of the doses, and an impermanent minor body weight decrease was noted in the 300 mg/kg males (P < 0.05). Notably, serum prolactin levels were lowered by 43.25% and 78.65% in the male rats in 100 and 300 mg/kg groups, respectively (P < 0.05). Further, the serum testosterone was elevated by 37% in the 30 and 100 mg/kg males. In conclusion, the maximum tolerated dose (MTD) was 500 mg/kg and the lethal dose was 1000 mg/kg in SD rats after a single administration of LPM570065. In 13-week repeated-dose oral toxicity, the no-observed-adverse-effect level (NOAEL) of LPM570065 was greater than 300 mg/kg for rats. Moreover, LPM570065 was not mutagenic or clastogenic. According to this result it can be concluded that the MTD of LMP570065 is approximately up to 3000 mg/person/day in clinic, and the effects of LMP570065 on sexual function also should be considered.

Toxicity effects of a novel potent triple reuptake inhibitor, LPM570065, on the fertility and early embryonic development in Sprague-Dawley rats.

Selective serotonin reuptake inhibitors (SSRIs) have developed as novel antidepressants and have been determined to possess higher efficacy and less adverse effects compared to other antidepressants. Our previous studies have showed that LPM570065, a new potent TRI, is relatively nontoxic in acute, subchronic toxicity and genotoxicity evaluations. In the current study, toxicity of LPM570065 was further evaluated on the fertility and early embryonic development in Sprague-Dawley rats. A total of 264 rats were treated with various concentrations of LPM570065 (30 mg/kg, 100 mg/kg, and 300 mg/kg) or used as control. Females rats were treated for two consecutive weeks, followed by mating via cohabitation up to the 7th gestation day (GD). The male rats were treated for four consecutive weeks, which were followed by first mating with treated female rats. Then, all males were treated up to the 9th week and followed by second mating with non-treated female rats, and were sacrificed. All surviving pregnant females were euthanized on GD 15. We evaluated the following parameters, namely, mortality, toxicity symptoms, body weight, amount of food consumed, sexual cycle, mating behavior, pregnancy, sperm production, gross necropsy, and weight of organs. Excessive salivation was observed post treatment in nearly all females and males in the 100 and 300 mg/kg LPM570065 treatment groups. Body weight gain was decreased in gravid rats treated with 300 mg/kg LPM570065 during GD 0-6 (P < 0.05). The application of 300 mg/kg of LPM57006 to male rats induced a decrease in implantation sites and lower fertility rates (P < 0.05). However, sperm concentration and count were higher in the LPM570065-treated groups (30 mg/kg, 100 mg/kg, and 300 mg/kg) compared to the controls. Moreover, duration of mating significantly decreased to 37.5% after nine weeks of LPM570065 treatment at a concentration of 300 mg/kg (P < 0.05). In conclusion, the no observable adverse effect level (NOAEL) was established at 100 mg/kg and 300 mg/kg for female and male rats, respectively. The NOAEL for fertility and early embryonic development was established at 300 mg/kg and 100 mg/kg for female and male rats, respectively.

Genotoxicity testing of sodium formononetin-3'-sulphonate (Sul-F) by assessing bacterial reverse mutation, chromosomal aberrations and micronucleus tests.

As part of a safety evaluation, we evaluated the potential genotoxicity of sodium formononetin-3'-sulphonate (Sul-F) using bacterial reverse mutation assay, chromosomal aberrations detection, and mouse micronucleus test. In bacterial reverse mutation assay using five strains of Salmonella typhimurium (TA97, TA98, TA100, TA102 and TA1535), Sul-F (250, 500, 1000, 2000, 4000 µg/plate) did not increase the number of revertant colonies in any tester strain with or without S9 mix. In a chromosomal assay using Chinese hamster lung fibroblast (CHL) cells, there were no increases in either kind of aberration at any dose of Sul-F (400, 800, and 1600 µg/mL) treatment groups with or without S9 metabolic activation. In an in vivo bone marrow micronucleus test in ICR mice, Sul-F at up to 2000 mg/kg (intravenous injection) showed no significant increases in the incidence of micronucleated polychromatic erythrocytes, and the proportion of immature erythrocytes to total erythrocytes. The results demonstrated that Sul-F does not show mutagenic or genotoxic potential under these test conditions.

Repeated sub-chronic oral toxicity study of xylooligosaccharides (XOS) in dogs.

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.

Acute and a 28-day repeated-dose toxicity study of total flavonoids from Clinopodium chinense (Benth.) O. Ktze in mice and rats.

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.

A 90-day subchronic toxicity study with sodium formononetin-3'-sulphonate (Sul-F) delivered to dogs via intravenous administration.

Sodium formononetin-3'-sulphonate (Sul-F) is a water-soluble derivate of formononetin, and an increasing number of studies have shown that Sul-F not only possesses favorable water solubility but also exhibits good lipid-lowering and bioactivities. In the current study, the toxicity of Sul-F was evaluated in dogs after 90-day intravenous infusion. Dogs were treated with Sul-F at dose of 0, 33.3, 100, and 300 mg/kg, and observed for 90-day followed by 28-day recovery period. Weekly measurement of body weight, temperature and food consumption were conducted. Ophthalmoscopy, ECG examination, urinalysis, serum biochemistry and hematology examination were performed at pre-test, on days 45 and 90, and following by 28-day recovery period. Histological examination was performed on day 90 and 28-day recovery period. No mortality, ophthalmic abnormalities or treatment-related findings in body weight, clinical chemistry, hematology, and histopathological examination were detected. However, a white crystal (non-metabolic Sul-F), transient vomiting and recoverable vascular stimulation were observed in 300 mg/kg/day Sul-F treated dogs. Under the conditions, the no-observed-adverse-effect-level (NOAEL) for Sul-F was 100 mg/kg in dogs.

Acute toxicity of sodium formononetin-3'-sulphonate (Sul-F) in Sprague-Dawley rats and Beagle dogs.

Sodium formononetin-3'-sulphonate (Sul-F, C16H12O7SNa), a water-soluble derivate of formononetin, provided significant neuroprotective and cardioprotective effects in vitro and in vivo. The aim of this study was to evaluate acute toxicity of Sul-F after intravenous administration in rats and dogs. Animals were intravenously administered Sul-F at the maximum dosage of 2000 mg/kg and 1000 mg/kg in rats and dogs, respectively. After treatment, rats and dogs were monitored for 14 days. Body weight, clinical signs, the hematological and biochemical findings, and pathological examination were performed. The results showed that no Sul-F related clinical signs of toxicity or mortality were observed in rats. Of note, the transient vomiting was found in dogs after Sul-F administration 15-20 min. In addition, a white crystal, non-metabolic Sul-F, was found after urine volatilization in Sul-F treated animals (rats and dogs). However, neither biochemical findings nor histopathological changes due to Sul-F treatment were found in tests. In summary, the present study results provided practical guidance for selecting a safe dosage for Sul-F further studies and clinical trials in the future.