[Transcriptome data mining combined with clinical and animal experiments for identification of syndrome element marker genes during entire course of steroid-induced osteonecrosis of femoral head].

A research strategy combining transcriptome data mining and experimental verification was adopted to identify the marker genes characterizing the syndrome elements of phlegm, stasis, and deficiency in steroid-induced osteonecrosis of the femoral head(SONFH). Firstly, the common differentially expressed gene sets of SONFH with the syndromes of phlegm-stasis obstructing collaterals, vessel obstruction, and liver-kidney deficiency were obtained from the clinical transcriptomic analysis of a previous study. The differential expression trend analysis and functional gene mining were then employed to predict the candidate marker gene sets representing phlegm, stasis, and deficiency. The whole blood samples from SONFH patients, whole blood samples from SONFH rats, and affected femoral head tissue samples were collected for qPCR, which aimed to determine the expression levels of the candidate marker genes mentioned above. Furthermore, the receiver operating characteristic curve(ROC) was established to objectively evaluate the syndrome differentiation effectiveness of the candidate marker genes mentioned above. The transcriptome data analysis results showed that the candidate marker genes for phlegm was ELOVL fatty acid elongase 6(ELOVL6), and those for stasis were ankyrin 1(ANK1), glycophorin A/B(GYPA/B), and Rh-associated glycoprotein(RHAG). The candidate marker genes for deficiency were solute carrier family 2 member 1(SLC2A1) and stomatin(STOM). The qPCR results showed that compared with that in the non-SONFH group, ELOVL6 had the lowest expression level in the peripheral blood of the SONFH patients with the syndrome of phlegm-stasis obstructing collaterals(P<0.05). Compared with that in the normal control group, ELOVL6 had the lowest expression level in the peripheral blood and affected femoral head tissue of SONFH rats modeled for 4 weeks(P<0.01), and it showed better syndrome differentiation effectiveness of rats modeled for 4 weeks(AUC=0.850, P=0.006) than at other modeling time points(8, 12, 16, and 21 weeks, AUC of 0.689, 0.766, 0.588, and 0.662, respectively). Compared with that in the non-SONFH group, the expression levels of ANK1, GYPA, and RHAG were the lowest in the peripheral blood of SONFH patients with the vessel obstruction syndrome(P<0.05). The expression levels of the three genes were the lowest in the peripheral blood and affected femoral head tissue of SONFH rats modeled for 12 weeks(P<0.05, P<0.01), and their syndrome differentiation effectiveness in the rats modeled for 12 weeks(GYPA: AUC=0.861, P=0.012; ANK1: AUC=0.855, P=0.006; RHAG: AUC=0.854, P=0.009) was superior to that for 4, 8, 16, and 21 weeks(GYPA: AUC=0.646, 0.573, 0.691, and 0.617, respectively; ANK: AUC1=0.630, 0.658, 0.657, and 0.585, respectively; RHAG: AUC=0.592, 0.511, 0.515, and 0.536, respectively). Compared with the non-SONFH group, both SLC2A1 and STOM had the lowest expression levels in the peripheral blood of patients with the syndrome of liver and kidney deficiency(P<0.05). Compared with the normal control group, their expression levels were the lowest in the peripheral blood and affected femoral head tissue of SONFH rats modeled for 21 weeks(P<0.05, except STOM in the peripheral blood of rats). Moreover, the syndrome differentiation effectiveness of SLC2A1 in the rats modeled for 21 weeks(AUC=0.806, P=0.009) was superior to that for 4, 8, 12, and 16 weeks(AUC=0.520, 0.580, 0.741, 0.774, respectively), and STOM was meaningless in syndrome differentiation. In summary, the candidate marker gene for phlegm in SONFH is ELOVL6; the candidate marker genes for stasis are GYPA, RHAG, and ANK1; the candidate marker gene for deficiency is SLC2A1. The results help to reveal the biological connotations of phlegm, stasis, and deficiency in SONFH at the genetic level.

Antenatal steroid as an independent risk factor for vitamin K2 deficiency in newborns: A Chinese single-center, retrospective study.

OBJECTIVES: To identified vitamin K2 deficiency rate and risk factors among newborns in China and assess the importance of high-risk maternal intakes of vitamin K2. METHODS: This retrospective study was performed at the Neonatology Department, the Affiliated Hospital of Guangdong Medical University, China. Routinely collected mother-neonate hospitalization data from July 2020 to January 2021 were analyzed. In total, data from 200 neonates who had completed vitamin K2 tests were utilized to assess the prevalence of vitamin K2 deficiency and identify the potential risk factors. According to the vitamin K2 level, the neonates were divided into 2 groups: cases (vitamin K2 deficiency) and controls (no vitamin K2 deficiency). The potential risk factors for vitamin K2 deficiency were evaluated by univariate and multivariate logistic regression. RESULTS: The vitamin K2 level in 24 of the 200 neonates was undetectable (<0.05 ng/mL). The prevalence of low serum vitamin K2 (<0.1 ng/ml) was 33%. Study subjects with antenatal corticosteroids use had an approximately 5-fold greater risk of developing vitamin K2 deficiency. In the univariate analyses, small-for-gestational-age (SGA), caesarean section, maternal gestational diabetes and premature rupture of the membranes were risk factors for vitamin K2 deficiency. In the multivariate logistic regression analysis, high antenatal corticosteroids use, cesarean section, and SGA were independently associated with vitamin K2 deficiency. CONCLUSION: The present study demonstrated that antenatal corticosteroids use is independently associated with vitamin K2 deficiency. This finding highlights the importance of routine vitamin K2 supplementation in late-stage pregnant women and neonates in China.

Dried root of Rehmannia glutinosa extracts prevents steroid-induced avascular necrosis of femoral head by activating the wingless-type (Wnt)/ß-catenin signal pathway.

Steroid-induced avascular necrosis of femoral head (SANFH) is one of the most common complications caused by long-term or excessive clinical use of glucocorticoids. This study aimed to investigate the effects of dried root of Rehmannia glutinosa extracts (DRGE) in SANFH. First, SANFH rat model was established by dexamethasone (Dex). Tissue change and proportion of empty lacunae were detected by hematoxylin and eosin staining. Protein levels were detected by western bloting analysis. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) was performed to assess apoptosis of femoral head tissue. Cell viability and apoptosis of MC3T3-E1 cells were assessed by Cell Counting Kit-8 assay and flow cytometry. ALP activity and cell mineralization were detected by ALP staining assay and Alizarin red staining. The findings showed that DRGE improved tissue damage, inhibited apoptosis, and promoted osteogenesis in SANFH rats. In vitro, DRGE increased cell viability, inhibited cell apoptosis, promoted osteoblast differentiation, reduced the levels of p-GSK-3ß/GSK-3ß, but increased the levels of ß-catenin in cells treated with Dex. Furthermore, DKK-1, an inhibitor of the wingless-type (Wnt)/ß-catenin signaling pathway, reversed the effect of DRGE on cell apoptosis and ALP activity in cells treated with Dex. In conclusion, DRGE prevents SANFH by activating the Wnt/ß-catenin signaling pathway, indicating that DRGE may be a hopeful choice drug to prevent and treat patients with SANFH.

Melatonin Inhibits the Ferroptosis Pathway in Rat Bone Marrow Mesenchymal Stem Cells by Activating the PI3K/AKT/mTOR Signaling Axis to Attenuate Steroid-Induced Osteoporosis.

Steroid-induced osteoporosis (SIOP) is a form of secondary osteoporosis, but its specific mechanism remains unclear. Glucocorticoid (GC-)-induced death of osteoblasts and bone marrow mesenchymal stem cells (BMSCs) is an important factor in SIOP. Ferroptosis is an iron-dependent type of programmed cell death and can be induced by many factors. Herein, we aimed to explore whether GCs cause ferroptosis of BMSCs, identify pathways as possible therapeutic targets, and determine the underlying mechanisms of action. In this study, we used high-dose dexamethasone (DEX) to observe whether GCs induce ferroptosis of BMSCs. Additionally, we established a rat SIOP model and then assessed whether melatonin (MT) could inhibit the ferroptosis pathway to provide early protection against GC-induced SIOP and investigated the signaling pathways involved. In vitro experiments confirmed that DEX induces ferroptosis in BMSCs. MT significantly alleviates GC-induced ferroptosis of BMSCs. Pathway analysis showed that MT ameliorates ferroptosis by activating the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) axis. MT upregulates the expression of PI3K, which is an important regulator of ferroptosis resistance. PI3K activators mimic the antiferroptotic effect of MT, but when the PI3K pathway is blocked, the effect of MT is weakened. Using in vivo experiments, we confirmed the in vitro results and observed that MT can obviously protect against SIOP induced by GC. Notably, even after the initiation of GC-induced ferroptosis, MT can confer protection against SIOP. Our research confirms that GC-induced ferroptosis is closely related to SIOP. MT can inhibit ferroptosis by activating the PI3K/AKT/mTOR signaling pathway, thereby inhibiting the occurrence of SIOP. Therefore, MT may be a novel agent for preventing and treating SIOP.

The short-term effects of intranasal steroids on intraocular pressure in pediatric population.

PURPOSE: To evaluate the effect of intranasal mometasone furoate (INMF) on short-term intraocular pressure (IOP) alterations in children with allergic rhinitis (AR). METHODS: Children diagnosed with AR and to whom INMF nasal spray had been firstly prescribed were enrolled. Cases with any ocular diseases except for refractive errors were excluded. Complete ophthalmologic examinations including IOP measurements using Tonopen XL were performed before the treatment as well as at the first and sixth weeks of follow-up. Demographics and ophthalmologic findings were noted and statistically analyzed. RESULTS: Study population consisted of 62 right eyes of 62 children with a mean age of 8.55 ± 3.14 years. Of them, 29 were female (46.8%) and 33 were male (53.2%). Dilated fundoscopy revealed an enlarged Cup/Disc ratio in 12 eyes (19.4%). Family history of glaucoma was positive in 13 cases (21.0%). Mean best corrected visual acuity was found as 0.05 ± 0.08 logMAR. Initial IOP was 17.1 ± 2.3 mmHg; whereas it was measured as 18.2 ± 2.0 mmHg and 17.3 ± 2.1 mmHg at the first and sixth weeks of follow-up, respectively (p < 0.001). Both at the first and sixth weeks of follow-up, significant IOP rise was present in children with a positive family history of glaucoma (p < 0.001 and p = 0.003, respectively). Besides, increased IOP was found in participants with cupping revealed on fundoscopy at the first week of follow-up (p = 0.044). CONCLUSION: Since children have greater risk for steroid-induced ocular hypertensive response than adults, ophthalmologic evaluation must be recommended in children receiving intranasal steroids.

Circ_0058792 regulates osteogenic differentiation through miR-181a-5p/Smad7 axis in steroid-induced osteonecrosis of the femoral head.

Osteonecrosis of the femoral head (ONFH) caused by steroids is a severe orthopedic disorder resulting from the use of high-dose steroid drugs, characterized by structural changes in the bone, joint dysfunction, and femoral head collapse. CircRNAs and miRNAs have increasingly been suggested to play pivotal roles in osteogenic differentiation and osteogenesis. Significant upregulation of circ_0058792 was observed in patients with steroid-induced ONFH. Bioinformatic analysis showed that circ_0058792 might act as a sponge for miR-181a-5p. This study further investigated the mechanisms underlying the role of circ_0058792 and miR-181a-5p in osteogenic differentiation in methylprednisolone-induced ONFH rats and MC3T3-E1 cells. The results showed a notable decrease in the serum of miR-181a-5p in methylprednisolone-induced ONFH rats. Silencing of circ_0058792 using siRNAs and overexpression of miR-181a-5p significantly increased alkaline phosphatase activity and matrix mineralization capacity. Additionally, markers for osteogenic differentiation were significantly upregulated in miR-181a-5p-transfected cells. However, overexpression of circ_0058792 and the addition of the miR-181a-5p inhibitor reversed this increase. Smad7 was identified to be miR-181a-5p's direct target and circ_0058792 was confirmed to be miR-181a-5p's competing endogenous RNA (ceRNA). Upregulation of miR-181a-5p promotes phosphorylation of Smad2 and Smad3. Furthermore, circ_0058792 and miR-181a-5p had opposing effects on Smad7 expression. Collectively, these findings indicate that circ_0058792 regulates osteogenic differentiation by sponging miR-181a-5p via the TGF-ß/Smad7 pathway. These findings elucidated the functions of circ_0058792 and miR-181a-5p in the regulation of steroid-induced ONFH. Our findings also indicated that circ_0058792 and miR-181a-5p are possible diagnostic markers and therapeutic targets for treating steroid-induced ONFH.

Total flavonoids of Rhizoma drynariae ameliorate steroid­induced avascular necrosis of the femoral head via the PI3K/AKT pathway.

Steroid­induced avascular necrosis of the femoral head (SANFH) is a common orthopaedic disease that is difficult to treat. The present study investigated the effects of total flavonoids of Rhizoma drynariae (TFRD) on SANFH and explored its underlying mechanisms. The SANFH rat model was induced by intramuscular injection of lipopolysaccharides and methylprednisolone. Osteoblasts were isolated from the calvariae of neonatal rats and then cultured with dexamethasone (Dex). TFRD was used in vitro and in vivo, respectively. Haematoxylin and eosin staining was used to assess the pathological changes in the femoral head. Terminal deoxynucleotidyl transferase­mediated deoxyuridine triphosphate nick end labelling assay and flow cytometry were conducted to detect apoptosis of osteoblasts. The 2',7'­dichlorofluorescein­diacetate staining method was used to detect reactive oxygen species (ROS) levels in osteoblasts and the 3­(4,5­dimethylthiazol­2­yl)­2,5­diphenyltetrazolium bromide assay was used to detect osteoblast proliferation. The expression of caspase­3, Bax, Bcl­2, VEGF, runt­related transcription factor 2 (RUNX2), osteoprotegerin (OPG), osteocalcin (OCN), receptor activator of nuclear factor κB ligand (RANKL) and phosphoinositide 3­kinase (PI3K)/AKT pathway related­proteins were detected via western blotting. It was found that TFRD reduced the pathological changes, inhibited apoptosis, increased the expression of VEGF, RUNX2, OPG and OCN, decreased RANKL expression and activated the PI3K/AKT pathway in SANFH rats. TFRD promoted proliferation, inhibited apoptosis and reduced ROS levels by activating the PI3K/AKT pathway in osteoblasts. In conclusion, TFRD protected against SANFH in a rat model. In addition, TFRD protected osteoblasts from Dex­induced damage through the PI3K/AKT pathway. The findings of the present study may contribute to find an effective treatment for the management of SANFH.

Ground Glass-Like Inclusions: Associated with Liver Toxicity.

OBJECTIVE: The etiology of ground glass-like inclusions is heterogenous and the pathology has been described in various conditions including HBV infection, Lafora's disease, fibrinogen storage disease, type IV glycogenosis, and alcohol reversion therapy. Similar ground glass-like inclusions are also associated with immunosuppressed conditions and multiple medications, for which the clinical significance is still unclear. Additional cases, some with previously unreported unique etiologies, and their follow-up were described in this study. MATERIALS AND METHODS: Eleven cases were examined between 2008 and 2019 for this study. The clinical data and histologic slides were reviewed. All of the cases were negative for Hepatitis B virus. None of the patients declared alcohol intake or a history of epilepsy. RESULTS: Liver histology showed mild lobular inflammation in most of the cases (72%). Ground glass-like hepatocytes were distributed in the patchy-panlobular, periportal, and centrizonal pattern at 55%, 27%, and 18%, respectively. Clinical history revealed medication use in nine (82%) patients including NSAIDs, steroids, and chemotherapy. Ground glass-like inclusions were related to herbal toxicity in two of the patients. Liver function tests were elevated in all of the cases. Follow-up data revealed four patients with malignancy who died of their cancer. Seven patients showed resolution of elevated liver enzymes with a median follow-up period of 37 months (range 7-132 months). CONCLUSIONS: Medication is the most relevant etiology for the development of these inclusions. Ground glass-like inclusions may also seen in herbal toxicity. Transplantation was not an etiologic factor in our patients. Most of the patients displayed an indolent course with resolution of the elevated transaminases.

Repetitive 1.6 ATA hyperbaric oxygen therapy for bilateral ARCO Stage II steroid-associated osteonecrosis of the femoral head.

Hyperbaric oxygen (HBO2) therapy has been demonstrated to have beneficial effects on the early stages of steroid-associated osteonecrosis (SAON) of the femoral head. Since high HBO2 pressure (e.g., 2.4-2.5 atmospheres absolute/ATA) has been commonly considered to have a greater ability to restore tissue oxygenation in the femoral head than low pressure (e.g., 1.6 ATA), the latter HBO2 protocol is rarely used for SAON treatment. In this paper, we present the case of a 36-year-old female diagnosed with bilateral early stage (Association for Research on Osseous Circulation, ARCO stage II) SAON caused by steroid therapy for neuromyelitis optica spectrum disorder (NMOSD). Because the patient could not endure high HBO2 pressures, the treatment pressure was adjusted to 1.6 ATA, which was the highest pressure the patient could withstand. After 20 treatment sessions, her symptoms were relieved significantly. Her visual analog score (VAS: using a 0-10 score) decreased from 7 to 2, and after 50 treatment sessions her symptoms disappeared almost completely. A significant improvement was also observed radiologically by computed tomography (CT) and magnetic resonance imaging (MRI) examinations. This case study provides a potential HBO2 treatment protocol with reduced pressure for early-stage femoral head necrosis. Further research is needed to validate this finding and explore the potential mechanism of HBO2 on SAON.

Electroacupuncture combined with acarbose improves insulin sensitivity via peroxisome proliferator-activated receptor γ activation and produces a stronger glucose-lowering effect than acarbose alone in a rat model of steroid-induced insulin resistance.

BACKGROUND: Previous studies have reported that electroacupuncture (EA) induces a glucose-lowering effect by improving insulin resistance (IR) and reduces plasma free fatty acid (FFA) levels in rats with steroid-induced insulin resistance (SIIR). In addition, EA can activate cholinergic nerves and stimulate endogenous opioid peptides to lower plasma glucose in streptozotocin-induced hyperglycemic rats. The aim of this study was to investigate the glucose-lowering effects of 15 Hz EA at bilateral ST36 in combination with acarbose (ACA). We hypothesized that EA combined with ACA would produce a stronger glucose-lowering effect than ACA alone. METHODS: In this study, normal Wistar rats and SIIR rats were randomly divided into two groups: ACA and ACA + EA. To explore the potential mechanisms underlying the glucose-lowering effect, plasma FFA/insulin and insulin transduction signal pathway proteins were assayed. RESULTS: Combined ACA + EA treatment had a greater glucose-lowering effect than ACA alone in normal Wistar rats (-45% ± 3% vs -19% ± 3%, p < 0.001) and SIIR model rats (-43% ± 2% vs -16% ± 6%, p < 0.001). A significant reduction in plasma FFA levels, improvement in homeostatic model assessment of IR (HOMA-IR) index (-48.9% ± 4.0%, p < 0.001) and insulin sensitivity index (102% ± 16.9%, p < 0.001), and significant increases in insulin receptor substrate 1, glucose transporter 4, and peroxisome proliferator-activated receptor γ protein expressions in skeletal muscle, were also observed in the ACA + EA group of SIIR rats. CONCLUSION: Combined EA and ACA therapy had a greater glucose-lowering effect than ACA monotherapy; this combined therapy could be more effective at improving IR in SIIR rats, which may be related to a reduction in plasma FFA levels and an elevation of insulin signaling proteins. Whether this combined therapy has an effect in type 2 diabetes mellitus (T2DM) patients still needs to be explored.

Clinical evaluation of the safety and efficacy of a timosaponin A-III-based antiwrinkle agent against skin aging.

BACKGROUND: Timosaponin A-III (TA-III) is known to exist in the medicinal herb of Anemarrhena asphodeloides as one of major chemical components. AIMS: The photoprotective properties of TA-III on UVB-exposed HaCaT cells were evaluated on the antiwrinkle effects and skin safety in terms of clinical trial. METHODS: The level of matrix metalloproteinase (MMP)-1, tissue inhibitor of metalloproteinases (TIMPs), and pro-inflammatory cytokines were measured in HaCaT cells following UVB irradiation. To evaluate the clinical safety of an agent containing 0.25% of TA-III for use on human skin. Female subjects (n = 21) between the ages of 43 and 55 who met the criteria for subject selection were selected. They were beginning to form or had already formed wrinkles. RESULTS: UVB irradiation increased MMP-1 expression and pro-inflammatory cytokines. These increases were attenuated by TA-III pretreatment of UVB-exposed HaCaT cells. We found that the agent containing 0.25% of TA-III ameliorated skin wrinkling. A comparison between groups showed that wrinkle parameters were significantly reduced after 12 weeks of product use (P < 0.05). According to skin safety result, TA-III showed no dermatological toxicity was found in participants. CONCLUSIONS: In conclusion, TA-III could provide protection against photoaging and daily application of TA-III for 12 weeks significantly reduced signs of facial aging by limiting wrinkle formation.

Blood glucose levels in diabetic patients undergoing hyperbaric oxygen therapy.

INTRODUCTION: To determine if hyperbaric oxygen (HBO2) therapy has an effect on diabetic blood glucose levels (BGL) and, if so, the extent of this effect. Also, to examine factors that exacerbate any observed effect. METHODS: This was a retrospective review of prospectively collected quality data on diabetics undergoing HBO2. Pre- and post-treatment BGL were recorded. Pre-treatment BGL ⟨120 mg/dL received glucose supplementation. Hypoglycemia was defined as BGL ⟨70 mg/dL. BGL ⟨90 mg/dL was included as an elevated hypoglycemia threshold. RESULTS: 77 patients representing 1,825 treatments were included for analysis. No patient had deleterious side effects or required emergency care. BGL decreased in 75.4% of treatments in this group, with a median decrease of 25 mg/dL (IQR=54 mg/dL; range of decreased 374 mg/dL to increased 240 mg/dL). A statistically significant greater percentage of treatments of patients with type 2 diabetes resulted in a decrease in BGL (1598 or 77.5%) compared to treatments of patients with type 1 diabetes (169 or 51.5%) (χ2(1, N=1767) =55.37, p⟨0.001). 1.1% of treatments had post-HBO2 serum glucose ⟨90 mg/dL, and 0.2% of treatments had post-HBO2 serum glucose ⟨70 mg/dL. The majority (70%) of patients with post-HBO2 BGL ⟨90 mg/dL were maintained on insulin alone (χ2(2, N=20) =12.4, p=0.002). Well-controlled diabetics (i.e., those with all BGLs within 50 mg/dL over all pre-HBO2 treatments) had no post-HBO2 BGL ⟨70 mg/dL or ⟨90 mg/dL. CONCLUSION: Our results suggest that HBO2 does not cause a clinically significant decrease in diabetic patient BGL. No patient in our study had deleterious side effects or required emergency care. We found that glucose level of ⟨90 mg/dL occurred more often in those who use insulin. Hyperbaric patients who exhibit consistent BGL values may represent a group who could be managed similarly to the non-diabetic population.

Metabolism, pharmacokinetics, and hepatic disposition of xanthones and saponins on Zhimu treatments for exploratively interpreting the discrepancy between the herbal safety and timosaponin A3-induced hepatotoxicity.

Timosaponin A3, a saponin in Zhimu, elicited hepatotoxicity via oxidative stress. However, the clinical medication of Zhimu has been historically regarded as safe, probably associated with the antioxidants it contains. However, the related information on the in vivo levels of timosaponin A3 and antioxidants remained unclear on Zhimu treatments. Therefore, a combination of the in vitro metabolism, including microbiota-mediated and liver-mediated metabolism, and in vivo pharmacokinetics and hepatic disposition, was conducted for three xanthones (neomangiferin, mangiferin, and norathyriol) and three saponins (timosaponin B2, timosaponin B3, and timosaponin A3) on Zhimu treatments. Consequently, following oral administration of Zhimu decoction to rats, those saponins and xanthones were all observed in the plasma with severe liver first-pass effect, where mangiferin was of the maximum exposure. Despite the ignorable content in the herb, timosaponin A3 elicited sizable hepatic exposure as the microbiota-mediated metabolite of saponins in Zhimu. The similar phenomenon also occurred to norathyriol, the microbiota-mediated metabolite of xanthones. However, the major prototypes in Zhimu were of limited hepatic exposure. We deduced the hepatic collection of norathyriol, maximum circulating levels of mangiferin, and timosaponin B2 and mangiferin interaction may directly or indirectly contribute to the whole anti-oxidation of Zhimu, and then resisted the timosaponin A3-induced hepatotoxicity. Thus, our study exploratively interpreted the discrepancy between herbal safety and timosaponin A3-induced hepatotoxicity. However, given the considerable levels and slow eliminated rate of timosaponin A3 in the liver, more attention should be paid to the safety on the continuous clinical medication of Zhimu in the future.

Therapeutic effect of capsaicin nasal treatment in patients with mixed rhinitis unresponsive to intranasal steroids.

Literature is convincing regarding the efficacy of capsaicin nasal treatment in idiopathic rhinitis (IR). However, up to 50% of IR patients do not meet the strict inclusion criteria of the trials conducted so far. As a consequence, the efficacy of capsaicin is unknown in a significant number of IR patients that do not meet the strict inclusion/exclusion criteria (J Allergy Clin Immunol. 2014;133:1332, J Allergy Clin Immunol. 2017; [Epub ahead of print]). "Mixed rhinitis" (MR) patients have more than one major etiologic factor involved in the mucosal pathology. We have no idea about the efficacy of capsaicin nasal spray in these patients nor about the time interval to seek a second application. We report here that capsaicin nasal spray is effective in a broader group of IR than the purely selected ones described before, that subjective nasal hyper-reactivity is a good predictor of positive outcome, and that the time interval for seeking a second treatment is likely to be shorter in MR patients than in the strictly selected IR patients.

[Considerations on the treatment of IgA nephropathy on the basis of the results of the latest studies (STOP-IgAN, TESTING, NEFIGAN)]. / Terápiás megfontolások IgA-nephropathiában a legutolsó vizsgálatok (STOP-IgAN, TESTING, NEFIGAN) eredményei alapján.

IgA nephropathy is an immune-mediated chronic glomerulonephritis with a great variability in clinical presentation and outcome. The disease can progress to end-stage renal failure in 25% of patients. For this reason we should identify patients with potential to progress. Most important risk factors for progression are persistent proteinuria, hypertension, decreased renal function and some histological lesions. The actually suggested treatment is summarized in KDIGO Clinical Practice Guideline from 2012. They suggest to give firstly non-specific supportive treatment (especially renin-angiotensin system blocking agents). Recommendation about steroid/immunosuppression treatment is based on low level of evidence. Recently three studies were organised concerning benefits and risk of steroid/immunosuppressive treatment added together with specific supportive treatment. In the STOP-IgAN study, systemic steroid/immunosuppressive treatment significantly decreased proteinuria but did not stop progression. In the TESTING study, systemic steroid treatment significantly decreased proteinuria and progression. However, the study was recently discontinued due to several severe side effects of steroid treatment. Involvement of intestinal mucosal immunity in the pathogenesis of IgA nephropathy suggested the NEFIGAN study with budesonide treatment. Budesonide releases corticosteroid in distal small intestine and colon. Proteinuria was significantly decreased and renal function remained stabile. High number of withdrawals owing to adverse effects is a major concern implying a substantial systemic effect of budesonide. We need further information on the characteristics of patients who most likely benefit from steroid/immunosuppressive treatment given after or together with specific supportive treatment. Orv Hetil. 2017; 158(49): 1946-1952.

Safety investigation on total steroid saponins extracts from Dioscorea zingiberensis C.H. Wright: Sub-acute and chronic toxicity studies on dogs.

Sub-acute and chronic toxic effects of total steroidal saponins (TSSN) extracts from Dioscorea zingiberensis C.H. Wright on various internal organs and biochemical indicators have never been studied before and this study is the first of its kind to demonstrate sub-acute and chronic toxicities of TSSN on dogs. Administration of TSSN extracts at doses up to 3000 mg/Kg daily for 14 days, no biochemical and organ changes were observed on the experimental groups of dogs. Further, chronic toxicity study through oral administration of TSSN extracts at the gradual doses of 50, 250 and 500 mg/Kg for 90 days followed by a 2-week recovery assay revealed absence of significant architectural and morphological changes in internal organs which were confirmed through histopathological examination and merely no significant alteration in the biochemical indicators including hematologic and urine analysis and electrocardiogram compared to the control dogs. This toxicological evaluation came across with the finding that the herbal preparation can be considered as nontoxic and animals could tolerate the extracts at doses up to 500 mg/Kg with LD50 greater than 3000 mg/Kg. It may serve as a preliminary scientific evidence for further therapeutic investigations.

Steroids in traditional Chinese medicine: what is the evidence?

Local healthcare providers often question the possible steroidal activity of traditional Chinese medicine (TCM) herbs or herbal products and implicate them as a cause for adrenal insufficiency or Cushing's syndrome in patients with a history of TCM intake. We conducted a comprehensive database search for evidence of potential glucocorticoid, mineralocorticoid, androgenic or oestrogenic activity of herbs or herbal products. Overall, there are not many herbs whose steroidal activity is well established; among these, most cases were based on preclinical studies. Liquorice root may cause pseudoaldosteronism through interference with the steroidogenesis pathway. Although ginseng and cordyceps have some in vitro glucocorticoid activities, the corroborating clinical data is lacking. Deer musk and deer antler contain androgenic steroids, while epimedium has oestrogenic activity. On the other hand, adulteration of herbal products with exogenous glucocorticoids is a recurrent problem encountered locally in illegal products masquerading as TCM. Healthcare providers should stay vigilant and report any suspicion to the relevant authorities for further investigations.

Pharmacologic Impact (aka "Breaking Bad") of Medications on Wound Healing and Wound Development: A Literature-based Overview.

Patients with wounds often are provided pharmacologic interventions for their wounds as well as for their acute or chronic illnesses. Drugs can promote wound healing or substantively hinder it; some medications cause wound or skin reactions. A comprehensive review of extant literature was conducted to examine the impact of drug therapy on wound healing and skin health. MEDLINE and the Cumulative Index to Nursing and Allied Health Literature (CINAHL) were searched for English-language articles published between 2000 and 2016 using the terms drugs, medications, drug skin eruptions, adverse skin reactions, wound healing, delayed wound healing, nonhealing wound, herbals, and herbal supplements. The search yielded 140 articles (CINAHL) and 240 articles (MEDLINE) for medications and wound healing. For medications and adverse skin effects, the search identified 256 articles (CINAHL) and 259 articles (MEDLINE). The articles included mostly narrative reviews, some clinical trials, and animal studies. Notable findings were synthesized in a table per pharmacological class and/or agent focusing on wound healing impact and drug-induced adverse skin reactions. The medications most likely to impair wound healing and damage skin integrity include antibiotics, anticonvulsants, angiogenesis inhibitors, steroids, and nonsteroidal anti-inflammatory drugs. Conversely, drugs such as ferrous sulfate, insulin, thyroid hormones, and vitamins may facilitate wound healing. Selected clinical practices, including obtaining a detailed medication history that encompasses herbal supplements use; assessing nutrition status especially protein blood levels affecting drug protein binding; and scrutinizing patient history and physical characteristics for risk factors (eg, atopy history) can help diminish and/or eliminate adverse integumentary outcomes. "Deprescribing" (discontinuing unnecessary medications) should be utilized when possible. Contemporary wound care clinicians must be cognizant of these mitigating clinical approaches.

Treatment of steroid-induced osteonecrosis of the femoral head using porous Se@SiO2 nanocomposites to suppress reactive oxygen species.

Reducing oxidative stress (ROS) have been demonstrated effective for steroid-induced osteonecrosis of the femoral head (steroid-induced ONFH). Selenium (Se) plays an important role in suppressing oxidative stress and has huge potential in ONFH treatments. However the Se has a narrow margin between beneficial and toxic effects which make it hard for therapy use in vivo. In order to make the deficiency up, a control release of Se (Se@SiO2) were realized by nanotechnology modification. Porous Se@SiO2 nanocomposites have favorable biocompatibility and can reduced the ROS damage effectively. In vitro, the cck-8 analysis, terminal dexynucleotidyl transferase (TdT)-mediated dUTP nick end labeling (TUNEL) stain and flow cytometry analysis showed rare negative influence by porous Se@SiO2 nanocomposites but significantly protective effect against H2O2 by reducing ROS level (detected by DCFH-DA). In vivo, the biosafety of porous Se@SiO2 nanocomposites were confirmed by the serum biochemistry, the ROS level in serum were significantly reduced and the curative effect were confirmed by Micro CT scan, serum Elisa assay (inflammatory factors), Western blotting (quantitative measurement of ONFH) and HE staining. It is expected that the porous Se@SiO2 nanocomposites may prevent steroid-induced ONFH by reducing oxidative stress.