Outcomes of Vasopressin-Receptor Agonists Versus Norepinephrine in Adults With Perioperative Hypotension: A Systematic Review.

Consensus statements recommend the use of norepinephrine and/or vasopressin for hypotension in cardiac surgery. However, there is a paucity of data among other surgical subgroups and vasopressin analogs. Therefore, the authors conducted a systematic review of randomized controlled trials (RCTs) to compare vasopressin-receptor agonists with norepinephrine for hypotension among those undergoing surgery with general anesthesia. This review was registered prospectively (CRD42022316328). Literature searches were conducted by a medical librarian to November 28, 2023, across MEDLINE, EMBASE, CENTRAL, and Web of Science. The authors included RCTs enrolling adults (≥18 years of age) undergoing any surgery under general anesthesia who developed perioperative hypotension and comparing vasopressin receptor agonists with norepinephrine. The risk of bias was assessed by the Cochrane risk of bias tool for randomized trials (RoB-2). Thirteen (N = 719) RCTs were included, of which 8 (n = 585) enrolled patients undergoing cardiac surgery. Five trials compared norepinephrine with vasopressin, 4 trials with terlipressin, 1 trial with ornipressin, and the other 3 trials used vasopressin as adjuvant therapy. There was no significant difference in all-cause mortality. Among patients with vasoplegic shock after cardiac surgery, vasopressin was associated with significantly lower intensive care unit (N = 385; 2 trials; mean 100.8 v 175.2 hours, p < 0.005; median 120 [IQR 96-168] v 144 [96-216] hours, p = 0.007) and hospital lengths of stay, as well as fewer cases of acute kidney injury and atrial fibrillation compared with norepinephrine. One trial also found that terlipressin was associated with a significantly lower incidence of acute kidney injury versus norepinephrine overall. Vasopressin and norepinephrine restored mean arterial blood pressure with no significant differences; however, the use of vasopressin with norepinephrine was associated with significantly higher mean arterial blood pressure versus norepinephrine alone. Further high-quality trials are needed to determine pooled treatment effects, especially among noncardiac surgical patients and those treated with vasopressin analogs.

High-risk adverse drug reactions: consideration of limited dialysis therapy for toxic epidermal necrolysis (TEN).

Toxic epidermal necrolysis (TEN) is a rare but often lethal drug reaction involving the skin. Treatment is often centered around suppurative care, and the mortality rate remains unacceptably high, although the clinical and epidemiological features of TEN have been well documented for decades. Recent studies have placed an emphasis on certain medications in the pathophysiology of severe TEN, and our colleagues previously reported several cases of clinical improvement in TEN patients following hemodialysis. Here, we discuss the major considerations for initiating dialysis in TEN patients. By doing so, we hope to encourage others to explore this potential avenue for treating TEN, one of the most serious medical emergencies in the field of dermatology.

Impact of Professional Society Guideline Publications in Medicine Subspecialties From 2012 to 2022: Implications for Clinical Care and Health Policy.

Clinical guidelines have become an integral part of clinical care. We assessed professional society-based clinical guidelines from 2012 to 2022 to elucidate the trends in numbers of documents, recommendations, and classes of recommendations. Our results found that 40% of the guidelines do not follow all recommendations made by the Institute of Medicine for trustworthy documents. There has been a significant increase in documents in cardiology, gastroenterology, and hematology/oncology. In addition, of more than 20,000 recommendations, there was significant variability in recommendations made by different professional societies within a specialty. In documents from 11 of the 14 professional societies, more than 50% of the recommendations are supported with the lowest levels of evidence. In cardiology, in addition to the guideline documents, 140 nonguideline documents provide 1812 recommendations using the guideline verbiage, and 74% of the recommendations are supported by the lowest level of evidence. These data have important implications for health care because guidelines and guideline-like documents can be used for health policy issues such as assessment of quality of care, medical liability, education, and payment.

Total glycosides contribute to the anti-diarrheal effects of Qiwei Baizhu Powder via regulating gut microbiota and bile acids.

Qiwei Baizhu Powder (QWBZP) is a traditional Chinese medicine formula for treating diarrhea induced by various causes. It elicits an anti-diarrheal effect by regulating the gut microbiota (diversity, structure, and abundance). However, the contribution of different components in the QWBZP decoction to this effect remains unclear. In this study, we used the QWBZP decoction as a reference standard to investigate the effects of total glycosides (TGs) extracted from QWBZP decoction on the gut microbiota and bile acid metabolism in mice with antibiotic-associated diarrhea (AAD). The results of 16S rRNA gene sequencing and liquid chromatography-mass spectrometry (LC-MS) analysis showed that the effect of total glycosides of Qiwei Baizhu Powder (QWBZP-TG) on specific intestinal bacteria and bile acids was similar to that of the QWBZP decoction, but the intensity of this effect was more significant in the case of QWBZP-TG. The QWBZP decoction and QWBZP-TG promoted the proliferation of Lactobacillus and inhibited the growth of Proteus, Clostridium, Eubacterium, Facklamia, and Escherichia in AAD mice. They also increased the levels of deoxycholic acid and beta-muricholic acid and decreased those of taurocholate acid, tauro-alpha-muricholic acid, and tauro-beta-muricholic acid in AAD mice. Lactobacillus was the key bacterial genus responding to QWBZP-TG. Thus, this study provides novel insights into the bioactive components of QWBZP and their contribution to its effects.

Soybean isoflavones modulate gut microbiota to benefit the health weight and metabolism.

Soybean isoflavones (SIs) are widely found in food and herbal medicines. Although the pharmacological activities of SIs have been widely reported, their effects on the intestinal microecology of normal hosts have received little attention. Five-week-old Kunming (KM) mice were administered SIs (10 mg/kg/day) for 15 days. Food intake, body weight, and digestive enzyme activity were measured. Small intestine microbiota, including lumen-associated bacteria (LAB) and mucosa-associated bacteria (MAB), were analyzed using 16S ribosomal ribonucleic acid (16S rRNA) gene sequencing. Short-chain fatty acids (SCFAs) were analyzed using gas chromatography-mass spectrometry (GC-MS). The results showed that the mice that consuming SIs showed a higher food intake but a lower body weight gain rate than that of normal mice. Sucrase, cellulase, and amylase activities reduced, while protease activity increased after SIs intervention. Moreover, SIs increased the intestinal bacterial diversity in both LAB and MAB of normal mice. The composition of LAB was more sensitive to SIs than those of MAB. Lactobacillus, Adlercreutzia, Coprococcus, Ruminococcus, Butyricicoccus, and Desulfovibrio were the differential bacteria among the LAB of mice treated with SIs. In addition, acetic acid, valeric acid, isobutyric acid, isovaleric acid, and caproic acid decreased, while butyric acid and propionic acid increased in the mice treated with SIs. Taken together, SIs are beneficial for weight control, even in short-term interventions. The specific mechanism is related to regulating the gut microbiota, changing digestive enzyme activities, and further affecting carbohydrate absorption and metabolism.

In Vitro Biotransformation of Total Glycosides in Qiwei Baizhu Powder by the Gut Microbiota of Normal and Diarrheal Mice: Novel Insight Into the Biotransformation of Multi-Glycosides by the Gut Microbiota.

The gut microbiota (GM) is involved in the metabolism of glycosides and is beneficial for enhancing their bioactivity. However, the metabolism of multi-glycosides by the GM under normal and pathological conditions is unclear. In this study, the total glycosides (TG) of the traditional Chinese medicine (TCM) formula Qiwei Baizhu Powder (QWBZP) were extracted to represent a multi-glycoside system. Ultra-high-performance liquid chromatography quadrupole time-of-flight tandem mass spectrometry (UHPLC-Q-TOF-MS/MS) was used to rapidly identify the components and in vitro metabolites of QWBZP-TG. The metabolic profiles of QWBZP-TG in the GM of normal and diarrheal mice were also compared. A total of 68 compounds and seven metabolites were identified in the QWBZP-TG and metabolic samples, respectively. Deglycosylation was the main metabolic pathway of in vitro multi-glycoside metabolism. Liquiritin apioside, isoliquiritin apioside, liquiritin, protopanaxadiol (PPD)-type, and oleanane (OLE)-type ginsenosides were relatively easy to metabolize by the GM. At first, the deglycosylation capability of the GM of normal mice was superior to that of diarrheal mice, but the deglycosylation capability of diarrheal mice gradually recovered and produced abundant deglycosylation metabolites. In conclusion, deglycosylation metabolites may be the bioactive components of QWBZP. Glycoside-bacteria interaction may be a key mechanism for QWBZP to therapy diarrhea.

A Novel Estrogen Receptor ß Agonist Diminishes Ovarian Cancer Stem Cells via Suppressing the Epithelial-to-Mesenchymal Transition.

Epithelial ovarian cancer is the most lethal malignancy of the female reproductive tract. A healthy ovary expresses both Estrogen Receptor α (ERα) and ß (ERß). Given that ERα is generally considered to promote cell survival and proliferation, thereby, enhancing tumor growth, while ERß shows a protective effect against the development and progression of tumors, the activation of ERß by its agonists could be therapeutically beneficial for ovarian cancer. Here, we demonstrate that the activation of ERß using a newly developed ERß agonist, OSU-ERb-12, can impede ovarian cancer cell expansion and tumor growth in an ERα-independent manner. More interestingly, we found that OSU-ERb-12 also reduces the cancer stem cell (CSC) population in ovarian cancer by compromising non-CSC-to-CSC conversion. Mechanistically, we revealed that OSU-ERb-12 decreased the expression of Snail, a master regulator of the epithelial-to-mesenchymal transition (EMT), which is associated with de novo CSC generation. Given that ERα can mediate EMT and facilitate maintenance of the CSC subpopulation and that OSU-ERb-12 can block the transactivity of ERα, we conclude that OSU-ERb-12 reduces the CSC subpopulation by inhibiting EMT in an ERα-dependent manner. Taken together, our data indicate that the ERß agonist OSU-ERb-12 could be used to hinder tumor progression and limit the CSC subpopulation with the potential to prevent tumor relapse and metastasis in patients with ovarian cancer.

Effect of Debaryomyces hansenii combined with Qiweibaizhu powder extract on the gut microbiota of antibiotic-treated mice with diarrhea.

The aim of this study was to investigate the effects of an extract of Qiweibaizhu powder combined with Debaryomyces hansenii on the gut microbiota of antibiotic-treated mice with diarrhea. Mice were gavaged with a mixture of gentamycin sulfate and cefradine to induce diarrhea. After diarrhea was observed, 25% dose of ultra-micro Qiweibaizhu powder extract combined with 25% dose of Debaryomyces hansenii (QCD) was gavaged to mice with diarrhea. DNA of intestinal contents in mice was extracted for 16S rRNA gene sequence analysis by high-throughput sequencing following treatment finished. The results showed that the QCD increased the species richness and diversity, but did not recover the diversity to the original level. Antibiotics and QCD significantly altered the composition of gut microbiota at different taxonomic levels. At the genus level, the relative abundance of Bacteroidales S24-7 group_unidentified and Bacteroides returned to baseline after QCD treatment. Additionally, QCD suppressed the growth of Oscillospira and Ruminococcus, and promoted the proliferation of Erysipelotrichaceae_norank and Blautia compared with the healthy and diarrheal mice. Our results indicated that QCD modulated the diversity and composition of the gut microbiota in antibiotic-treated mice with diarrhea. The synergistic effect between Qiweibaizhu powder extract and Debaryomyces hansenii may be related to Bifidobacterium and Bacteroidales S24-7 group_unidentified.

ALDH1A1 Contributes to PARP Inhibitor Resistance via Enhancing DNA Repair in BRCA2-/- Ovarian Cancer Cells.

Poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) are approved to treat recurrent ovarian cancer with BRCA1 or BRCA2 mutations, and as maintenance therapy for recurrent platinum-sensitive ovarian cancer (BRCA wild-type or mutated) after treatment with platinum. However, the acquired resistance against PARPi remains a clinical hurdle. Here, we demonstrated that PARP inhibitor (olaparib)-resistant epithelial ovarian cancer (EOC) cells exhibited an elevated aldehyde dehydrogenase (ALDH) activity, mainly contributed by increased expression of ALDH1A1 due to olaparib-induced expression of BRD4, a member of bromodomain and extraterminal (BET) family protein. We also revealed that ALDH1A1 enhanced microhomology-mediated end joining (MMEJ) activity in EOC cells with inactivated BRCA2, a key protein that promotes homologous recombination (HR) by using an intrachromosomal MMEJ reporter. Moreover, NCT-501, an ALDH1A1-selective inhibitor, can synergize with olaparib in killing EOC cells carrying BRCA2 mutation in both in vitro cell culture and the in vivo xenograft animal model. Given that MMEJ activity has been reported to be responsible for PARPi resistance in HR-deficient cells, we conclude that ALDH1A1 contributes to the resistance to PARP inhibitors via enhancing MMEJ in BRCA2-/- ovarian cancer cells. Our findings provide a novel mechanism underlying PARPi resistance in BRCA2-mutated EOC cells and suggest that inhibition of ALDH1A1 could be exploited for preventing and overcoming PARPi resistance in EOC patients carrying BRCA2 mutation.

Influence of Debaryomyces hansenii on bacterial lactase gene diversity in intestinal mucosa of mice with antibiotic-associated diarrhea.

AIM: The current study aimed to investigate the effects of Debaryomyces hansenii on the diversity of bacterial lactase gene in the intestinal mucosa of antibiotic-associated diarrhea (AAD) mice. METHODS: Eighteen mice were randomly divided into three groups (6 mice per group): healthy control group, diarrhea model group and D. hansenii treatment group. The antibiotic-associated diarrhea model was established by intragastric administration with a mixture of cephradine and gentamicin sulfate (23.33 mL·kg-1·d-1) twice a day for 5 days continuously. After establishing the AAD model, the mice in the D. hansenii treatment group were gavaged with D. hansenii for three days, while other groups were gavaged with distilled water. Then, the intestinal mucosa of all three groups was collected and DNA was extracted in an aseptic environment for the following analysis. RESULTS: The difference in the richness and homogeneity of the bacterial lactase gene among all samples were inapparent, as the difference in the Chao1, ACE, Simpson and Shannon indices among the three groups were insignificant (P>0.05). NMDS analysis also showed that the distance of the samples among the three groups was unobvious. Furthermore, the bacterial lactase gene in the mucosa mainly originated from Actinobacteria, Firmicutes and Proteobacteria. Compared with the healthy control group, the abundance of lactase genes originating from Cupriavidus, Lysobacter, Citrobacter, Enterobacter and Pseudomonas was increased in the D. hansenii treatment group, while the lactase gene from Acidovorax and Stenotrophomonas decreased (p < 0.01 or p < 0.05) in the diarrhea model group and the D. hansenii treatment group. CONCLUSION: D. hansenii was capable of improving the growth of some key lactase-producing bacteria like Deinococcus, Cupriavidus and Lysobacter for treating AAD.

Bacterial diversity in intestinal mucosa of antibiotic-associated diarrhea mice.

To probe into the mechanism of antibiotic-associated diarrhea (AAD), the bacterial diversity and composition in the intestinal mucosa of AAD mice were investigated. Twelve specific pathogen-free Kunming mice were divided into control group and model group. The mouse model of AAD was established by gavaging with antibiotics (mixture of gentamycin sulfate and cefradine) at a total dose of 23.33 ml kg-1 day-1 for 5 days continuously, twice a day. The mice in the control group were given with an equal amount of sterile water. Then, the intestinal mucosa DNA was extracted for 16S rRNA gene sequence analysis by high-throughput sequencing. The results showed that the alpha diversity of the two groups did not differ significantly from each other, while the composition of intestinal mucosa bacteria differed dramatically between the two groups. The model group showed a higher abundance of Proteobacteria and Actinobacteria. More importantly, Lactobacillus was significantly less abundant (p = 0.000), while Enterococcus was significantly more abundant (p = 0.019) in the model group than in the control group. Furthermore, antibiotic treatment increased the abundance of Citrobacter, Stenotrophomonas, and Glutamicibacter,whereas antibiotics decreased the abundance of Mycoplasma and Helicobacter. In addition, 6 and 11 unique genera were found in the control group and model group, respectively. The combination of gentamycin sulfate and cefradine changed the intestinal mucosa bacterial composition, reduced colonization resistance and damaged the intestinal mucosal barrier by reducing the abundance of Lactobacillus.

Inhibition of miR-328-3p Impairs Cancer Stem Cell Function and Prevents Metastasis in Ovarian Cancer.

Cancer stem cells (CSC) play a central role in cancer metastasis and development of drug resistance. miRNA are important in regulating CSC properties and are considered potential therapeutic targets. Here we report that miR-328-3p (miR-328) is significantly upregulated in ovarian CSC. High expression of miR-328 maintained CSC properties by directly targeting DNA damage binding protein 2, which has been shown previously to inhibit ovarian CSC. Reduced activity of ERK signaling in ovarian CSC, mainly due to a low level of reactive oxygen species, contributed to the enhanced expression of miR-328 and maintenance of CSC. Inhibition of miR-328 in mouse orthotopic ovarian xenografts impeded tumor growth and prevented tumor metastasis. In summary, our findings provide a novel mechanism underlying maintenance of the CSC population in ovarian cancer and suggest that targeted inhibition of miR-328 could be exploited for the eradication of CSC and aversion of tumor metastasis in ovarian cancer. SIGNIFICANCE: These findings present inhibition of miR-328 as a novel strategy for efficient elimination of CSC to prevent tumor metastasis and recurrence in patients with epithelial ovarian cancer.

DDB2 increases radioresistance of NSCLC cells by enhancing DNA damage responses.

Radiotherapy resistance is one of the major factors limiting the efficacy of radiotherapy in lung cancer patients. The extensive investigations indicate the diversity in the mechanisms underlying radioresistance. Here, we revealed that DNA damage binding protein 2 (DDB2) is a potential regulator in the radiosensitivity of non-small cell lung cancer (NSCLC) cells. DDB2, originally identified as a DNA damage recognition factor in the nucleotide excision repair, promotes the survival and inhibits the apoptosis of NSCLC cell lines upon ionizing radiation (IR). Mechanistic investigations demonstrated that DDB2 is able to facilitate IR-induced phosphorylation of Chk1, which plays a critical role in the cell cycle arrest and DNA repair in response to IR-induced DNA double-strand breaks (DSBs). Indeed, knockdown of DDB2 compromised the G2 arrest in the p53-proficient A549 cell line and reduced the efficiency of homologous recombination (HR) repair. Taken together, our data indicate that the expression of DDB2 in NSCLC could be used as a biomarker to predict radiosensitivity of the patients. Targeting Chk1 can be used to increase the efficacy of radiotherapy in patients of NSCLC possessing high levels of DDB2.

Purification and characterization of a novel ribosome-inactivating protein from seeds of Trichosanthes kirilowii Maxim.

A novel ribosome-inactivating protein, designated Trichosanthrip, was purified from mature seeds of Trichosanthes kirilowii Maxim by cation-exchange and gel-filtration chromatography. Trichosanthrip migrated as a single band in SDS-PAGE, with an apparent molecular mass of approximately 13kDa. The molecular mass of Trichosanthrip was 10,964.617Da as determined by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Trichosanthrip showed N-glycosidase activity on 28 S rRNA and strongly inhibited cell-free protein synthesis, with an IC(50) of 1.6ng/ml. Liquid chromatography-tandem mass spectrometry showed that Trichosanthrip was a novel protein with similar sequence to other proteins present in members of the Cucurbitaceae.