Network Pharmacology and Molecular Docking Validation to Explore the Pharmacological Mechanism of Zhuling Decoction against Nephrotic Syndrome.

BACKGROUND: In recent years, the incidence and prevalence of Nephrotic Syndrome (NS) have been increasing. Zhuling decoction (ZLD), a classical Chinese medicine, has been clinically proven to be effective for the treatment of NS. However, its underlying mechanism and pharmacodynamic substances remain unclear. OBJECTIVE: This study aimed to explore the mechanism of action and chemical components of ZLD against NS using network pharmacology and molecular docking. METHODS: Traditional Chinese Medicine Systems Pharmacology (TCMSP), Bioinformatics Analysis Tool for Molecular Mechanism of Traditional Chinese Medicines (BATMAN-TCM), and SwissTargetPrediction databases were used to screen the principal ingredients and the associated targets of ZLD. NS-related targets were obtained from the Online Mendelian Inheritance in Man (OMIM), GeneCards, Therapeutic Target Database (TTD), and Drugbank databases. Shared targets were derived by the intersection of ZLD- and NS-associated targets. Protein-interaction relationships were analyzed using the STRING database and Cytoscape. A visualized drug-active compound-target network of ZLD was established using Cytoscape. Analyses of gene enrichment were performed using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) methods by the Database for Annotation, Visualization, and Integrated Discovery (DAVID) database. Molecular docking was performed to assess the binding activity between active components and hub targets. RESULTS: Polyporusterone E, cerevisterol, alisol B, and alisol B 23-acetate were the primary potential ingredients of ZLD. HMGCR, HSD11B1, NOS2, NR3C1, and NR3C2 were the hub targets of ZLD against NS. Molecular docking showed that polyporusterone E, cerevisterol, and alisol B had high binding activities with targets HMGCR, HSD11B1, and NOS2. CONCLUSION: In summary, this study suggests that the main active compounds (polyporusterone E, cerevisterol, alisol B) may have important roles for ZLD acting against NS by binding to hub targets (HMGCR, HSD11B1, and NOS2) and modulating PI3K-Akt, Ras, MAPK, and HIF-1 signaling pathways.

Case Report: Respiratory paralysis associated with polymyxin B therapy.

Polymyxin B (PMB) and colistin are bactericidal polypeptide antibiotics discovered in 1947 and 1949 for the treatment of gram-negative bacterial infections. Polymyxin was used clinically in the 1950s, but it was gradually replaced by other antibiotics in the 1980s because of its high nephrotoxicity and neurotoxicity. In recent years, the increase of multidrug-resistant negative bacteria has led to the resurgence of polymyxin use. However, its side effects are not clear. Respiratory paralysis caused by PMB-related neuromuscular blockade is a rare but potentially fatal effect. We report a case of respiratory paralysis probably caused by polymyxin B infusion.

Risk factors for acute kidney injury after major abdominal surgery in the elderly aged 75 years and above.

OBJECTIVES: The study aimed to investigate the incidence and risk factors of acute kidney injury (AKI) in elderly patients (aged ≥ 75 years) undergoing major nonvascular abdominal surgery. METHODS: The study was a retrospective study that evaluated the incidence of AKI in patients within 48 h after major abdominal surgeries. Patients' preoperative characteristics and intraoperative management, including the use of nephrotoxic medications, were evaluated for associations with AKI using a logistic regression model. RESULTS: A total of 573 patients were included in our analysis. A total of 33 patients (5.76%) developed AKI, and 30 (90.91%), 2 (6.06%) and 1 (3.03%) reached the AKI stages 1, 2 and 3, respectively. Older age (adjusted OR, aOR 1.112, 95% confidence interval, CI 1.020-1.212), serum albumin (aOR 0.900, 95% CI 0.829-0.977), baseline eGFR (aOR 3.401, 95% CI 1.479-7.820), the intraoperative occurrence of hypotension (aOR 3.509, 95% CI 1.553-7.929), and the use of hydroxyethyl starch in combination with nonsteroidal anti-inflammatory drugs (aOR 3.596, 95% CI 1.559-8.292) or furosemide (aOR 5.724, 95% CI 1.476-22.199) were independent risk factors for postoperative AKI. CONCLUSIONS: Several risk factors, including intraoperative combined administration of HES and furosemide, are independent factors for AKI during abdominal surgeries. Anesthesiologists and surgeons should take precautions in treating at-risk patients.

Interaction Between Chinese Medicine and Warfarin: Clinical and Research Update.

Background: Warfarin is a commonly used oral anticoagulant. It has a narrow therapeutic window and wide variation in individualized dosing, and is used clinically for the treatment of thromboembolic diseases. Due to the widespread use of traditional Chinese medicine (TCM) in China and the complex composition and diverse mechanisms of action of TCM, the combination of TCM and warfarin in patients has led to fluctuations in the international normalized ratio of warfarin or bleeding. To ensure rational clinical use, we summarize the TCMs with which warfarin interacts and the possible mechanisms, with a view to providing a clinical reference. Aim of the study: To summarize the mechanisms by which Chinese herbal medicines affect the enhancement or weakening of the anticoagulant effect of warfarin, to provide theoretical references for clinicians and pharmacists to use warfarin safely and rationally, and to avoid the adverse effects associated with the combination of Chinese herbal medicines and warfarin. Methods: A computerized literature search of electronic databases, including PubMed, MEDLINE, Cochrane Library, Web of Science (WOS), China National Knowledge Infrastructure (CNKI) and WANFANG Data was performed. Key words used in the literature search were "warfarin", "Chinese medicine", "traditional Chinese medicine", "Chinese patent medicine" etc. and their combinations in a time limit from January 1, 1990 to May 1, 2021. A total of 64 articles were obtained following the selection process, including clinical reports, pharmacological experiments and in vitro experiments which were reviewed to determine the mechanism of the anticoagulant effect of herbal medicine on warfarin. Results: The mechanisms affecting the anticoagulant effect of warfarin are complex, and herbal medicines may enhance and diminish the anticoagulant effect of warfarin through a variety of mechanisms; thus, clinical use needs to be cautious. Some herbal medicines have shown inconsistent results in both in vivo and ex vivo experiments, pharmacology and clinical studies, and should be the focus of future research. Conclusion: With the widespread use of TCM, the combination of warfarin and TCM is more common. This article will promote clinicians' knowledge and understanding of the TCMs which interact with warfarin, in order to avoid the occurrence of adverse clinical treatment processes, and improve the efficacy and safety.

Association of preoperative medication with postoperative length of stay in elderly patients undergoing hip fracture surgery.

BACKGROUND: For elderly patients who are about to undergo surgery, research on the effects of preoperative medication on postoperative outcomes is rare, especially preoperative discontinuation-requiring medication (PDRM) which needed to be discontinued because of its increased risk of postoperative complications. AIM: To investigate whether preoperative medication (PDRM and polypharmacy) is associated with postoperative length of hospital stay (LOS) in elderly patients undergoing hip fracture surgery. METHODS: Patients aged ≥ 65 who were scheduled for hip (limited to femoral tuberosity) fracture surgery were included. Baseline characteristics, preoperative medication and postoperative LOS were collected from the electronic medical record. The primary outcome was postoperative LOS. RESULTS: A total of 369 hip fracture patients were included. There were 188 and 122 patients exposed to PDRM and polypharmacy, respectively. Multivariate analysis models were constructed using significant factors for prolonged postoperative hospital stay from univariate analysis: Model I (body mass index (BMI), Charlson comorbidity index (CCI) ≥ 7, creatinine clearance rate (Ccr) < 60 and PDRM) and Model II (BMI, Ccr ≥ 7, Ccr < 60 and polypharmacy). CCI was the most significant factor. Its adjusted odds ratio was as large as 2.7 and attributable risk was 63%. In preoperative medication use, both polypharmacy and PDRM showed significant association with postoperative LOS. CONCLUSION: The present study supported the impact of PDRM on postoperative LOS in geriatric hip fracture patients. The results added a further aspect to preoperative medication optimization in elderly patients undergoing hip fracture surgery.

An elderly female with adult-onset Still's disease initially misdiagnosed as prosthetic joint infection after total knee arthroplasty: lessons in differential diagnosis and treatment.

BACKGROUND: High fever, knee swelling and pain after knee arthroplasty are often considered as symptoms of acute prosthetic joint infection. However, similar symptoms can also present as primary manifestations of adult-onset Still's disease, which creates some interference in differential diagnosis. To our knowledge, this is the first published case of misdiagnosis of adult Still's disease after total knee arthroplasty, who was initially misdiagnosed as an prosthetic joint infection due to the above-mentioned symptoms. The symptoms of the knee infection was not relieve after several revisions and continous antibiotic treatment. Finally, after several consultations and repeated evaluation it was diagnosed as adult-onset Still's disease. CASE PRESENTATION: A 77-year-old female who underwent bilateral total knee arthroplasty 6 years ago was admitted to our hospital with high fever, right knee effusion and painful knee. Based on the results of joint fluid aspiration and culture, we treated the right knee as acute hematogenous prosthetic joint infection. After three debridement and revision surgeries, the patient's symptoms continued to persist. Subsequent manifestations of other symptoms such as typical rash and sore throat and laboratory examination suggested the possibility of adult-onset Still's disease. So she underwent diagnostic steroid hormone therapy at the recommendation of a rheumatologist, and a final revision was performed after symptom was controlled. At the one-year follow-up, the patient's symptoms completely resolved and the knee revision was functioning well. CONCLUSIONS: When joint swelling and pain occurs after knee arthroplasty, the possibility of joint infection should not only be considered, but rheumatic autoimmune diseases should also be differentiated. Because the manifestations of joint infection and rheumatic immune disease sometimes overlap highly, when reasonable treatment over a period of time fails to relieve symptoms and signs, we should notice subtle differences in symptoms and laborotary tests and look for other diagnostic possibilities in time.

Chinese Patent Medicines in the Treatment of Coronavirus Disease 2019 (COVID-19) in China.

BACKGROUND: Coronavirus Disease 2019 (COVID-19) is an emerging and rapidly evolving disease, with no recommended effective anti-coronavirus drug treatment. Traditional Chinese Patent Medicines (CPMs) have, however, been widely used to treat COVID-19 in China, and a number of clinical practice results have shown them to have a significant role in its treatment. Consequently, numerous guidelines and expert consensus have recommended the use of CPMs to treat COVID-19. AIM OF THE STUDY: The objectives of this review are to provide up-to-date information on the pharmacology and clinical research on CPMs in the treatment of COVID-19, discuss the research findings, and to better guide clinical application and scientific research on CPMs in the treatment of COVID-19. METHODS: The frequencies of CPM recommendations by guidelines and expert consensus for treatment of COVID-19 in China were ranked. This report identifies the top 10 CPMs, which include Huoxiang Zhengqi capsule (HXZQC), Lianhua Qingwen capsule (LHQWC), Jinhua Qinggan granule (JHQGG), Shufeng Jiedu capsule (SFJDC), Tanreqing injection (TRQI), Xiyanping injection (XYPI), Xuebijing injection (XBJI), Shenfu injection (SFI), Shengmai injection (SMI), and Angong Niuhuang pill (AGNHP). Relevant studies from 2000 to 2020 on these top 10 CPMs, covering usage, dosage, mechanism, curative effect, and precautions, were collected from pharmacopoeia, reports, and theses via library and digital databases (including PubMed, CNKI, Google Scholar, Web of Science, and Elsevier). RESULTS: The properties of the top 10 CPMs included antiviral, antibacterial, anti-inflammatory, antipyretic and analgesic, anti-acute lung injury, anti-shock, immune regulation, and enhancement of pulmonary function. In addition, clinical research results and Chinese treatment data showed that the CPMs had good therapeutic efficacy in the treatment of COVID-19, and adverse reactions were minimal. CONCLUSIONS: Knowledge of the characteristics of the top 10 CPMs and precautions that should be taken may help clinicians to rationally improve therapeutic efficacy, and promote the role of Chinese Medicine in the control of the COVID-19 global epidemic.

Recommendation of Antimicrobial Dosing Optimization During Continuous Renal Replacement Therapy.

Continuous Renal Replacement Therapy (CRRT) is more and more widely used in patients for various indications recent years. It is still intricate for clinicians to decide a suitable empiric antimicrobial dosing for patients receiving CRRT. Inappropriate doses of antimicrobial agents may lead to treatment failure or drug resistance of pathogens. CRRT factors, patient individual conditions and drug pharmacokinetics/pharmacodynamics are the main elements effecting the antimicrobial dosing adjustment. With the development of CRRT techniques, some antimicrobial dosing recommendations in earlier studies were no longer appropriate for clinical use now. Here, we reviewed the literatures involving in new progresses of antimicrobial dosages, and complied the updated empirical dosing strategies based on CRRT modalities and effluent flow rates. The following antimicrobial agents were included for review: flucloxacillin, piperacillin/tazobactam, ceftriaxone, ceftazidime/avibactam, cefepime, ceftolozane/tazobactam, sulbactam, meropenem, imipenem, panipenem, biapenem, ertapenem, doripenem, amikacin, ciprofloxacin, levofloxacin, moxifloxacin, clindamycin, azithromycin, tigecycline, polymyxin B, colistin, vancomycin, teicoplanin, linezolid, daptomycin, sulfamethoxazole/trimethoprim, fluconazole, voriconazole, posaconzole, caspofungin, micafungin, amphotericin B, acyclovir, ganciclovir, oseltamivir, and peramivir.

Ginsenoside Rg1 attenuates tau phosphorylation in SK-N-SH induced by Aß-stimulated THP-1 supernatant and the involvement of p38 pathway activation.

AIM: In the present study we aimed to investigate the neuroprotective effect of ginsenoside Rg1 (GRg1) on neuronal damage examined in an adopted in vitro inflammatory neurodegeneration model and the involvement of p38 MAPK signal pathway. MAIN METHODS: The supernatant from Aß(1-40)-stimulated THP-1 monocytes was used as culture medium for SK-N-SH neuroblastoma cells which was used as target neuronal cells. The cell viability of SK-N-SH cells was assessed by detecting lactate dehydrogenase (LDH) leakage; the content of pro-inflammatory cytokine was measured by radioimmunoassay; the expressions of tau phosphorylation, p-38 and synaptophysin (SYN) were evaluated by western blot assay. The microtubule associated protein-2 (MAP-2) expression was confirmed by immunostaining. KEY FINDINGS: Our results showed that incubation of the supernatant from Aß(1-40)-stimulated THP-1 cells with SK-N-SH neuroblastoma cells for 24h significantly increased LDH leakage, tau and p-38 phosphorylation in SK-N-SH cells with increased interleukin (IL)-1ß release into the supernatant of THP-1 cells. Pretreatment of THP-1 cells with GRg1 (50, 100 and 150µM) for 30min before Aß(1-40)-stimulation inhibited THP-1 cell-mediated Aß neurotoxicity towards SK-N-SH neuroblastoma and also decreased IL-1ß release into THP-1 supernatant dose-dependently. An inhibitor of p38 MAPK, SB203580, had the same effect. SIGNIFICANCE: These results suggested that activation of the p38 cell signal pathway may be involved in monocyte-mediated Aß neurotoxicity towards SK-N-SH cells. Data obtained from this study demonstrated that GRg1 represented a potential treatment strategy for Alzheimer's disease (AD).

Ginsenoside Rg1 prevents SK-N-SH neuroblastoma cell apoptosis induced by supernatant from Aß1-40-stimulated THP-1 monocytes.

Excessive accumulation of amyloid-ß (Aß) has been proposed as a pivotal event in Alzheimer's disease (AD) pathogenesis. Possible mechanisms underlying Aß-induced neurotoxicity include inflammation and apoptosis. Here, the protective effect of ginsenoside Rg1 (GRg1) on neuronal damage was examined in an in vitro inflammatory neurodegeneration model. Supernatant from Aß(1-40)-stimulated THP-1 monocytes was added to SK-N-SH neuroblastoma cell culture medium. Incubation of SK-N-SH cells with cell-free supernatant from Aß(1-40) (125nM)-treated THP-1 monocytes for 24 h significantly increased lactate dehydrogenase (LDH) release, cell apoptosis, Bax and caspase-3 expression in SK-N-SH cells. However, pretreating THP-1 monocytes with GRg1 (50, 100 or 150 µM) for 30 min markedly reduced IL-1ß, IL-8 and TNF-α levels in Aß(1-40)-stimulated supernatant. LDH release, cell apoptosis, Bax and caspase-3 expression in SK-N-SH cells were significantly decreased when cultured with cell-free supernatant from Aß(1-40)-stimulated THP-1 monocytes that were pretreated with GRg1. The results suggest that Aß(1-40)-induced neuronal injury and apoptosis may be mediated by inflammatory monocyte reactions, and GRg1 exerts a protective effect against Aß(1-40)-induced neuronal injury and apoptosis, likely through its anti-inflammatory mechanism.

ERK pathway activation is required for amyloid-ß(1-40)(-)induced neurotoxicity of THP-1 human monocytes towards SK-N-SH neuroblastoma.

Alzheimer's disease (AD) is characterized by amyloid-ß peptide deposition, increased activated microglia, and progressive loss of neurons in the brain. Although Aß1₋40 can elicit inflammation in microglia, the intracellular signaling events mediating these effects are poorly defined. Here we show that cell-free supernatant from Aß1₋40-treated THP-1 monocytes induced cytotoxicity towards neuroblastoma SK-N-SH cells. Exposure of THP-1 monocytes to Aß1₋40 leads to increased tyrosine phosphorylation and extracellular signaling-regulated kinase (ERK) and increased levels of inflammatory cytokines (IL-1ß, IL-8, and TNF-α) in the supernatant of THP-1 monocytes. Pretreatment of THP-1 monocytes with either a protein tyrosine kinase (PTK) inhibitor or an ERK inhibitor protects SK-N-SH cells from the cytotoxic effect of conditional supernatant from Aß1₋40-treated THP-1 monocytes. Aß1₋40-treated THP-1 monocytes also lead to upregulation of cyclooxygenase-2 and iNOS expression and increased of nitric oxide production. These results suggest that Aß1₋40-induced activation of PTK/MEK/ERK pathway in THP-1 monocytes leads to the release of inflammatory factors that are toxic to SK-N-SH cells and might contribute to the onset of AD.

Allergic shock and death associated with protamine administration in a diabetic patient.

BACKGROUND: Insulin is used to treat patients with both type 1 and type 2 diabetes mellitus. Allergic reactions to insulin might be triggered by insulin itself or inactive ingredients in the insulin formulation, including proteins such as protamine in neutral protamine Hagedorn (NPH) insulin. The use of highly purified animal insulin and human recombinant insulin has reduced the incidence of anaphylactic reactions to insulin from ~30% to <1%. OBJECTIVE: We report a case of fatal allergic shock after the administration of protamine in a patient with a history of allergy to fish and a protamine-containing insulin. CASE SUMMARY: A 72-year-old Chinese male patient (height, 175 cm; weight, 80 kg) with a history of diabetes and progressive limb weakness was diagnosed with spinal vascular malformations after admission to the Xuan Wu Hospital of Capital Medical University, Beijing, People's Republic of China. He underwent epidural spinal cord arteriovenous fistula embolization with a liquid embolic agent (ethylene vinyl alcohol copolymer) after spinal cord angiography. During the operation, heparin was infused every hour with 6250, 2500, 2500, and 1250 IU, respectively. The last dose of heparin was administered ~10 minutes before the operation was completed. This was followed by the administration of protamine to neutralize the remaining heparin in the patient's body. Blurry vision and dizziness 5 minutes after protamine administration were followed by pruritus and hives over his neck and face. Oxygen was administered and 10 mg of dexamethasone with 2 mg of epinephrine was injected. The patient's heart rate dropped, his blood pressure decreased, and his arterial oxygen saturation (SaO2) declined progressively. About 10 minutes after the administration of protamine sulfate, the patient developed bradycardic arrest. Cardiopulmonary resuscitation efforts were undertaken and the patient was administered epinephrine 2 mg IV, atropine 0.5 mg IV, and subsequently, intravenous dopamine (50 mg/h). Ten minutes later, the patient's heart rate gradually increased, but blood pressure fluctuated, and SaO2 ranged from 90% to 100%. Despite the initial response, the patient lost consciousness and heart rate declined progressively within 5 hours. Vasoactive agents including dopamine, norepinephrine, and adrenaline were administered. After all these measures proved ineffectual, the patient died. It was later determined that the patient had a history of allergic reactions to fish as well as to a premixed insulin that contained soluble human insulin 30% and low-protein intensive insulin zinc 70% (NPH). The Naranjo adverse drug reaction probability scale score for the association of protamine with the allergic reaction was 4, suggesting a possible relationship. CONCLUSION: This case report highlights a preventable fatal allergic reaction possibly associated with protamine administration in a patient with a history of allergy to a protamine-containing insulin.