Cardiovascular and renal safety outcomes of hypoxia-inducible factor prolyl-hydroxylase inhibitor roxadustat for anemia patients with chronic kidney disease: a systematic review and meta-analysis.

This systematic review and meta-analysis were conducted to evaluate the cardiac and kidney-related adverse effects of roxadustat for the treatment of anemia in CKD patients. 18 trials with a total of 8806 participants were identified for analysis. We employed a fixed-effects model for analysis. The pooled result revealed no significant difference in the risk of occurrence of cardiac disorders when comparing CKD patients receiving roxadustat with the placebo (RR = 1.049; CI [0.918 to 1.200]) or ESA (RR = 1.066; CI [0.919 to 1.235]), in both dialysis-dependent (DD) (RR = 1.094; CI [0.925 to 1.293]) or non-dialysis-dependent (NDD) (RR = 1.036; CI [0.916 to 1.171]) CKD patients. No significant difference was observed in the risk of kidney-related adverse events when comparing roxadustat with the placebo (RR = 1.088; CI [0.980 to 1.209]) or ESA (RR = 0.968; CI [0.831 to 1.152]), in DD (RR = 2.649; CI [0.201 to 34.981]) or NDD (RR = 1.053; CI [0.965 to 1.149]) CKD patients. A high risk of hyperkalemia was observed in the roxadustat group in DD (RR = 0.939; CI [0.898 to 0.981]). Incidence of hypertension was higher in the roxadustat for NDD patients (RR = 1.198; CI [1.042 to 1.377]), or compared to the placebo (RR = 1.374; CI [1.153 to 1.638]). In summary, the risk of cardiac or kidney-related events observed in the roxadustat was not significantly increase whether in DD or NDD patients. However, attention must be paid to the occurrence of hyperkalemia for DD patients and hypertension in NDD patients using roxadustat.

BaoShenTongLuo formula protects against podocyte injury by regulating AMPK-mediated mitochondrial biogenesis in diabetic kidney disease.

BACKGROUND: Mitochondrial dysfunction is considered to be an important contributor in podocyte injury under diabetic conditions. The BaoShenTongLuo (BSTL) formula has been shown to reduce podocyte damage and postpone the progression of diabetic kidney disease (DKD). The potential mechanisms underlying the effects of BSTL, however, have yet to be elucidated. In this study, we aimed to investigate whether the effects of BSTL are related to the regulation of mitochondrial biogenesis via the adenosine monophosphate-activated protein kinase (AMPK) pathway. METHODS: High-Performance Liquid Chromatography Electrospray Ionization Mass Spectrometer (HPLC-ESI-MS) analysis was performed to investigate the characteristics of pure compounds in BSTL. db/db mice and mouse podocyte clone-5 (MPC5) cells were exposed to high glucose (HG) to induce DKD and podocyte damage. Body weight, random blood glucose, urinary albumin/creatinine ratio (UACR), indicators of renal function and renal histological lesions were measured. Markers of podocyte injury, mitochondrial morphology, mitochondrial deoxyribonucleic acid (mtDNA) content, mitochondrial respiratory chain complexes activities, reactive oxygen species (ROS) production, and mitochondrial membrane potential (MMP) levels were assessed. Protein expressions of AMPK, peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α), transcription factor A (TFAM), mitochondrial fusion protein 2 (MFN2) and dynamin-related protein 1 (DRP1) were also detected. MPC5 cells were transfected with AMPKα small interfering RNA (AMPKα siRNA) to determine the underlying mechanisms of BSTL improvement of mitochondrial function under diabetic conditions. RESULTS: In vivo, treatment with BSTL reduced the UACR levels, reversed the histopathological changes in renal tissues, and alleviated the podocyte injury observed in db/db mice. After BSTL treatment, the decreased mtDNA content and mitochondrial respiratory chain complex I, III, and IV activities were significantly improved, and these effects were accompanied by maintenance of the protein expression of p-AMPKαT172, PGC-1α, TFAM and MFN2. The in vitro experiments also showed that BSTL reduced podocyte apoptosis, suppressed excessive cellular ROS production, and reversed the decreased in MMP that were observed under HG conditions. More importantly, the effects of BSTL in enhancing mitochondrial biogenesis and reducing podocyte apoptosis were inhibited in AMPKα siRNA-treated podocytes. CONCLUSION: BSTL plays a crucial role in protecting against podocyte injury by regulating the AMPK-mediated mitochondrial biogenesis in DKD.

Metabolic reprogramming: A novel therapeutic target in diabetic kidney disease.

Diabetic kidney disease (DKD) is one of the most common microvascular complications of diabetes mellitus. However, the pathological mechanisms contributing to DKD are multifactorial and poorly understood. Diabetes is characterized by metabolic disorders that can bring about a series of changes in energy metabolism. As the most energy-consuming organs secondary only to the heart, the kidneys must maintain energy homeostasis. Aberrations in energy metabolism can lead to cellular dysfunction or even death. Metabolic reprogramming, a shift from mitochondrial oxidative phosphorylation to glycolysis and its side branches, is thought to play a critical role in the development and progression of DKD. This review focuses on the current knowledge about metabolic reprogramming and the role it plays in DKD development. The underlying etiologies, pathological damages in the involved cells, and potential molecular regulators of metabolic alterations are also discussed. Understanding the role of metabolic reprogramming in DKD may provide novel therapeutic approaches to delay its progression to end-stage renal disease.

Real-world pharmacological treatment patterns of patients with threatened miscarriage in China from 2014 to 2020: A cross-sectional analysis.

WHAT IS KNOWN AND OBJECTIVE: Approximately half of the patients with threatened miscarriage suffer an abortion, and consistent medication therapy to prevent threatened miscarriage is lacking. Our goal was to investigate the real-world pharmacological treatment patterns of patients with threatened miscarriage in China, with a focus on the trend and rationality of progestogen use over the last 7 years. METHODS: We performed a cross-sectional analysis of data from the Hospital Prescription Analysis Cooperation Project that is overseen by the Chinese Pharmaceutical Association. Information was extracted from prescriptions of outpatients with threatened miscarriage between January 2014 and December 2020. We quantified the types of medications using the first level anatomical therapeutic chemical (ATC) classification code and the frequency of use of medicines classified as category X by the United States Food and Drug Administration (FDA). We also calculated the prevalence of the most frequently used progestogens by assessing prescription rates, determined the sum of the defined daily doses (DDDs) and defined daily cost (DDC) and evaluated the rationality of progestogens according to drug labels and guidelines. RESULTS AND DISCUSSION: Of the 91,464 patients included in this study, 69.4% were from the eastern region, 92.5% were from tertiary hospitals, and 72.9% were between 25 and 34 years old. The average number of medications per patient was 1.4. The following types of medicines were the most prevalent: "genitourinary system and sex hormones" (90.7%), "alimentary tract and metabolism" (10.8%) and "blood and blood-forming organs" (9.9%). Progestogens were prescribed for 81,080 patients (88.6%), among which oral progesterone (39.7%) was the most commonly used, followed by oral dydrogesterone (34.4%), progesterone injection (26.0%), oral allylestrenol (0.7%) and progesterone gel (0.4%). In other words, 10,991 (12.0%) patients used more than one progestogen, and the top three combinations were oral dydrogesterone plus progesterone injection (5.6%), oral progesterone plus progesterone injection (4.7%) and oral dydrogesterone plus oral progesterone (1.1%). The prescription rate of dydrogesterone increased gradually, whereas that of progesterone, especially progesterone injection, obviously decreased. Among 34,760 prescriptions of progestogens with complete usage information, the primary errors of progestogen use were "low frequency" (18.4%), "high single dose" (15.9%) and "low single dose" (11.3%). In addition, 137 prescriptions were identified with drug-progestogen interactions, and 61 were identified with contraindications for progestogens. A total of 4.5% of prescriptions included FDA category X medicines. WHAT IS NEW AND CONCLUSION: Our findings are the first to provide information on medication use in patients with threatened miscarriage over the last seven years in China. Medicines targeting the "genitourinary system and sex hormones," especially progestogens, were the most commonly prescribed medications, among which dydrogesterone was the most prevalent. However, it is remarkable that the use of progestogens for the treatment of threatened abortion is still controversial; thus, high-quality large sample studies are still required, especially among Chinese patients. Since usage errors in progestogen records and exposure to category X medicines were common, more efforts are needed to guarantee the safety and rationality of medicines used in pregnant women.

Clinical practice and teaching of pharmaceutical care procedures for obstetric diseases.

OBJECTIVES: Our goal was to explore the pharmaceutical service and teaching methods of obstetric clinical pharmacists to establish standardised pharmaceutical care procedures for obstetric diseases. METHODS: According to the evidence-based medicine method, the "Standard of Pharmaceutical Care" was established to standardise the procedure and content of the pharmaceutical care procedure including preface, purpose, scope of application, responsibilities, procedures, references, and appendix, with seven parts in total. The object of the pharmaceutical care procedure was selected by the harmfulness of the disease and the drugs used. The clinical pharmacists in obstetrics formulated the pharmaceutical care procedure for each disease according to the standard and carried out clinical practice and teaching.A retrospective study was conducted to investigate the impact of the pharmaceutical care procedure before and after its implementation on both clinical practice and training. Obstetric pharmaceutical consultation and adverse reaction were the key indicators for clinical practice.The graduation assessment for students was strictly carried out in accordance with the regulations of the Chinese Hospital Association Pharmaceutical Affairs Professional Committee including communication and consultation capacity interview, case assessment, and training procedure assessment. RESULTS: We established the standards for the pharmaceutical care procedures for three diseases: pregnancy with diabetes; pregnancy with thyroid disease; and pregnancy with hypertensive disorder. The clinical pharmacist conducted the pharmaceutical care procedure, participated in drug treatment management, and improved the recognition of the role of clinical pharmacists by the obstetric clinicians, often inviting the clinical pharmacists to participate in the consultations. The clinical pharmacists discovered and addressed any adverse reactions in a timely manner through patient drug education, subsequently reducing the underreporting of adverse reactions and improving the patient's medication compliance, which aimed to improve the medical quality of patients in our hospital. Second, the use of the pharmaceutical care procedure as a teaching tool helped to train students to grasp the key points of drug treatment and care of the disease and improve the students' scores in the graduation assessment (P<0.05). CONCLUSIONS: As a pharmacy service and teaching method that can be promoted and implemented, the pharmaceutical care procedure is beneficial for clinical pharmacists to carry out in-depth pharmaceutical services and can also be used as a teaching tool for clinical pharmacist training.

Analysis and improvement measures of telephone drug consultation in a specialized hospital of obstetrics and gynaecology in China.

WHAT IS KNOWN AND OBJECTIVE: Drug consultation is an important part of pharmaceutical care offered by clinical pharmacists. We explored the characteristics of telephone drug consultations in an obstetrics and gynaecology speciality hospital to provide a reference as to how to improve drug consultation and pharmaceutical care. METHODS: We retrospectively analysed records of telephone consultations regarding medication use between 2014 and 2019 in our hospital. Any consultation cases with incomplete records were excluded from our analysis. Of the 1353 consultation cases included in our study, we further classified them into different categories based on the content of the consultations, the type of medications being inquired about, and the groups of people who sought medication guidance. Pareto analysis was performed to separate the main issues the callers were concerned about from the more minor concerns. RESULTS AND DISCUSSION: The medication issues that prompted the caller to consult with our clinical pharmacists could be divided into 12 categories, among which the main issues concerned usage and dosage, choice of drug variety, drug incompatibility (drug mixture in infusion bag or tube), adjustment of the treatment plan, and skin tests (cumulative percentage 76.3%). The minor issues involved medication use during pregnancy and lactation and adverse reactions. The top three types of drugs that callers asked about were antimicrobials (600 cases, 44.4%), anti-tumour drugs (151 cases, 11.2%) and reproductive system drugs (111 cases, 8.2%). The callers could be divided into four groups as follows: doctors (865 cases, 63.9%), nurses (280 cases, 20.7%), patients (116 cases, 8.6%) and other medical professionals (92 cases, 6.8%). WHAT IS NEW AND CONCLUSION: Usage and dosage, choice of drug variety, drug incompatibility, adjustment of treatment plan and skin tests represented the main issues for telephone drug consultations in our hospital. Doctors and nurses were most likely to consult clinical pharmacists regarding these issues. Improved drug consultation services are needed to allow more patients to have access to advice from pharmacists. Such access would better enable pharmacists to fulfil their roles in advising the appropriate use of drugs to ensure better patient care and medication compliance.

CD44-Targeting Oxygen Self-Sufficient Nanoparticles for Enhanced Photodynamic Therapy Against Malignant Melanoma.

OBJECTIVE: Nanotechnology-based photodynamic therapy (PDT) is a relatively new anti-tumor strategy. However, its efficacy is limited by the hypoxic state in the tumor microenvironment. In the present study, a poly(lactic-co-glycolic acid) (PLGA) nanoparticle that encapsulated both IR820 and catalase (CAT) was developed to enhance anti-tumor therapy. MATERIALS AND METHODS: HA-PLGA-CAT-IR820 nanoparticles (HCINPs) were fabricated via a double emulsion solvent evaporation method. Dynamic light scattering (DLS), transmission electron microscopy (TEM), laser scanning confocal microscopy, and an ultraviolet spectrophotometer were used to identify and characterize the nanoparticles. The stability of the nanoparticle was investigated by DLS via monitoring the sizes and polydispersity indexes (PDIs) in water, PBS, DMEM, and DMEM+10%FBS. Oxygen generation measurement was carried out via visualizing the oxygen bubbles with ultrasound imaging system and an optical microscope. Inverted fluorescence microscopy and flow cytometry were used to measure the uptake and targeting effect of the fluorescent-labeled nanoparticles. The live-dead method and tumor-bearing mouse models were applied to study the HCINP-induced enhanced PDT effect. RESULTS: The results showed that the HCINPs could selectively target melanoma cells with high expression of CD44, and generated oxygen by catalyzing H2O2, which increased the amount of singlet oxygen, ultimately inhibiting tumor growth significantly. CONCLUSION: The present study presents a novel nanoplatform for melanoma treatment.

Core­shell type thermo­nanoparticles loaded with temozolomide combined with photothermal therapy in melanoma cells.

A novel core­shell type thermo­nanoparticle (CSTNP) co­loaded with temozolomide (TMZ) and the fluorescein new indocyanine green dye IR820 (termed IT­CSTNPs) was designed and combined with a near­infrared (NIR) laser to realize its photothermal conversion. The IT­CSTNPs were prepared using a two­step synthesis method and comprised a thermosensitive shell and a biodegradable core. IR820 and TMZ were entrapped in the shell and the core, respectively. Dynamic light scattering results demonstrated that the average hydrodynamic size of the IT­CSTNPs was 196.4±3.1 nm with a ζ potential of ­24.9±1.3 mV. The encapsulation efficiencies of TMZ and IR820 were 6.1 and 16.6%, respectively. Temperature increase curves under NIR laser irradiation indicated that the IT­CSTNPs exhibited the desired photothermal conversion efficiency. The in vitro drug release curves revealed a suitable release capability of IT­CSTNP under physiological conditions, whereas NIR laser irradiation accelerated the drug release. Inverted fluorescence microscopy and flow cytometry results revealed that the uptake of IT­CSTNPs by A375 melanoma cells occurred in a concentration­dependent manner. Confocal laser scanning microscopy results indicated that IT­CSTNPs entered tumour cells via endocytosis and were located in intercellular lysosomes. In summary, the present study explored the photothermal conversion capability, cellular uptake, and intracellular localization of IT­CSTNPs.

Photoprotection of Cerium Oxide Nanoparticles against UVA radiation-induced Senescence of Human Skin Fibroblasts due to their Antioxidant Properties.

Ultraviolet (UV) irradiation, particularly ultraviolet A (UVA), stimulates reactive oxygen species (ROS) production in the epidermis and dermis, which plays a major part in the photoageing of human skin. Several studies have demonstrated that cerium oxide nanoparticles (CeO2 NP) can exhibit an antioxidant effect and free radical scavenging activity. However, the protective role of CeO2 NP in skin photoageing and the underlying mechanisms are unclear. In this study, we investigated the effects of CeO2 NP on UVA-irradiated human skin fibroblasts (HSFs) and explored the potential signalling pathway. CeO2 NP had no apparent cytotoxicity, and could reduce the production of proinflammatory cytokines, intracellular ROS, senescence-associated ß-galactosidase activity, and downregulate phosphorylation of c-Jun N-terminal kinases (JNKs) after exposure to UVA radiation. Based on our findings, CeO2 NPs have great potential against UVA radiation-induced photoageing in HSFs via regulating the JNK signal-transduction pathway to inhibit oxidative stress and DNA damage.

Nanoparticle-based photothermal and photodynamic immunotherapy for tumor treatment.

Nanoparticle-based phototherapies, such as photothermal therapy (PTT) and photodynamic therapy (PDT), exhibit strong efficacy, minimal invasion and negligible side effects in tumor treatment. These phototherapies have received considerable attention and been extensively studied in recent years. In addition to directly killing tumor cells through heat and reactive oxygen species, PTT and PDT can also induce various antitumor effects. In particular, the resultant massive tumor cell death after PTT and PDT triggers immune responses, including the redistribution and activation of immune effector cells, the expression and secretion of cytokines and the transformation of memory T lymphocytes. The antitumor effects can be enhanced by immune checkpoint blockage therapy. This article reviewed the recent advances of nanoparticle-based PTT and PDT, summarized the studies on nanoparticle-based photothermal and photodynamic immunotherapies in vitro and in vivo, and discussed challenges and future research directions.

Advances on chimeric antigen receptor-modified T-cell therapy for oncotherapy.

Tumor treatment is still complicated in the field of medicine. Tumor immunotherapy has been the most interesting research field in cancer therapy. Application of chimeric antigen receptor T (CAR-T) cell therapy has recently achieved excellent clinical outcome in patients, especially those with CD19-positive hematologic malignancies. This phenomenon has induced intense interest to develop CAR-T cell therapy for cancer, especially for solid tumors. However, the performance of CAR-T cell treatment in solid tumor is not as satisfactory as that in hematologic disease. Clinical studies on some neoplasms, such as glioblastoma, ovarian cancer, and cholangiocarcinoma, have achieved desirable outcome. This review describes the history and evolution of CAR-T, generalizes the structure and preparation of CAR-T, and summarizes the latest advances on CAR-T cell therapy in different tumor types. The last section presents the current challenges and prospects of CAR-T application to provide guidance for subsequent research.

Enhanced anti-tumor efficacy of temozolomide-loaded carboxylated poly(amido-amine) combined with photothermal/photodynamic therapy for melanoma treatment.

Chemotherapy is an important treatment for malignant tumors; however, its efficacy and clinical application are limited by its side effects and drug resistance properties. Chemotherapy and phototherapy exhibit synergistic anti-tumor effects. In the present study, a carboxylated poly(amido-amine) (PAMAM) with low cytotoxicity was synthesized as a delivery nanocarrier for loading chemotherapeutic drugs, temozolomide (TMZ), and fluorescent dye indocyanine green (ICG). Hyaluronic acid (HA), which targets the CD44-overexpressing cancer cells, was modified on the nanocarrier surface to enhance the selective killing of melanoma cells. Temperature effect and singlet oxygen production experiments showed that the ICG-loaded nanoparticles exhibited good capability to generate heat and singlet oxygen under near-infrared (NIR) light (808 nm) irradiation. In vivo imaging measurement confirmed that the ICG-encapsulated nanoparticle was delivered successfully and effectively accumulated in the tumor site. In vitro and in vivo experiments revealed that the joint application of TMZ- and ICG-loaded nanoparticle can kill melanoma cells and suppress growth after NIR light irradiation. Thus, HA-modified carboxylated PAMAM loaded with TMZ and ICG serves as a promising nanoplatform for melanoma treatment.