Pharmacokinetics, Pharmacodynamics, and Safety of Single Dose HSK7653 Tablets in Chinese Subjects with Normal or Impaired Renal Function.

OBJECTIVE: HSK7653 is a novel, ultralong-acting dipeptidyl peptidase-4 (DPP-4) inhibitor, promising for type 2 diabetes mellitus with a dosing regimen of once every 2 weeks. This trial investigates the pharmacokinetics (PKs), pharmacodynamics (PDs),and safety of HSK7653 in outpatients with normal or impaired renal function. METHODS: This is a multicenter, open-label, nonrandomized, parallel-controlled phase I clinical study that investigates the pharmacokinetic profiles of HSK7653 after a single oral administration in 42 subjects with mild (n = 8), moderate (n = 10), severe renal impairment (n = 10), and end-stage renal disease (without dialysis, n = 5) compared with matched control subjects with normal renal function (n = 9). Safety was evaluated throughout the study, and the pharmacodynamic effects were assessed on the basis of a DPP-4 inhibition rate. RESULTS: HSK7653 exposure levels including the maximum plasma concentration (Cmax), area under the plasma concentration-time curve from zero to last time of quantifiable concentration (AUC0-t), and area under the plasma concentration-time curve from zero to infinity (AUC0-inf) showed no significant differences related to the severity of renal impairment. Renal clearance (CLR) showed a certain downtrend along with the severity of renal impairment. The CLR of the group with severe renal impairment and the group with end-stage renal disease were basically similar. The DPP-4 inhibition rate-time curve graph was similar among the renal function groups. All groups had favorable safety, and no serious adverse events occurred. CONCLUSIONS: HSK7653 is a potent oral DPP-4 inhibitor with a long plasma half-life, supporting a dosing regimen of once every 2 weeks. Impaired renal function does not appear to impact the pharmacokinetic and pharmacodynamic properties of HSK7653 after a single administration in Chinese subjects. HSK7653 is also well tolerated without an increase in adverse events with increasing renal impairment. These results indicate that dose adjustment of HSK7653 may not be required in patients with renal impairment. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05497297.

Endophytic Penicillium oxalicum CX-1 prevented Phytophthora cactorum blight on Salvia miltiorrhiza and promoted plant growth.

AIM: The main purpose of this study was to study the preventive effect of Penicillium sp. CX-1 on Phytophthora cactorum causing Salvia miltiorrhiza blight and its positive effect on plant growth. METHODS AND RESULTS: The endophytic strain CX-1 was isolated from the medicinal plant Corydalis saxicola Bunting and identified as Penicillium oxalicum. The growth inhibitory capacity of CX-1 against Ph. cactorum was 74.4% in the strain co-culture test and 86.2% in filtrate-modified plates. In the pot experiment, the in vivo control of CX-1 against Ph. cactorum in S. miltiorrhiza was 36.0%, which was higher than that of an anti-Phytophthora fungicide (23.4%). In addition, CX-1 had a potent ability to solubilize phosphate and also showed the ability to produce the plant hormone indole-3-acetic acid (IAA) and siderophores, which increase the bioavailability of iron to plants. It was demonstrated through pot experiments that CX-1 could significantly promote plant growth. As determined by real-time quantitative PCR, the expression of some S. miltiorrhiza tanshinone-related biosynthesis genes was significantly upregulated following colonization by CX-1. CONCLUSION: Strain CX-1 could effectively inhibit Ph. cactorum, the causative agent of S. miltiorrhiza blight, and significantly promoted the growth of plants through several different routes.

Neutralizing monoclonal antibody in patients with coronavirus disease 2019: an observational study.

BACKGROUND: Clinical data on patients infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) delta variant are limited, especially on clinical status after the application of antibody therapy. METHODS: We evaluated clinical status in patients with the SARS-CoV-2 delta variant after BRII-196 and BRII-198 treatment in an infectious disease hospital in China. We collected data on clinical symptoms, laboratory tests, radiological characteristics, viral load, anti-SARS-CoV-2 antibodies, treatment, and outcome. RESULTS: In mid-June 2021, 36 patients with delta variant infection were identified in Shenzhen. The most common symptoms at illness onset were cough (30.6%), fever (22.2%), myalgia (16.7%), and fatigue (16.7%). A small number of patients in this study had underlying diseases, including diabetes (5.6%) and hypertension (8.3%). The application of BRII-196 and BRII-198 can rapidly increase anti-SARS-CoV-2 IgG. The median peak IgG levels in the antibody treatment group were 32 times higher than those in the control group (P < 0.001). The time from admission to peak IgG levels in the antibody treatment group (mean: 10.2 days) was significantly shorter than that in the control group (mean: 17.7 days). Chest CT score dropped rapidly after antibody therapy, with a mean duration of 5.74 days from admission to peak levels. CONCLUSION: The results of this study suggest that the application of BRII-196 and BRII-198 antibody therapy improved clinical status in patients with SARS-CoV-2 delta variant infection.

Separation of soy isoflavones from soy sauce residue by MIL-100(Fe).

Soy sauce residue (SSR) is a valuable biological resource, which contains soy isoflavones (SIs) with antioxidant activity and can be used to scavenge radicals. Herein, MIL-100(Fe) was synthesized for the extraction of SIs from SSR. Under the optimal adsorption conditions, the adsorption capacity of MIL-100(Fe) for SIs was 51.81 mg/g, which could achieve a purity of 56.17% and a recovery of 93.8%. These results demonstrated MIL-100(Fe) possessed effective properties of adsorption and purification for SIs. The content of SIs in the purified product was 167 times than that of SSR. The purified total SIs had a good antioxidant activity. The established method had a good scavenging ability toward 2, 2-diphenyl-1-picrylhydrazyl, superoxide and hydroxyl radicals, with IC50 values of 0.177, 0.116 and 0.082 mg/mL, respectively. Besides, the ferrous ion chelating potency was better than others, with IC50 values of 0.63 ± 0.0044 mg/mL. The established method was suitable for large-scale separation of purified total SIs and provided a reference for purification of bioactive factors from complex substrates.

Antiviral Efficacy and Safety of Molnupiravir Against Omicron Variant Infection: A Randomized Controlled Clinical Trial.

Background: The rapid worldwide spread of the Omicron variant of SARS-CoV-2 has unleashed a new wave of COVID-19 outbreaks. The efficacy of molnupiravir, an approved drug, is still unknown in patients infected with the Omicron variant. Objective: Evaluated the antiviral efficacy and safety of molnupiravir in patients infected with SARS-CoV-2 Omicron variant, with symptom duration within 5 days. Methods: We conducted a randomized, controlled trial involving patients with mild or moderate COVID-19. Patients were randomized to orally receive molnupiravir (800 mg) plus basic treatment or only basic treatment for 5 days (BID). The antiviral efficacy of the drug was evaluated using reverse transcriptase polymerase chain reaction. Results: Results showed that the time of viral RNA clearance (primary endpoint) was significantly decreased in the molnupiravir group (median, 9 days) compared to the control group (median, 10 days) (Log-Rank p = 0.0092). Of patients receiving molnupiravir, 18.42% achieved viral RNA clearance on day 5 of treatment, compared to the control group (0%) (p = 0.0092). On day 7, 40.79%, and 6.45% of patients in the molnupiravir and control groups, respectively, achieved viral RNA clearance (p = 0.0004). In addition, molnupiravir has a good safety profile, and no serious adverse events were reported. Conclusion: Molnupiravir significantly accelerated the SARS-CoV-2 Omicron RNA clearance in patients with COVID-19. Clinical Trial Registration: [chictr.org.cn], identifier [ChiCTR2200056817].

Pulmonary Sequelae in Patients After Recovery From Coronavirus Disease 2019: A Follow-Up Study With Chest CT.

Objective: The pulmonary sequelae of coronavirus disease 2019 (COVID-19) have not been comprehensively evaluated. We performed a follow-up study analyzing chest computed tomography (CT) findings of COVID-19 patients at 3 and 6 months after hospital discharge. Methods: Between February 2020 and May 2020, a total of 273 patients with COVID-19 at the Shenzhen Third People's Hospital were recruited and followed for 6 months after discharge. Chest CT scanning was performed with the patient in the supine position at end-inspiration. A total of 957 chest CT scans was obtained at different timepoints. A semi-quantitative score was used to assess the degree of lung involvement. Results: Most chest CT scans showed bilateral lung involvement with peripheral location at 3 and 6 months follow-up. The most common CT findings were ground-glass opacity and parenchymal band, which were found in 136 (55.3%) and 94 (38.2%) of the 246 patients at 3 months follow-up, and 82 (48.2%) and 76 (44.7%) of 170 patients at 6 months follow-up, respectively. The number of lobes involved and the total CT severity score declined over time. The total CT score gradually increased with the increasement of disease severity at both 3 months follow-up (trend test P < 0.001) and 6 months follow-up (trend test P < 0.001). Patients with different disease severity represented diverse CT patterns over time. Conclusions: The most common CT findings were ground-glass opacity and parenchymal bands at the 3 and 6 months follow-up. Patients with different disease severity represent diverse CT manifestations, indicating the necessary for long-term follow-up monitoring of patients with severe and critical conditions.

Corticosterone induces neurotoxicity in PC12 cells via disrupting autophagy flux mediated by AMPK/mTOR signaling.

AIMS: Our previous study indicated that chronic stress caused autophagy impairment and subsequent neuron apoptosis in hippocampus. However, the mechanism underlying the stress-induced damage to neurons is unclear. In present work, we investigated whether stress-level glucocorticoids (GCs) GCs promoted PC12 cell damage via AMPK/mTOR signaling-mediated autophagy. METHODS: Chronic stress-induced PC12 cell injury model was built by treatment with high level corticosterone (CORT). Cell injury was evaluated by flow cytometry assay and transmission electron microscopy observation. RESULTS: Autophagy flux was measured based on the changes in LC3-II and P62 protein expressions, and the color alteration of mCherry-GFP-LC3-II transfection. Our results showed that CORT not only increased cell injury and apoptosis, but also dysregulated AMPK/mTOR signaling-mediated autophagy flux, as indicated by the upregulated expression of LC3-II and P62 proteins, and the lowered ration of autolysosomes to autophagosomes. Mechanistically, our results demonstrated that autophagy activation by AMPK activator metformin or mTOR inhibitor rapamycin obviously promotes cell survival and autophagy flux, improved mitochondrial ultrastructure, and reduced expression of Cyt-C and caspase-3 in CORT-induced PC12 cells. CONCLUSION: These results indicate that high CORT triggers PC12 cell damage through disrupting AMPK/mTOR-mediated autophagy flux. Targeting this signaling may be a promising approach to protect against high CORT and chronic stress-induced neuronal impairment.

Overexpression of secretagogin promotes cell apoptosis and inhibits migration and invasion of human SW480 human colorectal cancer cells.

OBJECTIVE: In order to investigate the effect of secretagogin (SCGN) on colorectal cancer (CRC) cells apoptosis, invasion and migration in vitro. METHODS: Expression of SCGN in CRC tissues and the paired adjacent non-tumorous tissues (n = 36) and four human CRC cell lines (HT29, HCT116, SW480 and SW620) were detected. SW480 cells were transfected with the SCGN overexpression plasmid (eGFP-SCGN), si-SCGN-773, and the corresponding negative controls (NCs). Then, cell-cycle distribution, cell apoptosis, migration, invasion and expression of apoptosis- and metastasis-related proteins were detected. RESULTS: SCGN was significantly downregulated in CRC tissues as compared with the adjacent non-tumorous tissues. The expression of SCGN in HT29 and SW480 cells were lower than those in HT116 and SW620 cells. We transfected SW480 cells with SCGN overexpression plasmid eGFP-SCGN and found the increased cell apoptosis, with cell arresting at G0/G1 phase. SW480 cells with SCGN overexpression showed wider wound width and fewer invaded cells than control and blank cells, with upregulated Bax, cleaved Caspase 3 and E-cadherin, and downregulated Bcl-2 and Vimentin. We also transfected SW480 cells with si-SCGN-773 and found si-SCGN increased cell migration and invasion, but did not affect cell apoptosis and expression of related proteins. CONCLUSION: We concluded that the overexpression of SCGN in SW480 cells promoted cell apoptosis and inhibited cell migration and invasion.

Immunoregulatory effects on Caco-2 cells and mice of exopolysaccharides isolated from Lactobacillus acidophilus NCFM.

On the basis of our previous results on potential immunoregulation of Lactobacillus acidophilus NCFM, the immunoregulatory effects of exopolysaccharides (EPS) isolated from L. acidophilus NCFM and their regulating mechanisms are further investigated in the current research. Stimulated by EPS preparations, four immune-related genes in the human colorectal adenocarcinoma cell line Caco-2 cells, namely, interleukin-1α (IL-1α), chemokine C-C motif 2 (CCL2), tumor necrosis factor α (TNF-α), and pentraxin 3 (PTX3), first showed an increase at 2-4 h, peaked at 4 h, and then decreased at 4-12 h. Similar trends were observed in vivo: four genes showed transient expression (highest on the 4th day) in the cecum and colon of mice. Meanwhile, the organ coefficient, clearance index and phagocytic index all significantly increased with time extension and dose increase of EPS stimulation. EPS triggered NF-κB and p38 mitogen-activated protein kinase (p38 MAPK) signaling pathways in Caco-2 cells, and the activated pathways initiated the genes expression. EPS compounds from L. acidophilus NCFM may play an important role in host immunoregulation and might be applied as a new type of immunoregulatory agent in functional foods.

Tetramethylpyrazine attenuates PPAR-γ antagonist-deteriorated oxazolone-induced colitis in mice.

Tetramethylpyrazine (TMP) is suggested to have anti-inflammatory activity. The aim of this study was to determine the role of peroxisome proliferator activated receptor γ (PPAR-γ) signaling in the pharmacologic effect of TMP on oxazolone (OXZ)-induced colitis. TMP (80 mg/kg/day i.p.) was administered daily 48 h after intrarectal instillation of OXZ, with or without PPAR-γ inhibitor [bisphenol A diglycidyl ether (BADGE) 30 mg/kg] during the 4 days before sacrifice. The inflammatory response was assessed by the disease activity index, macroscopy, histology and myeloperoxidase (MPO) activity. Expression levels of PPAR-γ, NF-κB p65, COX-2, iNOS and TNF-α mRNA in colon mucosa were determined by FQ-PCR, levels of PPAR-γ and NF-κB p65 protein were analyzed by immunohistochemistry, and the total and phosphorylated levels of p38 MAPK were assessed by western blotting. TMP significantly attenuated the damage caused by OXZ and substantially reduced the rise in MPO activity, TNF-α, iNOS, NF-κB p65 and COX-2 expression, as well as the increase in PPAR-γ production; however, no changes in the activation of p38 MAPK were observed. Inhibition of PPAR-γ signaling aggravated inflammation of colon mucosa, and increased p38 phosphrylation. TMP counteracted the effect of inhibition of PPAR-γ. We suggest that the effect of TMP treatment in ulcerative colitis may be related to PPAR-γ signaling, but is independent of PPAR-γ.

[Lactobacillus plantarum NDC 75017 affects il-6 gene expression in Caco-2 cells].

OBJECTIVE: We tested the expression of immune-related gene interleukin 6 (il-6) in vitro to understand the influence from Lactobacillus plantarum NDC 75017 on host cells and further to reveal the regulatory mechanism. METHODS: Caco-2 cells were cocultured with L. plantarum NDC 75017 for 0, 2, 4, 6, 8, 10 and 12 h, the total RNA were extracted; then the expressions of il-6 and tlr2 genes were analyzed by Real Time RT-PCR. The phosphorylation level of NF-KB was analyzed by Western Blot after the Caco-2 cells stimulation with L. plantarum NDC 75017 at 0, 0.5, 1, 2 and 4 h. Caco-2 cells were pretreated with pyrrolidine dithiocarbamate for 30 min before being treated with L. plantarum NDC 75017 for 2 h, then the total RNA was extracted and the expressions of il-6 and tlr2 genes were analyzed by Real Time RT-PCR. RESULTS: Lactobacillus plantarum NDC 75017 could induce the expressions of il-6 and tlr2 in Caco-2 cells, the il-6 and tlr2 expressions peaked at 8 h and 6 h after cocultured with L. plantarum NDC 75017. L. plantarum NDC 75017 could rapidly activate the phosphorylation of NF-kappaB, and the expressions of il-6 and tlr2 were decreased notably after pretreated with pyrrolidine dithiocarbamate. CONCLUSION: L. plantarum NDC 75017 could up-regulate and then down-regulate the expression of il6 through rapidly activating tlr2-mediated NF-kappaB signaling pathway in Caco-2 cells.