Oxytocin ameliorates cognitive impairments by attenuating excitation/inhibition imbalance of neurotransmitters acting on parvalbumin interneurons in a mouse model of sepsis-associated encephalopathy.

Inflammation plays a crucial role in the initiation and progression of sepsis, and it also induces alterations in brain neurotransmission, thereby contributing to the development of sepsis-associated encephalopathy (SAE). Parvalbumin (PV) interneurons are pivotal contributors to cognitive processes in various central dysfunctions including SAE. Oxytocin, known for its ability to augment the firing rate of gamma-aminobutyric acid (GABA)ergic interneurons and directly stimulate inhibitory interneurons to enhance the tonic inhibition of pyramidal neurons, has prompted an investigation into its potential effects on cognitive dysfunction in SAE. In the current study, we administered intranasal oxytocin to the SAE mice induced by lipopolysaccharide (LPS). Behavioral assessments, including open field, Y-maze, and fear conditioning, were used to evaluate cognitive performance. Golgi staining revealed hippocampal synaptic deterioration, local field potential recordings showed weakened gamma oscillations, and immunofluorescence analysis demonstrated decreased PV expression in the cornu ammonis 1 (CA1) region of the hippocampus following LPS treatment, which was alleviated by oxytocin. Furthermore, immunofluorescence staining of PV co-localization with vesicular glutamate transporter 1 or vesicular GABA transporter indicated a balanced excitation/inhibition effect of neurotransmitters on PV interneurons after oxytocin administration in the SAE mice, leading to improved cognitive function. In conclusion, cognitive function improved after oxytocin treatment. The number of PV neurons in the hippocampal CA1 region and the balance of excitatory/inhibitory synaptic transmission on PV interneurons, as well as changes in local field potential gamma oscillations in the hippocampal CA1 region, may represent its specific mechanisms.

miR­3120/Hsc70 participates in forced swim stress­induced mechanical hyperalgesia in rats in an inflammatory state.

The heat shock cognate 71 kDa protein (Hsc70) is a stress­inducible ATPase that can protect cells against harmful stimuli. Transient receptor potential vanilloid 1 (TRPV1) is a well­documented nociceptor. Notably, Hsc70 can inhibit TRPV1 expression and function, suggesting that Hsc70 may have pain regulation potential. However, the role of Hsc70 in stress­induced hyperalgesia remains unclear. In the present study, the participation of Hsc70 and its regulator microRNA (miR)­3120 were investigated in forced swim (FS) stress­induced mechanical hyperalgesia in rats in an inflammatory state. Complete Freund's adjuvant (CFA) hind paw injection was performed to induce inflammatory pain in rats (CFA rats). Furthermore, in FS + CFA rats, FS stress was performed for 3 days before CFA injection. The levels of Hsc70, miR­3120 and their downstream molecule TRPV1 were measured in the dorsal root ganglion (DRG) with western blotting, immunofluorescence, reverse transcription­quantitative polymerase chain reaction and fluorescence in situ hybridization. The results revealed that FS stress significantly exacerbated CFA­induced mechanical pain. Furthermore, CFA upregulated Hsc70 and TRPV1 expression, which was partially inhibited or further enhanced by FS stress, respectively. In FS + CFA rats, intrathecal injection of a lentiviral vector overexpressing Hsc70 (LV­Hsc70) could decrease TRPV1 expression and improve the mechanical pain. Additionally, the expression levels of miR­3120, a regulator of Hsc70, were markedly upregulated on day 3 following FS stress. Finally, miR­3120 was identified to be colocalized with Hsc70 and expressed in all sizes of DRG neurons. In CFA rats, DRG injection of miR­3120 agomir to induce overexpression of miR­3120 resulted in similar TRPV1 expression and behavioral changes as those caused by FS stress, which were abolished in the presence of LV­Hsc70. These findings suggested that miR­3120/Hsc70 may participate in FS stress­induced mechanical hyperalgesia in rats in an inflammatory state, possibly via disinhibiting TRPV1 expression in the DRG neurons.

Efficacy and safety of systematic corticosteroids among severe COVID-19 patients: a systematic review and meta-analysis of randomized controlled trials.

The benefits and harms of corticosteroids for patients with severe coronavirus disease 2019 (COVID-19) remain unclear. We systematically searched PubMed, Embase, and Cochrane Central Register of Controlled Trials from December 31, 2019 to October 1, 2020 to identify randomized controlled trials (RCTs) that evaluated corticosteroids in severe COVID-19 patients. The primary outcome was all-cause mortality at the longest follow-up. Secondary outcomes included a composite disease progression (progression to intubation, ventilation, extracorporeal membrane oxygenation, ICU transfer, or death among those not ventilated at enrollment) and incidence of serious adverse events. A random-effects model was applied to calculate risk ratio (RR) with 95% confidence intervals (CIs). We used the Grading of Recommendations Assessment, Development, and Evaluation approach to evaluate the certainty of the evidence. Seven RCTs involving 6250 patients were included, of which the Randomized Evaluation of COVID-19 Therapy (RECOVERY) trial comprised nearly 78% of all included subjects. Results showed that corticosteroids were associated with a decreased all-cause mortality (27.3 vs. 31.1%; RR: 0.85; 95% CI: 0.73-0.99; P = 0.04; low-certainty evidence). Trial sequential analysis suggested that more trials were still required to confirm the results. However, such survival benefit was absent if RECOVERY trial was excluded (RR: 0.83; 95% CI: 0.65-1.06; P = 0.13). Furthermore, corticosteroids decreased the occurrence of composite disease progression (30.6 vs. 33.3%; RR: 0.77; 95% CI: 0.64-0.92; P = 0.005), but not increased the incidence of serious adverse events (3.5 vs. 3.4%; RR: 1.16; 95% CI: 0.39-3.43; P = 0.79).

Comparison of oxycodone and morphine on the proliferation, apoptosis and expression of related molecules in the A549 human lung adenocarcinoma cell line.

The present study aimed to compare the effects of oxycodone and morphine hydrochloride on the proliferation, apoptosis and migration of A549 lung cancer cells. A549 human lung cancer cells were cultured in vitro and treated with oxycodone or morphine at various concentrations (10, 20 and 40 µg/ml). Cell migration was determined using a wound healing assay, whereas apoptosis was detected using flow cytometry. Reverse transcription quantitative-polymerase chain reaction was performed in order to assess the apoptosis-related gene expression levels, including p53, B-cell lymphoma (Bcl)-2 and Bcl-2-associated X protein (Bax). The levels of vascular endothelial growth factor (VEGF) and urokinase-type plasminogen activator (uPA) were detected using enzyme-linked immunosorbent assays. The expression levels of intercellular cell adhesion molecule (ICAM)-1 were determined by immunofluorescence. In the present study, oxycodone and morphine induced apoptosis in A549 lung cancer cells with similar potency; however, >20 µg/ml oxycodone was more effective at inhibiting cell proliferation (P<0.05) and migration (P<0.05), as compared with morphine at the same concentration. Oxycodone induced a dose-dependent increase in the expression levels of p53 and Bax apoptosis-related genes, whereas it decreased the gene expression levels of Bcl-2. Furthermore, oxycodone decreased, whereas morphine increased, the expression levels of ICAM-1 in a concentration-dependent manner. In addition, at 40 µg/ml, the expression levels of VEGF and uPA in the morphine group were significantly higher than those demonstrated in the oxycodone group (P<0.05). In conclusion, oxycodone was more effective in inhibiting the proliferation and migration of A549 lung cancer cells, as compared with morphine.

Protective Effects of Antioxidant Peptide SS-31 Against Multiple Organ Dysfunctions During Endotoxemia.

Oxidative stress causes mitochondrial impairment, the failure of energy production, and consequent organ dysfunctions. The aim of the present study was to investigate the potential therapeutic effects of mitochondrial antioxidant SS-31 on sepsis-induced organ dysfunctions and to explore the possible mechanism. Sepsis was induced by cecal ligation and puncture. Immediately and at 5 h after the operation, SS-31 (5 mg/kg) or vehicle was administered intraperitoneally. The levels of organ dysfunctions, malondialdehyde, superoxide dismutase, proinflammatory cytokines, pulmonary wet-to-dry weight ratio, myeloperoxidase activity, histological scores, nuclear factor kappa B p65, inducible nitric oxide synthase, reactive oxygen species, adenosine triphosphate, and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive cells were assessed at the indicated time points. The 7-day survival rate was estimated by the Kaplan-Meier method. In the present study, SS-31 treatment significantly improved sepsis-induced organ dysfunctions as evidenced by decreased histological scores, increased arterial partial oxygen tension, and deceased serum alanine aminotransferase, urea nitrogen, and creatinine levels, which was accompanied by decreased levels of malondialdehyde, tumor necrosis factor-alpha, pulmonary myeloperoxidase activity, nuclear factor kappa B p65, inducible nitric oxide synthase, reactive oxygen species, and TUNEL-positive cells. In conclusion, our data suggested that the protective effects of SS-31 on sepsis-induced organ dysfunctions were associated with the inhibition of proinflammatory cytokines, oxidative stress, and apoptosis.

Low molecular weight heparin prevents lipopolysaccharide induced-hippocampus-dependent cognitive impairments in mice.

Sepsis-associated encephalopathy (SAE) is a common complication after sepsis development, which is associated with the poor prognosis. However, no effective agent is currently available to treat this complication. The objective of the present study was to investigate whether low-molecular-weight heparin (LMWH) has protective effects against sepsis-induced cognitive impairments. Male mice were randomly divided into the control + vehicle, control + LMWH, lipopolysaccharide (LPS) + vehicle, or LPS + LMWH group. LMWH was administrated 30 min after the LPS administration (5 mg/kg) and daily afterward for 2 days. The survival rate was estimated by the Kaplan-Meier method. Behavioral tests were performed by open field and fear conditioning tests at day 7 after LPS administration. The levels of tumor necrosis factor alpha, interleukin (IL)-1ß, IL-6, IL-10, malondialdehyde, and superoxide dismutase, Toll-like receptor 4, nuclear factor kappa B p65, inducible nitric oxide synthase, cyclooxygenase-2, occluding, high mobility group box-1, brain derived neurotrophic factor, and IBA1 positive cells were assessed at the indicated time points. LMWH attenuated LPS-induced hippocampus-dependent cognitive impairments, which was accompanied by decreased hippocampal IL-1ß, malondialdehyde, Toll-like receptor 4, nuclear factor kappa B p65, inducible nitric oxide synthase, cyclooxygenase-2, high mobility group box-1 protein, and IBA1 positive cells, and increased occluding and brain derived neurotrophic factor levels. In conclusion, LMWH treatment protects against sepsis-induced cognitive impairments by attenuating hippocampal microglial activation, cytokine and oxidative stress production, disruption of blood-brain barrier, and the loss of synaptic plasticity related proteins.

Experimental sepsis in pigs--effects of vasopressin on renal, hepatic, and intestinal dysfunction.

INTRODUCTION: Low-dose arginine vasopressin (AVP) has been proposed as an adjunctive vasopressor for the treatment of advanced vasodilatory shock. However, its effects on renal, hepatic, and intestinal dysfunction during sepsis remain controversial. METHODS: Fecal peritonitis was induced in 20 anesthetized, invasively monitored, mechanically ventilated female pigs. Following the time point of septic shock (defined as mean artery pressure (MAP) ≤65 mmHg), animals were randomly assigned to the following groups (n = 10): 1) a norepinephrine group with MAP between 65 and 75 mmHg; and 2) an AVP group with a constant infusion rate of 0.5 mU.kg(-1).min(-1). RESULTS: MAP, pulmonary capillary wedge pressure, hematocrit, TNF-α, IL-6, and IL-10 were similar in the two groups during the 28-h observation period. Infusion of AVP was associated with lower total norepinephrine and fluid requirements. There was a statistically significant improvement in renal function as assessed by increased urine output and renal blood flow, and decreased serum creatinine, in the AVP group when compared with the norepinephrine group (P < 0.05). Histological analyses of the intestine, liver, and kidney showed similar light microscopical appearance of the two groups. Apoptotic cells in the liver were significantly fewer in the AVP group when compared with the norepinephrine group (P < 0.05). CONCLUSION: An adjunctive AVP to norepinephrine infusion exhibits a favorable impact on renal function without deleterious effects on the liver and intestine in a porcine model of experimental sepsis when compared with norepinephrine infusion alone.

Effects of combined levosimendan and vasopressin on pulmonary function in porcine septic shock.

This study aims to determine whether levosimendan combined with arginine vasopressin infusion supplemented with norepinephrine can improve hemodynamics and pulmonary dysfunction. The study was tested in a fecal peritonitis-induced septic shock model, we observed that levosimendan combined with arginine vasopressin supplemented with norepinephrine therapy resulted in lower mean pulmonary artery pressure, lactate concentrations, arterial total nitrate/nitrite, and high-mobility group box 1 levels; decreased lung wet/dry ratio, and pulmonary levels of interleukin-6, total histological scores, and improved pulmonary gas exchange when compared with norepinephrine group. Levosimendan combined with arginine vasopressin supplemented with norepinephrine infusion shows potential benefit in sepsis-induced acute lung injury by decreasing mean pulmonary artery pressure and attenuating inflammatory responses in the lung compared to norepinephrine infusion alone.