Potential Role of Remimazolam in Alleviating Bone Cancer Pain in Mice via Modulation of Translocator Protein in Spinal Astrocytes.

Bone cancer pain (BCP) is a complex clinical challenge, with current treatments often falling short of providing adequate relief. Remimazolam, a benzodiazepine receptor agonist recognized for its anxiolytic effects, has emerged as a potential agent in managing BCP. This study explores the analgesic properties of remimazolam and its interaction with the translocator protein (TSPO), previously known as the peripheral benzodiazepine receptor, in spinal astrocytes. In the context of BCP, previous research has indicated that TSPO expression in spinal astrocytes may serve a protective regulatory function in neuropathic pain models. Building on this, the BCP mice received various doses of remimazolam on the 15th day post-inoculation, and pain behavior was assessed over time. The results showed that BCP induced an upregulation of TSPO and astrocyte activation in the spinal dorsal horn, alongside increased extracellular signal-regulated kinase (ERK) signaling and inflammatory cytokine expression. Remimazolam administration resulted in a dose-dependent reduction of pain behaviors, which corresponded with a decrease in both ERK pathway activation and inflammatory factor expression. This suggests that remimazolam's analgesic effects are mediated through its action as a TSPO agonist, leading to the attenuation of neuroinflammation and pain signaling pathways. Importantly, the analgesic effects of remimazolam were reversed by the TSPO antagonist PK11195, underscoring the pivotal role of TSPO in the drug's mechanism of action. This reversal also reinstated the heightened levels of ERK activity and inflammatory mediators, further confirming the involvement of TSPO in the modulation of these pain-related processes. These findings open new avenues for the therapeutic management of bone cancer pain, positioning remimazolam as a promising candidate for further investigation and development.

Weaning Performance of Beef Cattle Calves Based on Concentrate Intake.

This study was conducted to investigate the effects of weaning based upon different concentrate intake on growth performance, health, and antioxidant status of Southern Chinese Cattle. Thirty female calves were used in the trial. Weaning strategy was the primary variable of interest and treatments included weaning when a calf consumed 1000 (W1000), 750 (W750), or 500 (W500) g of starter for three consecutive days. All calves received colostrum within 4 h of birth and colostrum intake was monitored to ensure all calves consumed 1.5 L within 12 h of birth. Calves were then fed fresh milk up to 2 L/d for 7 days. Between d 7 and 13, calves were fed a liquid feed composed of 50% fresh milk, and 50% milk replacer (MR) at maximum rate of 3 L/d. For the remainder of the study, calves were provided 3 L/d MR. Concentrate (starter), and grass hay were available ad libitum starting on d 1. Milk, MR, starter, and hay intakes were recorded daily. Calf body weights and measurements were recorded at birth and every 4 wk until weaning. Average weaning ages were 48 ± 4.5, 58 ± 4.6, and 65 ± 4.8 for W500, W750, and W1000, respectively. Between wk 8 and wk 21, calves in the W500 and W750 treatments had higher (p < 0.05) starter intakes than calves in the W1000 treatment. Body height, body length, circumference of cannon bone, circumference of the chest did not differ with weaning strategy (p > 0.05). There was no difference in body weight (BW) and average daily gain (ADG) on wk 5 when any of the calves were weaned (p > 0.05). In wk 9, BW of calves in W1000 tended to be higher than that of W750 and W500 (p = 0.10). However, calves in W1000 lost their BW advantage in wk 13. Calves' ADG was not different during the whole experiment period among treatments. Calves in W750 had higher plasma BHBA and the total antioxidant capacity which has been associated with a positive impact on health. Data in this experiment suggest that weaning when calves consume 750 g of starter can enhance ADG, DMI, feed efficiency, and selected blood parameters compared with weaning when calves consume 500 g of starter.

Non­canonical Wnt signaling contributes to ventilator­induced lung injury through upregulation of WISP1 expression.

Mechanical ventilation may cause ventilator­induced lung injury (VILI). Canonical Wnt signaling has been reported to serve an important role in the pathogenesis of VILI. Bioinformatics analysis revealed that canonical and non­canonical Wnt signaling pathways were activated in VILI. However, the role of non­canonical Wnt signaling in the pathogenesis of VILI remains unclear. The present study aimed to analyze the potential role of non­canonical Wnt signaling in VILI pathogenesis. Lung injury was assessed via Evans blue albumin permeability and histological scoring, as well as by inflammatory cytokine expression and total protein concentration in bronchoalveolar lavage fluid. The relative protein expression of canonical and non­canonical Wnt signaling pathway components were examined via western blotting and immunohistochemistry. The results demonstrated that 6 h of mechanical ventilation at low tidal volume (LTV; 6 ml/kg) or moderate tidal volume (MTV; 12 ml/kg) induced lung injury in sensitive A/J mice. Ventilation with MTV increased the protein levels of Wnt­induced secreted protein 1 (WISP1), Rho­associated protein kinase 1 (ROCK1), phosphorylated (p)­Ras homolog gene family, member A and p­C­Jun N­terminal kinase (JNK). Inhibition of ROCK1 by Y27632 and JNK by SP600125 attenuated MTV­induced lung injury and decreased the expression of proteins involved in non­canonical Wnt signaling, including WISP1. In conclusion, non­canonical Wnt signaling participates in VILI by modulating WISP1 expression, which has been previously noted as critical for VILI development. Therefore, the non­canonical Wnt signaling pathway may provide a preventive and therapeutic target in VILI.

Cyclic stretch induced IL-33 production through HMGB1/TLR-4 signaling pathway in murine respiratory epithelial cells.

Interleukin 33 (IL-33), an inflammatory and mechanically responsive cytokine, is an important component of a TLR4-dependent innate immune process in mucosal epithelium. Although TLR4 also plays a role in sensing biomechanical stretch, a pathway of stretch-induced TLR4-dependent IL-33 biosynthesis has not been revealed. In the current study, we show that short term (6 h) cyclic stretch (CS) of cultured murine respiratory epithelial cells (MLE-12) increased intracellular IL-33 expression in a TLR4 dependent fashion. There was no detectable IL-33 in conditioned media in this interval. CS, however, increased release of the notable alarmin, HMGB1, and a neutralizing antibody (2G7) to HMGB1 completely abolished the CS mediated increase in IL-33. rHMGB1 increased IL-33 synthesis and this was partially abrogated by silencing TLR4 suggesting additional receptors for HMGB1 are involved in its regulation of IL-33. Collectively, these data reveal a HMGB1/TLR4/IL-33 pathway in the response of respiratory epithelium to mechanical stretch.

Effects of various weaning times on growth performance, rumen fermentation and microbial population of yellow cattle calves.

OBJECTIVE: This study was conducted to investigate the effects of weaning times on the growth performance, rumen fermentation and microbial communities of yellow cattle calves. METHODS: Eighteen calves were assigned to a conventional management group that was normally weaned (NW, n = 3) or to early weaned (EW) group where calves were weaned when the feed intake of solid feed (starter) reached 500 g (EW500, n = 5), 750 g (EW750, n = 5), or 1,000 g (EW1,000, n = 5). RESULTS: Compared with NW, the EW treatments increased average daily gain (p<0.05). The calves in EW750 had a higher (p<0.05) starter intake than those in EW1,000 from wk 9 to the end of the trial. The concentrations of total volatile fatty acids in EW750 were greater than in NW and EW1,000 (p<0.05). The EW treatments decreased the percentage of acetate (p<0.05). The endogenous enzyme activities of the rumen were increased by EW (p<0.05). EW had no effect on the number of total bacteria (p>0.05), but changes in bacterial composition were found. CONCLUSION: From the present study, it is inferred that EW is beneficial for rumen fermentation, and weaning when the feed intake of the starter reached 750 g showed much better results.

IL-33 Signaling in Lung Injury.

Interleukin (IL)-33, a member of the IL-1 cytokine super-family, acts as both a traditional cytokine and an intracellular nuclear factor. It is generally released from damaged immune cells and signals through its receptor ST2 in an autocrine and paracrine fashion, plays important roles in type-2 innate immunity, and functions as an "alarmin" or a danger signal for cellular damage or cellular stress. Here, we review recent advances of the role of IL-33 in lung injury and explore its potential significance as an attractive therapeutic target.

[Delayed effect of isoflurane on hippocampal proteome after anesthesia in adult and aged rats].

OBJECTIVE: To investigate the delayed alteration of hippocampus proteome after anesthesia with isoflurane in adult and aged rats. METHODS: Ten 8-month-old SD rats were randomly divided into group C adult and group I adult (5 in each group), and another ten 22-month-old SD rats were randomly divided into group C aged and group I aged (5 in each group).The rats in group I adult and group I aged received 2 h anesthesia with 1.2% isoflurane. The rats in group C adult and group C aged inhaled 40% oxygen for contrast. The hippocampal proteome of each rat was measured by 2-dimensional gel electrophoresis and mass spectrometry. RESULTS: The vital signs of the rats in group I adult and group I aged were stable. There were 878+/-34 protein spots in group C adult, 864+/-49 protein spots in group I adult, 834+/-47 in group C aged, and 819+/-24 in group I aged. There were 12(4/8)different protein spots between group I adult and group C adult. There were 11(3/8)different protein spots between group I aged and group C aged. All of the protein spots were identified by MALDI-TOF-MS. Most of the different proteins were related to metabolism, anti-oxidation, and signal conditioning of synapse. CONCLUSION: Isoflurane may cause the alteration of hippocampal proteome in rats, which is age-related.