Interleukin-1ß triggers muscle-derived extracellular superoxide dismutase expression and protects muscles from doxorubicin-induced atrophy.

Doxorubicin, a conventional chemotherapeutic agent prescribed for cancer, causes skeletal muscle atrophy and adversely affects mobility and strength. Given that doxorubicin-induced muscle atrophy is attributable primarily to oxidative stress, its effects could be mitigated by antioxidant-focused therapies; however, these protective therapeutic targets remain ambiguous. The aim of this study was to demonstrate that doxorubicin triggers severe muscle atrophy via upregulation of oxidative stress (4-hydroxynonenal and malondialdehyde) and atrogenes (atrogin-1/MAFbx and muscle RING finger-1) in association with decreased expression of the antioxidant enzyme extracellular superoxide dismutase (EcSOD), in cultured C2C12 myotubes and mouse skeletal muscle. Supplementation with EcSOD recombinant protein elevated EcSOD levels on the cellular membrane of cultured myotubes, consequently inhibiting doxorubicin-induced oxidative stress and myotube atrophy. Furthermore, doxorubicin treatment reduced interleukin-1ß (IL-1ß) mRNA expression in cultured myotubes and skeletal muscle, whereas transient IL-1ß treatment increased EcSOD protein expression on the myotube membrane. Notably, transient IL-1ß treatment of cultured myotubes and local administration in mouse skeletal muscle attenuated doxorubicin-induced muscle atrophy, which was associated with increased EcSOD expression. Collectively, these findings reveal that the regulation of skeletal muscle EcSOD via maintenance of IL-1ß signalling is a potential therapeutic approach to counteract the muscle atrophy mediated by doxorubicin and oxidative stress. KEY POINTS: Doxorubicin, a commonly prescribed chemotherapeutic agent for patients with cancer, induces severe muscle atrophy owing to increased expression of oxidative stress; however, protective therapeutic targets are poorly understood. Doxorubicin induced muscle atrophy owing to increased expression of oxidative stress and atrogenes in association with decreased protein expression of extracellular superoxide dismutase (EcSOD) in cultured C2C12 myotubes and mouse skeletal muscle. Supplementation with EcSOD recombinant protein increased EcSOD levels on the cellular membrane of cultured myotubes, resulting in inhibition of doxorubicin-induced oxidative stress and myotube atrophy. Doxorubicin treatment decreased interleukin-1ß (IL-1ß) expression in cultured myotubes and skeletal muscle, whereas transient IL-1ß treatment in vivo and in vitro increased EcSOD protein expression and attenuated doxorubicin-induced muscle atrophy. These findings reveal that regulation of skeletal muscle EcSOD via maintenance of IL-1ß signalling is a possible therapeutic approach for muscle atrophy mediated by doxorubicin and oxidative stress.

Correlation Between Plasma NLRP3, IL-1ß, and IL-18 and Diabetic Nephropathy in Patients With Type 2 Diabetes.

Context: Diabetic nephropathy (DN) is a common microvascular complication in diabetic patients. The pathogenesis of DN is complex. Inflammatory response may play a key role as a common downstream pathway. Objective: The study intended to explore the relationship between the levels of plasma nucleotide-binding oligomeric domain-like receptor protein 3 (NLRP3 inflammasome), interleukin-1ß (IL-1ß), and IL-18 and the progression of type 2 diabetic nephropathy to clarify their relationship with type 2 diabetes mellitus (T2DM) and to provide evidence for clinical treatment. Design: The research team performed a controlled observational study. Setting: The study took place at Baoding No. 1 Central Hospital in Baoding, Hebei, China. Participants: Participants were 153 patients with T2DM who received treatment at the hospital between October 2020 and October 2021. The research team allocated 30 participants without evidence of DN to the control group. Based on the DN stage, the team assigned the 123 remaining participants to one of five observation groups: (1) 32 participants with stage 1 DN to the DN1 group, (2) 31 participants with stage 2 DN to the DN2 group, (3) 30 participants with stage 3 DN to the DN3 group, (4) 30 participants with stage 4 DN to the DN4 group, and (5) 29 participants with stage 5 DN to the DN5 group. Outcome Measures: The research team measured participants' levels of "nucleotide binding oligomeric domain-like receptor protein 3" (NLRP3), interleukin-1 beta (IL-1ß), and IL-18 and used the Spearman rank correlation analysis to determine the correlation between those levels and the DN stages. Results: The levels of NLRP3 , IL-1ß and IL-18 in all the five observation groups were significantly higher than those in the control group (all P < .01). The levels were also significantly higher: (1) in the DN2, DN3, DN4, and DN5 groups than those in the DN1 group (all P < .01); (2) in the DN3, DN4, and DN5 groups than those in the DN2 group (all P < .01); (3) in the DN4 and DN5 groups than those in the DN3 group (all P < .01); and (4) in the DN5 groups than those in the DN4 group (all P < .01). The Spearman rank correlation analysis showed that the NLRP3, IL-1ß, and IL-18 levels were significantly positively correlated with the DN stage (P = .01). Conclusions: NLRP3, IL-1ß and IL-18 played an important role in the progression of T2DM, and their levels increased with the aggravation of DN. Therefore, the plasma levels of NLRP3, IL-1ß and IL-18 can be useful as indicators of the occurrence and development of DN and can provide clinical guidance for the early diagnosis of DN and for the determination and adjustment of treatment plans.

Regulation of Inflammatory Response in Human Osteoarthritic Chondrocytes by Novel Herbal Small Molecules.

In this study, 34 Traditional Chinese Medicine (TCM) compounds were screened for potential anabolic and anti-inflammatory properties on human osteoarthritic (OA) chondrocytes. The anabolic effects were assessed by measuring the glycosaminoglycan (GAG) relative to the DNA content using a 3D pellet culture model. The most chondrogenic compounds were tested in an inflammatory model consisting of 3 days of treatment with cytokines (IL-1ß/TNF-α) with or without supplementation of TCM compounds. The anti-inflammatory effects were assessed transcriptionally, biochemically and histologically. From the 34 compounds, Vanilic acid (VA), Epimedin A (Epi A) and C (Epi C), 2''-O-rhamnosylicariside II (2-O-rhs II), Icariin, Psoralidin (PS), Protocatechuicaldehyde (PCA), 4-Hydroxybenzoic acid (4-HBA) and 5-Hydroxymethylfurfural (5-HMF) showed the most profound anabolic effects. After induction of inflammation, pro-inflammatory and catabolic genes were upregulated, and GAG/DNA was decreased. VA, Epi C, PS, PCA, 4-HBA and 5-HMF exhibited anti-catabolic and anti-inflammatory effects and prevented the up-regulation of pro-inflammatory markers including metalloproteinases and cyclooxygenase 2. After two weeks of treatment with TCM compounds, the GAG/DNA ratio was restored compared with the negative control group. Immunohistochemistry and Safranin-O staining confirmed superior amounts of cartilaginous matrix in treated pellets. In conclusion, VA, Epi C, PS, PCA, 4-HBA and 5-HMF showed promising anabolic and anti-inflammatory effects.

[Recombinant human interleukine-1beta (betaleukine) usage for acute radiation sickness of severe degree treatment at canines].

Recombinant human interleukine-1beta (betaleukune) of Institute of especially pure biopreparation production had been examined as a treatment means at acute radiation disease of severe degree at dogs. Dogs were irradiated totally in doses above the LD95/45. Betaleukine had been administered s/c twice in day in 15 min - 2 h after irradiation. All the dogs, including control ones, received in acute period 8-24/26 days after irradiation antibiotics ampicillin and gentamycin i/m. Betaleukine increased 45 day-survival by 37% at 4 Gy and by 25% at 4.4 Gy. The effect correlated with more high level of nadir and more early beginning the leucocyte number restoration. We observed the regularity at all the dogs that received betaleukine as survived as died, but in the latter case in a lesser degree certainly. Besides the noticed character of leucocytes kinetics had been repeated at all the blood cell types but in the different degree. It had been concluded on the base of these observations that betaleukine acts on hemopoietic stem cells preferentially. The effect is in preventing death of a stem cells part, or in stimulating survived stem cells proliferation, or in both together. Betaleukin can be regarded as a suitable means of urgent pathogenic therapy at radiation accidents.