Identification of two novel lipid metabolism-related long non-coding RNAs (SNHG17 and LINC00837) as potential signatures for osteosarcoma prognosis and precise treatment.

OBJECTIVE: Dysregulated lipid metabolism enhances the development and advancement of many cancers, including osteosarcoma (OS); however, the underlying mechanisms are still largely unknown. Therefore, this investigation aimed to elucidate novel potential lipid metabolism-related long non-coding RNAs (lncRNAs) that regulate OS development and provide novel signatures for its prognosis and precise treatment. MATERIALS AND METHODS: The GEO datasets (GSE12865 and GSE16091) were downloaded and analyzed using R software packages. Immunohistochemistry (IHC) was used to evaluate protein levels in OS tissues while real-time qPCR was used to measure lncRNA levels, and MTT assays were used to assess OS cell viability. RESULTS: Two lipid metabolism-associated lncRNAs (LM-lncRNAs), small nucleolar RNA host gene 17 (SNHG17) and LINC00837, were identified as efficient and independent prognostic indicators for OS. In addition, further experiments confirmed that SNHG17 and LINC00837 were significantly elevated in OS tissues and cells than para-cancerous counterparts. Knockdown of SNHG17 and LINC00837 synergistically suppressed the viability of OS cells, whereas overexpression of the two lncRNAs promoted OS cell proliferation. Moreover, bioinformatics analysis was conducted to construct six novel SNHG17-microRNA-mRNA competing endogenous RNA (ceRNA) networks, and three lipid metabolism-associated genes (MIF, VDAC2, and CSNK2A2) were found to be abnormally upregulated in OS tissues, suggesting that they were potential effector genes of SNHG17. CONCLUSION: In summary, SNHG17 and LINC00837 were found to promote OS cell malignancy, suggesting their use as ideal biomarkers for OS prognosis and treatment.

OL-FS13 alleviates experimental cerebral ischemia-reperfusion injury.

Cerebral ischemia-reperfusion (I/R) is the main cause of neurological injury after stroke. However, existing treatments for I/R injury are relatively poor, and relevant drugs need to be further explored. Amphibians have received increasing attention as a resource bank of bioactive peptides. However, reports on neuroprotective peptides from amphibians remain extremely rare. Here, we identified a new neuroprotective peptide (OL-FS13, amino acid sequence: FSLLLTWWRRRVC) from the odorous frog species Odorrana livida using a constructed cDNA library. OL-FS13 significantly improving infarct volume, behavioral and histological abnormalities in rats, and also showed neuroprotective activities in PC12 cell (by oxygen glucose deprivation/reoxygenation, OGD/R). Mechanistically, OL-FS13 increased the level of antioxidative enzymes to resist oxidative stress and alleviated endoplasmic reticulum (ER) stress induced by I/R and OGD/R. The use of ML385 (Nrf2 inhibitor) indicated that OL-FS13 relieved nerve damage caused by oxidative and ER stress by increasing the nuclear displacement of Nrf2. Collectively, this research provides a novel drug candidate for the clinical cerebral I/R curation.

Amphibian-derived peptide homodimer OA-GL17d promotes skin wound regeneration through the miR-663a/TGF-ß1/Smad axis.

Background: Amphibian-derived peptides exhibit considerable potential in the discovery and development of new therapeutic interventions for clinically challenging chronic skin wounds. MicroRNAs (miRNAs) are also considered promising targets for the development of effective therapies against skin wounds. However, further research in this field is anticipated. This study aims to identify and provide a new peptide drug candidate, as well as to explore the underlying miRNA mechanisms and possible miRNA drug target for skin wound healing. Methods: A combination of Edman degradation, mass spectrometry and cDNA cloning were adopted to determine the amino acid sequence of a peptide that was fractionated from the secretion of Odorrana andersonii frog skin using gel-filtration and reversed-phase high-performance liquid chromatography. The toxicity of the peptide was evaluated by Calcein-AM/propidium iodide (PI) double staining against human keratinocytes (HaCaT cells), hemolytic activity against mice blood cells and acute toxicity against mice. The stability of the peptide in plasma was also evaluated. The prohealing potency of the peptide was determined by MTS, scratch healing and a Transwell experiment against HaCaT cells, full-thickness injury wounds and scald wounds in the dorsal skin of mice. miRNA transcriptome sequencing analysis, enzyme-linked immunosorbent assay, real-time polymerase chain reaction and western blotting were performed to explore the molecular mechanisms. Results: A novel peptide homodimer (named OA-GL17d) that contains a disulfide bond between the 16th cysteine residue of the peptide monomer and the sequence 'GLFKWHPRCGEEQSMWT' was identified. Analysis showed that OA-GL17d exhibited no hemolytic activity or acute toxicity, but effectively promoted keratinocyte proliferation and migration and strongly stimulated the repair of full-thickness injury wounds and scald wounds in the dorsal skin of mice. Mechanistically, OA-GL17d decreased the level of miR-663a to increase the level of transforming growth factor-ß1 (TGF-ß1) and activate the subsequent TGF-ß1/Smad signaling pathway, thereby resulting in accelerated skin wound re-epithelialization and granular tissue formation. Conclusions: Our results suggest that OA-GL17d is a new peptide drug candidate for skin wound repair. This study emphasizes the importance of exogenous peptides as molecular probes for exploring competing endogenous RNA mechanisms and indicates that miR-663a may be an effective target for promoting skin repair.

Short Hexapeptide Optimized from Rice-Derived Peptide 1 Shows Promising Anti-hyperuricemia Activities.

Plant-derived peptides are a treasure trove for new-generation anti-hyperuricemia drugs. In the current study, we optimized a short hexapeptide rice-derived peptide 1 (RDP1)-M3 (AAAAGA) according to the anti-hyperuricemia RDP1 peptide identified from rice in our previous research. Results showed that RDP1-M3 exerted better hyperuricemia-alleviating and xanthine oxidase (XOD)-inhibiting potency in mice than RDP1. The biodistribution of RDP1-M3 was also analyzed. RDP1-M3 directly decreased XOD and uric acid levels in vivo and in vitro. In addition, RDP1-M3 reduced the expression of urate transporter 1 and glucose transporter 9, increased the level of organic anion transporter 1, reduced the expression of NOD-like receptor superfamily pyrin 3 inflammasomes, and reduced the levels of interleukin-1ß and tumor necrosis factor-α of hyperuricemic mice. Thus, our results indicated that the optimized short hexapeptide RDP1-M3 may be a candidate drug for anti-hyperuricemia.

A new peptide originated from amphibian skin alleviates the ultraviolet B-induced skin photodamage.

Although amphibian-derived bioactive peptides have attracted increasing attention for their potential use in the treatment of photodamage, research is still in its infancy. In this study, we obtained a new antioxidant peptide, named OA-GI13 (GIWAPWPPRAGLC), from the skin of the odorous frog Odorrana andersonii and determined its effects on ultraviolet B (UVB)-induced skin photodamage as well as its possible molecular mechanisms. Results showed that OA-GI13 directly scavenged free radicals, maintained the viability of hydrogen peroxide-challenged keratinocytes, promoted the release of superoxide dismutase, catalase, and glutathione, and reduced the level of lactate dehydrogenase. Furthermore, topical application of OA-GI13 in mice alleviated dorsal skin erythema and edema and protected the skin against UVB irradiation by increasing antioxidant levels and decreasing peroxide, malondialdehyde, and 8-hydroxydeoxyguanosine levels. OA-GI13 also alleviated oxidative stress injury in vivo and in vitro, possibly by inhibiting p38 protein phosphorylation. Our study confirmed the anti-photodamage effects of this novel amphibian-derived peptide, thus providing a new molecule for the development of drugs and topical agents for the treatment of skin photodamage.

Amphibian-derived peptide homodimer promotes regeneration of skin wounds.

Despite the increasing treatments in skin wound repair, existing therapeutic drugs cannot meet current needs. As such, skin wound repair remains a considerable clinical challenge, and thus the discovery of new pro-healing agents is crucial. Here, we identified the first naturally occurring peptide homodimer named as OA-GP11 dimer (OA-GP11d) from Odorrana andersonii (odorous frog) through the combinational methods of peptidomics and genomics. OA-GP11d was linked by the intramolecular disulfide formed by the 10th cysteine residues from the monomer of peptide with sequence of GPLSGINAECM, which effectively promoted the repair of full-thickness and burn wounds in mice. The underlying molecular mechanisms revealed that OA-GP11d not only accelerated the migration and cell-scratch healing of mouse keratinocytes, but also activated the mitogen-activated protein kinases (MAPKs) signaling pathway (phosphorylation of p38 and ERK subgroups) in immortalized human keratinocytes (HaCaT). Besides, OA-GP11d reduced the phosphorylation of nuclear factor-κB (NF-κB) and inhibitor of NF-κB (I-κB) induced by lipopolysaccharide stimulation in mouse macrophages, and inhibited the release of associated inflammatory factors tumor necrosis factor (TNF)-α and interleukin (IL)-6. OA-GP11d is the first identified naturally occurring peptide dimer with significant pro-healing potency. Our results highlight the importance of amphibians as a source of novel pro-healing agents and suggest OA-GP11d as a potential new pro-regenerative drug candidate.

Effect of Artificial Tiger Bone Powder (Jintiange Capsule®) on Vertebral Height Ratio, Cobb's Angle, Bone Mineral Density, and Visual Analog Score.

OBJECTIVES: To investigate the effect of Jintiange capsule on acute bone atrophy (vertebral height, Cobb's angle, bone mineral density, and visual analog score (VAS) in patients with osteoporotic vertebral compression fracture. METHODS: A total of 106 patients with osteoporotic vertebral compression fractures were selected and randomly divided into study and control group. Vertebral height ratio (VHR), Cobb's angle, bone mineral density (BMD), and VAS analyses were performed as study indexes. The study was performed from January 2019 to December 2019 as a double-blind, randomized, controlled trial and all the participants were blinded throughout the study. There were 24 males and 29 females in the study group, with 14 cases of thoracic fractures and 39 cases of lumbar fractures. The age was 61-75 years, with an average of 67.5 ± 2.7 years, and the course of disease was 1-9 days, with an average of 2.7 ± 0.5 days. There were 22 males and 31 females in the control group, with 17 cases of thoracic fractures and 36 cases of lumbar fractures. Patients in the control group received conventional postoperative treatment, while patients in the study group were treated with Jintiange capsule. The treatment continued for 3 months. The ages of the participants were from 60 to 70 years, while the average ages of both groups were 67 ± 2.8 years and the study recruited participants of both sexes. RESULTS: The clinical efficacy, vertebral imaging indexes before and after treatment, as well as pain and daily activity dysfunction scores were compared. The effect of the Jintiange capsule was followed for 3 months and both the groups were compared. The total effective score of the study group was significantly increased (90.6%) in contrast to the control group (67.9) and the P value was less than the 0.5. The vertebral height and bone mineral density of the study group was significantly improved compared to the control group (P < 0.034) using t-test. However, the Cobb's angle of the study group was significantly (P < 0.047) lower than the control group using t-test after the treatment. On the other hand, the VAS score and Oswestry score of the study group were significantly lower than control group at 1 month and 3 months after treatment (P < 0.05). There was no significance difference (all P > 0.05) in term of gender and ages in both the recruited groups. CONCLUSION: It can be concluded that Jintiange capsule can significantly improve the clinical efficacy rate, vertebral height, Cobb's angle, and bone mineral density, pain relief, and daily activity function.

Effectiveness of transverse tibial bone transport in treatment of diabetic foot ulcer: A systematic review and meta-analysis.

Background: Diabetic foot ulcerations (DFUs) are a common but highly morbid complication of long-standing diabetes, carrying high rates of associated major amputation and mortality. Transverse tibial bone transport (TTT) has recently been applied for treatment of DFUs with the aim of accelerating wound healing. This study was performed to evaluate the effectiveness and safety of TTT in patients with DFUs. Methods: Two authors independently retrieved the platforms of PubMed, Embase and CENTRAL, to identify studies associated with treatment of DFUs with TTT. Quantitative meta-analyses were performed to pool all available outcomes about the effectiveness and complications of TTT operation, with fixed- (I2<50%) or random-effect (I2>50%) model according to I2. Results: A total of 7 studies, involving 818 participants, were included, with 661 participants treated with TTT operation. The pooled healing rate and limb salvage rate were 0.96 (95%CI: 0.93~0.98) and 0.98 (95%CI: 0.95~1.00) respectively after treatment with TTT. The pooled mean healing time was 15.03 (95%CI: 9.05~21.00) months. When compared with the pre-operative baseline values, the ankle-brachial index (ABI, MD: 0.23; 95%CI: 0.03~0.44; p<0.001), skin temperature (MD: 1.56; 95%CI: 0.30~2.81; p<0.001), and visual analogue scale (VAS, MD: 3.70; 95%CI: 1.97~5.44; p<0.001) were significantly improved at the final follow-up. When compared with non-TTT group, the TTT group was associated with higher healing rate (OR: 10.43; 95%CI: 3.96~27.43; p<0.001) and limb salvage rate (OR: 9.65; 95%CI: 3.30~28.20; p<0.001). Concerning the complications of the TTT process, the pooled risks of fracture at transportation site and pin-site infection were 0.02 (95%CI: 0.00~0.04) and 0.08 (95%CI: 0.00~0.22), respectively; and the DFU recurrence rate in TTT group was significantly lowered comparing to that of the non-TTT group (RR: 0.18; 95%CI: 0.06~0.49; p=0.001). Conclusions: TTT operation was associated with high healing rate and limb salvage rate, and could significantly improve the ABI, skin temperature, and VAS after operation. When compared with the control group, TTT group provided significantly higher healing rate and limb salvage rate. However, TTT operation should be conducted with caution concerning the incidences of fracture at tibia, infection at pin channels and necrosis of skin overlying the anterior tibia.

The beneficial roles of poisonous skin secretions in survival strategies of the odorous frog Odorrana andersonii.

The evolution of predatory, anti-predatory, and defensive strategies regarding environmental adaptation in animals is of significant research interest. In particular, amphibians, who represent a transition between aquatic and terrestrial vertebrates, play an important role in animal evolution. The bioactive skin secretions of amphibians are of specific interest due to their involvement in the crucial physiological functions of amphibian skin. We previously isolated and identified several bioactive peptides, including those showing antioxidant, antimicrobial, and wound-healing properties, from the skin secretions of the odorous frog species Odorrana andersonii. Currently, however, the biological significance of skin secretions in O. andersonii survival remains unclear. Here, we studied the biological significance of skin glands and secretions in regard to environmental adaptations of O. andersonii. Our research found that O. andersonii may secrete and excrete bioactive secretions through many glands (peptides and proteins as the main components in glands) distributed in the skin. The skin secretions not only displayed toxicity but also showed antioxidant, antibacterial, and repair promoting activities, suggesting that they play a protective role in O. andersonii when facing environmental threats. These bioactive skin secretions appear to act as a chemical survival strategy in O. andersonii, allowing the species to gain advantages in survival behavior.

Hollow polydopamine nanoparticles loading with peptide RL-QN15: a new pro-regenerative therapeutic agent for skin wounds.

BACKGROUND: Although the treatments of skin wounds have greatly improved with the increase in therapeutic methods and agents, available interventions still cannot meet the current clinical needs. Therefore, the development of new pro-regenerative therapies remains urgent. Owing to their unique characteristics, both nanomaterials and peptides have provided novel clues for the development of pro-regenerative agents, however, more efforts were still be awaited and anticipated. RESULTS: In the current research, Hollow polydopamine (HPDA) nanoparticles were synthesized and HPDA nanoparticles loading with RL-QN15 (HPDAlR) that was an amphibian-derived peptide with obvious prohealing activities were prepared successfully. The characterization, biodistribution and clearance of both HPDA nanoparticles and HPDAlR were evaluated, the loading efficiency of HPDA against RL-QN15 and the slow-releasing rate of RL-QN15 from HPDAlR were also determined. Our results showed that both HPDA nanoparticles and HPDAlR exerted no obvious toxicity against keratinocyte, macrophage and mice, and HPDA nanoparticles showed no prohealing potency in vivo and in vitro. Interestingly, HPDAlR significantly enhanced the ability of RL-QN15 to accelerate the healing of scratch of keratinocytes and selectively modulate the release of healing-involved cytokines from macrophages. More importantly, in comparison with RL-QN15, by evaluating on animal models of full-thickness injured skin wounds in mice and oral ulcers in rats, HPDAlR showed significant increasing in the pro-regenerative potency of 50 and 10 times, respectively. Moreover, HPDAlR also enhanced the prohealing efficiency of peptide RL-QN15 against skin scald in mice and full-thickness injured wounds in swine. CONCLUSIONS: HPDA obviously enhanced the pro-regenerative potency of RL-QN15 in vitro and in vivo, hence HPDAlR exhibited great potential in the development of therapeutics for skin wound healing.

Novel amphibian-derived antioxidant peptide protects skin against ultraviolet irradiation damage.

Given the adverse impact of ultraviolet irradiation on human skin, as well as currently limited interventions, the discovery of new molecules with anti-photodamage potency remains critical. In this research, we obtained a new bioactive peptide (named OS-LL11, amino acid sequence 'LLPPWLCPRNK') from Odorrana schmackeri. Results showed that OS-LL11 could directly scavenge free radicals and sustain the viability of mouse keratinocytes challenged by ultraviolet B (UVB) irradiation or hydrogen peroxide (H2O2) by decreasing the levels of lipid peroxidation, malondialdehyde, and reactive oxygen species while increasing the level of catalase, Keap-1, HO-1, GCLM, and NQO1. Interestingly, topical application of OS-LL11 protected mouse skin against UVB irradiation damage by up-regulating the levels of superoxide dismutase, glutathione, and nitric oxide, but down-regulating the levels of H2O2, IL-1α, IL-1ß, IL-6, TNF-α, 8-OHdG, Bcl-2, and Bax, as well as the number of apoptotic bodies. Our research demonstrated the anti-photodamage activity of a novel amphibian-derived peptide and the potential underlying mechanisms related to its free radical scavenging ability and antioxidant, anti-inflammatory, and anti-apoptotic activities. This study provides a new molecule for the development of anti-skin photodamage drugs or cosmetics and highlights the prospects of amphibian-derived peptides in photodamaged skin intervention.

Discovery of a novel short peptide with efficacy in accelerating the healing of skin wounds.

Despite extensive efforts to develop efficacious therapeutic approaches, the treatment of skin wounds remains a considerable clinical challenge. Existing remedies cannot sufficiently meet current needs, so the discovery of novel pro-healing agents is of growing importance. In the current research, we identified a novel short peptide (named RL-QN15, primary sequence 'QNSYADLWCQFHYMC') from Rana limnocharis skin secretions, which accelerated wound healing in mice. Exploration of the underlying mechanisms showed that RL-QN15 activated the MAPK and Smad signaling pathways, and selectively modulated the secretion of cytokines from macrophages. This resulted in the proliferation and migration of skin cells and dynamic regulation of TGF-ß1 and TGF-ß3 in wounds, which accelerated re-epithelialization and granulation tissue formation and thus skin regeneration. Moreover, RL-QN15 showed significant therapeutic potency against chronic wounds, skin fibrosis, and oral ulcers. Our results highlight frog skin secretions as a potential treasure trove of bioactive peptides with healing activity. The novel peptide (RL-QN15) identified in this research shows considerable capacity as a candidate for the development of novel pro-healing agents.

Peptide OM-LV20 exerts neuroprotective effects against cerebral ischemia/reperfusion injury in rats.

Ischemia/reperfusion (I/R) is a common injury leading to ischemic stroke. At present, I/R treatment remains limited, highlighting the urgent need for the discovery and development of new protective drugs for brain injury. Here, we investigated the neuroprotective effects of short peptide OM-LV20 previously identified from amphibian against I/R rats. Results showed that intraperitoneal administration of OM-LV20 (20 ng/kg) significantly reduced infarct area formation, improved behavioral abnormalities, and protected cortical and hippocampal neurons against death caused by I/R. Moreover, the underlying molecular mechanism was involved with the regulation of the MAPK and BDNF/AKT signaling pathways, as well as the levels of cyclic adenosine monophosphate, pituitary adenylate cyclase-activating polypeptide receptor, and tryptophan hydroxylase 1. To the best of our knowledge, this research was the first report to describe the neuroprotective effects of an amphibian skin secretion-derived peptide in I/R rats and highlighted OM-LV20 as a promising drug candidate for the development of novel anti-stroke therapies.

Discovery of a novel rice-derived peptide with significant anti-gout potency.

As a metabolic disease, gout, which seriously affects the normal life of patients, has become increasingly common in modern society. However, the existing medicines cannot completely meet the clinical needs. In the current study, a novel short peptide (named rice-derived-peptide-2 (RDP2), AAAAGAMPK-NH2, 785.97 Da) was isolated and identified from water extract of shelled Oryza sativa fruits, without toxic side effects but excellent stability. Our results indicated that RDP2 (the minimum effective concentration is 5 µg kg-1) induced a significant reduction in serum uric acid levels in hyperuricemic mice via suppressing xanthine oxidase activity and urate transporter 1 expression, as well as alleviated renal damage through inhibiting the activation of NLRP3 inflammasome. In addition, RDP2 can also alleviate paw swelling and inflammatory reactions in mice after subcutaneous injection of monosodium urate crystals. As mentioned above, we obtained a novel peptide which could work through all stages of gout, not only reducing uric acid levels and renal damage in hyperuricemic mice, but also alleviating inflammatory responses associated with acute gout attack, and thus provided a new peptide molecular template for the development of anti-gout drugs.

RDP3, A Novel Antigout Peptide Derived from Water Extract of Rice.

Gout and hyperuricemia can seriously affect the quality of life; at present, however, existing medicines are unable to meet all clinical needs. In the current study, a novel peptide (i.e., rice-derived-peptide-3 (RDP3), AAAAMAGPK-NH2, 785.97 Da) in water extract obtained from shelled Oryza sativa fruits was identified. Testing revealed that RDP3 (minimum effective concentration 100 µg/kg) did not show both hemolytic and acute toxicity, and reduced uric acid levels in the serum of hyperuricemic mice by inhibiting xanthine oxidase activity and decreasing urate transporter 1 expression. RDP3 also alleviated renal injury in hyperuricemic mice by decreasing NLRP3 inflammasome expression. Furthermore, RDP3 alleviated formalin-induced paw pain and reduced monosodium urate crystal-induced paw swelling and inflammatory factors in mice. Thus, this newly identified peptide reduced uric acid levels and renal damage in hyperuricemic mice and showed anti-inflammatory and analgesic activities, indicating the potential of RDP3 as an antigout medicine candidate.