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Purpose This study aimed to evaluate the clinical outcomes, failure rates, and complications associated with a second revision anterior cruciate ligament reconstruction using an Achilles tendon allograft in a mono-loop fashion, which allows simultaneous reconstruction of the anterior cruciate ligament and the anterolateral ligament. The hypothesis was that this combined technique is safe and leads to satisfactory clinical outcomes at mid-term follow-up. Methods A retrospective analysis was conducted on 20 patients who underwent a second revision ACL reconstruction between January 2018 and December 2022. All patients received an Achilles tendon allograft with a bone plug, used in a mono-loop technique to reconstruct both ACL and ALL. Exclusion criteria included multi-ligament injuries, posterior tibial slope > 12°, or follow-up shorter than 24 months. Clinical evaluation included pre- and postoperative scores: Tegner, subjective IKDC, Lysholm, and KOOS, as well as physical examination and Rolimeter testing. Mean follow-up was 32.2 months. Results The mean patient age was 36.8 ± 6.3 years. All clinical scores improved postoperatively: Tegner (from 64.3 to 87), subjective IKDC (55.1 to 64.4), Lysholm (58.2 to 76.9), and KOOS (59.7 to 70.1). Anteroposterior laxity decreased from 7.2 ± 2.1 mm preoperatively to 1.2 ± 1.3 mm postoperatively. A total of 55% of patients returned to their desired sports level, 25% to a lower level, and only one patient (5%) did not return owing to residual laxity. No postoperative complications or re-revisions were reported. Conclusions The mono-loop technique for simultaneous ACL and ALL reconstruction using an Achilles tendon allograft during a second revision procedure is safe and effective. It results in satisfactory mid-term outcomes, low failure rates, and no significant complications, providing a viable single-stage alternative for complex revision cases. Study design Cohort study; Level of evidence, 3.

Ecosystems associated with retreating glaciers are undergoing rapid transformation in the context of a changing climate. Invertebrate fauna, including the Chironomidae insect family (non-biting midges), is part of the active biology that characterizes glaciers and their surrounding habitats. The underlying microbiology, present in both the insects’ guts and their physical habitat, represents a critical interface, controlling, on the one hand, the basis of nutrient geochemical cycling and, on the other, the health and nutritional physiology of its hosts. We aimed to assess the extent to which insect-borne bacteria resemble those found in icemelt water and the surrounding wet and terrestrial environments, in order to determine also whether the bacteria found associated with the insects could be interpreted mainly as specific dwellers, putatively involved with active physiological functions, or also as transient cells taken in for other purposes. To this end, we analyzed physical and biological samples from ten different chironomid species in two glacier-fed streams, one proglacial pond, and the surrounding habitats of three glacier systems (Agola, Amola and Mandrone) in the Italian Alps. The samples were analyzed using culture-independent amplified 16S rRNA gene bacterial metabarcoding sequencing. The bacterial diversity in glacial habitats was unexpectedly high, with numbers of sequence variants similar to those recorded in temperate, lowland, productive soils, and almost seven times higher than those found in insects. There was minimal coincidence in sequence variants between insects and habitats, amounting to just 4.9% shared cases, and the few taxa found in both insects and habitats were mostly overrepresented in the former. Additionally, there were no significant differences between insect species or between insect communities from different sites. A number of taxa occurring uniquely in insects or habitats showed peculiarities at all taxonomic levels, including specific phyla. Evidence of microevolutionary distinctness was observed in the form of sequence variants assigned to the same taxonomic name that differed in specific sequence bases and were found to be partitioned either in insect or environmental samples. Interestingly, sequence variants found in both insects and environments scored higher in bioinformatic identification, reaching deeper assigned ranks compared to variants occurring only in insects or the environment. In essence, the compared insect and environmental communities showed a very low level of symmetry and consequently a very high level of specificity to one or the other condition. The data provided limited support about the diet of chironomids in relation to the microbiota of the habitat. This suggests that the food resource for these insects likely consists mostly of dissolved organic matter and detritus of various origins, rather than intact bacteria with sequenceable genomes, as is the case elsewhere with ruminant herbivores or birds.

Cannabis sativa is a remarkable source of bioactive compounds, with over 150 distinct phytocannabinoids identified to date. Among these, cannabinoids are gaining attention as potential therapeutic agents for neurodegenerative diseases. Previous research showed that cannabinol (CBN), a minor cannabinoid derived from Δ9-tetrahydrocannabinol, exhibits antioxidant, anti-inflammatory, analgesic, and anti-bacterial effects. The objective of this study was to assess the protective potential of 24 h CBN pre-treatment, applied at different concentrations (5 µM, 10 µM, 20 µM, 50 µM, and 100 µM), in differentiated neuroblastoma × spinal cord (NSC-34) cells. Transcriptomic analysis was performed using next-generation sequencing techniques. Our results reveal that CBN had no negative impact on cell viability at the tested concentrations. Instead, it showed a significant effect on stress response and neuroplasticity-related processes. Specifically, based on the Reactome database, the biological pathways mainly perturbed by CBN pre-treatment were investigated. This analysis highlighted a significant enrichment in the Reactome pathway’s cellular response to stress, cellular response to stimuli, and axon guidance. Overall, our results suggest that CBN holds promise as an adjuvant agent for neurodegenerative diseases by modulating genes involved in neuronal cell survival and axon guidance.

Neurological disorders such as Alzheimer’s, Parkinson’s, amyotrophic lateral sclerosis, and schizophrenia are associated with altered neuronal excitability, resulting from dysfunctions in the molecular architecture and physiological regulation of ion channels and synaptic transmission. Ion channels and synapses are regarded as suitable therapeutic targets in modern pharmacology. Cannabinoids have received great attention as an original therapeutic approach for their effects on human health due to their ability to modulate the neurotransmitter release through interaction with the endocannabinoid system. In our study, we explored the effect of cannabinol (CBN) through next-generation sequencing analysis of NSC-34 cell physiology. Our findings revealed that CBN strongly influences the ontologies related to ion channels and synapse activity at all doses tested. Specifically, the genes coding for calcium and potassium voltage-gated channel subunits, and the glutamatergic and GABAergic receptors (Cacna1b, Cacna1h, Cacng8, Kcnc3, Kcnd1, Kcnd2, Kcnj4, Grik5, Grik1, Slc17a7, Gabra5), were up-regulated. Conversely, the genes involved into serotoninergic and cholinergic pathways (Htr3a, Htr3b, Htr1b, Chrna3, Chrnb2, Chrnb4), were down-regulated. These findings highlight the influence of CBN in the expression of genes involved into ion influx and synaptic transmission.

Treatment for traumatic brain injury (TBI) remains elusive despite compelling evidence from animal models for a variety of therapeutic targets. The activation of the NLRP3 (Nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3) inflammasome has been proposed as key point in the brain damage associated with TBI. NLRP3 was tested as potential target for reducing neuronal loss and promoting functional recovery in a mouse model of TBI. Male NLRP3 -/- ( n = 20) and wild type ( n = 27) mice were used. A closed TBI model was performed and inflammatory and apoptotic markers were evaluated. A group of WT mice also received BAY 11-7082, a NLRP3 inhibitor, to further evaluate the role of this pathway. At 24 h following TBI NLRP3 -/- animals demonstrated a preserved cognitive function as compared to WT mice, additionally brain damage was less severe and the inflammatory mediators were reduced in brain lysates. The administration of BAY 11-7082 in WT animals subjected to TBI produced overlapping results. At day 7 histology revealed a more conserved brain structure with reduced damage in TBI NLRP3 -/- animals compared to WT. Our data indicate that the NLRP3 pathway might be exploited as molecular target for the short-term sequelae of TBI.

β-caryophyllene (BCP) is a cannabinoid receptor 2 (CB2) agonist that tempers inflammation. An interaction between the CB2 receptor and peroxisome proliferator-activated receptor gamma (PPAR-γ) has been suggested and PPAR-γ activation exerts anti-arthritic effects. The aim of this study was to characterize the therapeutic activity of BCP and to investigate PPAR-γ involvement in a collagen antibody induced arthritis (CAIA) experimental model. CAIA was induced through intraperitoneal injection of a monoclonal antibody cocktail and lipopolysaccharide (LPS; 50 μg/100 μL/ip). CAIA animals were then randomized to orally receive either BCP (10 mg/kg/100 μL) or its vehicle (100 μL of corn oil). BCP significantly hampered the severity of the disease, reduced relevant pro-inflammatory cytokines, and increased the anti-inflammatory cytokine IL-13. BCP also decreased joint expression of matrix metalloproteinases 3 and 9. Arthritic joints showed increased COX2 and NF-ĸB mRNA expression and reduced expression of the PPARγ coactivator-1 alpha, PGC-1α, and PPAR-γ. These conditions were reverted following BCP treatment. Finally, BCP reduced NF-ĸB activation and increased PGC-1α and PPAR-γ expression in human articular chondrocytes stimulated with LPS. These effects were reverted by AM630, a CB2 receptor antagonist. These results suggest that BCP ameliorates arthritis through a cross-talk between CB2 and PPAR-γ.

Spinal cord injury (SCI) is a complex clinical and progressive condition characterized by neuronal loss, axonal destruction and demyelination. In the last few years, adenosine receptors have been studied as a target for many diseases, including neurodegenerative conditions. The aim of this study was to investigate the effects of an adenosine receptor agonist, PDRN, in an experimental model of SCI. Moreover, since adenosine receptors stimulation may also activate the Wnt pathway, we wanted to study PDRN effects on Wnt signaling following SCI. Spinal trauma was induced by extradural compression of spinal cord at T5-T8 level in C57BL6/J mice. Animals were randomly assigned to the following groups: Sham ( n = 10), SCI ( n = 14), SCI+PDRN (8 mg/kg/i.p.; n = 14), SCI+PDRN+DMPX (8 and 10 mg/kg/i.p., respectively; n = 14). DMPX was used as an adenosine receptor antagonist to evaluate whether adenosine receptor block might prevent PDRN effects. PDRN systemically administered 1 h following SCI, protected from tissue damage, demyelination, and reduced motor deficits evaluated after 10 days. PDRN also reduced the release of the pro-inflammatory cytokines TNF-α and IL-1β, reduced BAX expression and preserved Bcl-2. Furthermore, PDRN stimulated Wnt/β-catenin pathway and decreased apoptotic process 24 h following SCI, whereas DMPX administration prevented PDRN effects on Wnt/β-catenin signaling. These results confirm PDRN anti-inflammatory activity and demonstrate that a crosstalk between Wnt/β-catenin signaling is possible by adenosine receptors activation. Moreover, these data let us hypothesize that PDRN might promote neural repair through axonal regeneration and/or neurogenesis.

[This corrects the article DOI: 10.3389/fphar.2017.00459.].

Cannabinoids are reported to have neuroprotective properties and play a role in neurogenesis and neuroplasticity in in vitro and in vivo models. Cannabinol (CBN) is a minor cannabinoid produced by the degradation of Δ9-tetrahydrocannabinol in Cannabis sativa L. and exhibits anti-oxidant, analgesic, anti-bacterial, and anti-inflammatory effects. In this study, we explored the biological effects of 20 µM CBN (6.20 µg/mL) on differentiated NSC-34 cells by MTT assay and next-generation sequencing analysis on the transcriptome. KEGG and Gene Ontology enrichment analyses have been performed to evaluate potential CBN-associated processes. Our results highlighted the absence of any cytotoxic effect of CBN. The comparative transcriptomic analysis pointed out the downregulation of Cdkn2a, Cdkn2c and Cdkn2d genes, which are known to suppress the cell cycle. Ccne2, Cdk2, Cdk7, Anapc11, Anapc10, Cdc23, Cdc16, Anapc4, Cdc27, Stag1, Smc3, Smc1a, Nipbl, Pds5a, Pds5b, and Wapl genes, renowned for their role as cell cycle progression activators, were instead upregulated. Our work suggests that CBN regulates the expression of many genes related to the cell cycle, which are required for axonal maturation, migration, and synaptic plasticity, while not affecting the expression of genes involved in cell death or tumorigenesis.

Research on bioactive compounds has grown recently due to their health benefits and limited adverse effects, particularly in reducing the risk of chronic diseases, including neurodegenerative conditions. According to these observations, this study investigates the activity of sulforaphane (RS-GRA) on an in vitro model of differentiated NSC-34 cells. We performed a transcriptomic analysis at various time points (24 h, 48 h, and 72 h) and RS-GRA concentrations (1 µM, 5 µM, and 10 µM) to identify molecular pathways influenced by this compound and the effects of dosage and prolonged exposure. We found 39 differentially expressed genes consistently up- or downregulated across all conditions. Notably, Nfe2l2, Slc1a5, Slc7a11, Slc6a9, Slc6a5, Sod1, and Sod2 genes were consistently upregulated, while Ripk1, Glul, Ripk3, and Mlkl genes were downregulated. Pathway perturbation analysis showed that the overall dysregulation of these genes results in a significant increase in redox pathway activity (adjusted p-value 1.11 × 10−3) and a significant inhibition of the necroptosis pathway (adjusted p-value 4.64 × 10−3). These findings suggest RS-GRA’s potential as an adjuvant in neurodegenerative disease treatment, as both increased redox activity and necroptosis inhibition may be beneficial in this context. Furthermore, our data suggest two possible administration strategies, namely an acute approach with higher dosages and a chronic approach with lower dosages.