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Graphical abstract, Introduction Neomenthol, a cyclic monoterpenoid, is a stereoisomer of menthol present in the essential oil of Mentha spp. It is used in food as a flavoring agent, in cosmetics and medicines because of its cooling effects. However, neomenthol has not been much explored for its anticancer potential. Additionally, targeting hyaluronidase, Cathepsin-D, and ODC by phytochemicals is amongst the efficient approach for cancer prevention and/or treatment. Objectives To investigate the molecular and cell target-based antiproliferative potential of neomenthol on human cancer (A431, PC-3, K562, A549, FaDu, MDA-MB-231, COLO-205, MCF-7, and WRL-68) and normal (HEK-293) cell lines. Methods The potency of neomenthol was evaluated on human cancer and normal cell line using SRB, NRU and MTT assays. The molecular target based study of neomenthol was carried out in cell-free and cell-based test systems. Further, the potency of neomenthol was confirmed by quantitative real-time PCR analysis and molecular docking studies. The in vivo anticancer potential of neomenthol was performed on mice EAC model and the toxicity examination was accomplished through in silico, ex vivo and in vivo approaches. Results Neomenthol exhibits a promising activity (IC50 17.3 ± 6.49 μM) against human epidermoid carcinoma (A431) cells by arresting the G2/M phase and increasing the number of sub-diploid cells. It significantly inhibits hyaluronidase activity (IC50 12.81 ± 0.01 μM) and affects the tubulin polymerization. The expression analysis and molecular docking studies support the in vitro molecular and cell target based results. Neomenthol prevents EAC tumor formation by 58.84% and inhibits hyaluronidase activity up to 10% at 75 mg/kg bw, i.p. dose. The oral dose of 1000 mg/kg bw was found safe in acute oral toxicity studies. Conclusion Neomenthol delayed the growth of skin carcinoma cells by inhibiting the tubulin polymerization and hyaluronidase activity, which are responsible for tumor growth, metastasis, and angiogenesis.

Exosomes are cell-derived nanovesicles with diameters from 30 to 150 nm, released upon fusion of multivesicular bodies with the cell surface. They can transport nucleic acids, proteins, and lipids for intercellular communication and activate signaling pathways in target cells. In cancers, exosomes may participate in growth and metastasis of tumors by regulating the immune response, blocking the epithelial–mesenchymal transition, and promoting angiogenesis. They are also involved in the development of resistance to chemotherapeutic drugs. Exosomes in liquid biopsies can be used as non-invasive biomarkers for early detection and diagnosis of cancers. Because of their amphipathic structure, exosomes are natural drug delivery vehicles for cancer therapy., Graphical abstract This review summarizes the biology, function, and applications of exosomes in cancers. Exosomes can be used as non-invasive biomarkers for early detection and diagnosis of cancers. Exosomes also act as natural drug delivery vehicles for cancer therapy.Image 1

The tumor development and metastasis are closely related to the structure and function of the tumor microenvironment (TME). Recently, TME modulation strategies have attracted much attention in cancer immunotherapy. Despite the preliminary success of immunotherapeutic agents, their therapeutic effects have been restricted by the limited retention time of drugs in TME. Compared with traditional delivery systems, nanoparticles with unique physical properties and elaborate design can efficiently penetrate TME and specifically deliver to the major components in TME. In this review, we briefly introduce the substitutes of TME including dendritic cells, macrophages, fibroblasts, tumor vasculature, tumor-draining lymph nodes and hypoxic state, then review various nanoparticles targeting these components and their applications in tumor therapy. In addition, nanoparticles could be combined with other therapies, including chemotherapy, radiotherapy, and photodynamic therapy, however, the nanoplatform delivery system may not be effective in all types of tumors due to the heterogeneity of different tumors and individuals. The changes of TME at various stages during tumor development are required to be further elucidated so that more individualized nanoplatforms could be designed., Graphical abstract Image 1, Highlights • In responsive to the changes in TME, nanoparticles target tumor microenvironment and enhance the therapeutic effect. • Nanoparticles modulate the activation and maturation of DC. • Nanoparticles could reprogram polarization of TAM and relieve hypoxia. • Nanoparticles could transfer the immunosuppressive TME to immunosupportive.

Pulmonary administration route has been extensively exploited for the treatment of local lung diseases such as asthma, chronic obstructive pulmonary diseases and respiratory infections, and systemic diseases such as diabetes. Most inhaled medicines could be cleared rapidly from the lungs and their therapeutic effects are transit. The inhaled medicines with extended pulmonary exposure may not only improve the patient compliance by reducing the frequency of drug administration, but also enhance the clinical benefits to the patients with improved therapeutic outcomes. This article systematically reviews the physical and chemical strategies to extend the pulmonary exposure of the inhaled medicines. It starts with an introduction of various physiological and pathophysiological barriers for designing inhaled medicines with extended lung exposure, which is followed by recent advances in various strategies to overcome these barriers. Finally, the applications of the inhaled medicines with extended lung exposure for the treatment of various diseases and the safety concerns associated to various strategies to extend the pulmonary exposure of the inhaled medicines are summarized., Graphical abstract Strategies including molecular modification, polymeric conjugation, formulation technologies, etc. are being developed to extend pulmonary drug exposure. Inhaled medicines with extended lung exposure could be potentially favored for therapeutic efficacy.Image 1

Volumetric muscle loss (VML) injuries characterized by critical loss of skeletal muscle tissues result in severe functional impairment. Current treatments involving use of muscle grafts are limited by tissue availability and donor site morbidity. In this study, we designed and synthesized an implantable glycosaminoglycan-based hydrogel system consisting of thiolated hyaluronic acid (HA) and thiolated chondroitin sulfate (CS) cross-linked with poly(ethylene glycol) diacrylate to promote skeletal muscle regeneration of VML injuries in mice. The HA-CS hydrogels were optimized with suitable biophysical properties by fine-tuning degree of thiol group substitution to support C2C12 myoblast proliferation, myogenic differentiation and expression of myogenic markers MyoD, MyoG and MYH8. Furthermore, in vivo studies using a murine quadriceps VML model demonstrated that the HA-CS hydrogels supported integration of implants with the surrounding host tissue and facilitated migration of Pax7+ satellite cells, de novo myofiber formation, angiogenesis, and innervation with minimized scar tissue formation during 4-week implantation. The hydrogel-treated and autograft-treated mice showed similar functional improvements in treadmill performance as early as 1-week post-implantation compared to the untreated groups. Taken together, our results demonstrate the promise of HA-CS hydrogels as regenerative engineering matrices to accelerate healing of skeletal muscle injuries., Graphical abstract Image 1, Highlights • Synthesized a biomimetic HA-CS hydrogel system with properties tailored for skeletal muscle. • HA-CS hydrogels supported in vitro myoblast cell behavior. • Implanted cell-free HA-CS hydrogels promoted de novo skeletal muscle regeneration. • HA-CS hydrogels enhanced in vivo angiogenesis and innervation. • HA-CS hydrogels promoted functional recovery comparable to autograft transplants.

Fibrosis is a pathological reparative process that can occur in most organs and is responsible for nearly half of deaths in the developed world. Despite considerable research, few therapies have proven effective and been approved clinically for treatment of fibrosis. Artemisinin compounds are best known as antimalarial therapeutics, but they also demonstrate antiparasitic, antibacterial, anticancer, and anti-fibrotic effects. Here we summarize literature describing anti-fibrotic effects of artemisinin compounds in in vivo and in vitro models of tissue fibrosis, and we describe the likely mechanisms by which artemisinin compounds appear to inhibit cellular and tissue processes that lead to fibrosis. To consider alternative routes of administration of artemisinin for treatment of internal organ fibrosis, we also discuss the potential for more direct oral delivery of Artemisia plant material to enhance bioavailability and efficacy of artemisinin compared to administration of purified artemisinin drugs at comparable doses. It is our hope that greater understanding of the broad anti-fibrotic effects of artemisinin drugs will enable and promote their use as therapeutics for treatment of fibrotic diseases., Graphical abstract Artemisinin drugs, isolated from Artemisia, effectively prevent or treat multiple types of tissue fibrosis when administered to several preclinical animal models of varied etiologies.Image 1

Psoriatic arthritis (PsA) is a complicated psoriasis comorbidity with manifestations of psoriatic skin and arthritic joints, and tailoring specific treatment strategies for simultaneously delivering different drugs to different action sites in PsA remains challenging. We developed a need-based layered dissolving microneedle (MN) system loading immunosuppressant tacrolimus (TAC) and anti-inflammatory diclofenac (DIC) in different layers of MNs, i.e., TD-MN, which aims to specifically deliver TAC and DIC to skin and articular cavity, achieving simultaneous alleviation of psoriatic skin and arthritic joint lesions in PsA. In vitro and in vivo skin permeation demonstrated that the inter-layer retained TAC within the skin of ∼100 μm, while the tip-layer delivered DIC up to ∼300 μm into the articular cavity. TD-MN not only efficiently decreased the psoriasis area and severity index scores and recovered the thickened epidermis of imiquimod-induced psoriasis but also alleviated carrageenan/kaolin-induced arthritis even better than DIC injection through reducing joint swelling, muscle atrophy, and cartilage destruction. Importantly, TD-MN significantly inhibited the serum TNF-α and IL-17A in psoriatic and arthritic rats. The results support that this approach represents a promising alternative to multi-administration of different drugs for comorbidity, providing a convenient and effective strategy for meeting the requirements of PsA treatment., Graphical abstract A need-based layered dissolving microneedle system loading tacrolimus (TAC) and diclofenac sodium (DIC) in different layers specifically delivers TAC and DIC to skin and articular cavity, simultaneously alleviating psoriatic skin and arthritic joint lesions.Image 1

Summary Objective To investigate the mitigate efficacy of Chinese medicine Lingzhi (LZ) and San-Miao-San (SMS) combined with hyaluronic acid (HA)-gel in attenuating cartilage degeneration in traumatic osteoarthritis (OA). Methods The standardized surgery of anterior cruciate ligament transection (ACLT) was made from the medial compartment of right hind limbs of 8-week-old female SD rats and resulted in a traumatic OA. Rats (n ​= ​5/group) were treated once intra-articular injection of 50 ​μl HA-gel, 50 ​μl HA-gel+50 ​μg LZ-SMS, 50 ​μl of saline+50 ​μg LZ-SMS and null (ACLT group) respectively, except sham group. Limbs were harvested for μCT scan and histopathological staining 3-month post-treatment. Inflammatory cytokines from plasma and synovial fluid were detected using Immunology Multiplex Assay kit. The putative targets of active compounds in LZ-SMS and known therapeutic targets for OA were combined to construct protein–protein interaction network. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis was adopted to predict the potential targets and signaling pathway of LZ-SMS in OA through the tool of DAVID Bioinformatics. Results In vivo, HA-gel ​+ ​LZ-SMS treatment resulted in a higher volume ratio of hyaline cartilage (HC)/calcified cartilage (CC) and HC/Sum (total volume of cartilage), compared to ACLT and HA-gel groups. In addition, histological results showed the elevated cartilage matrix, chondrogenic and osteoblastic signals in HA-gel ​+ ​LZ-SMS treatment. Treatment also significantly altered subchondral bone (SCB) structure including an increase in BV/TV, Tb.Th, BMD, Conn.Dn, Tb.N, and DA, as well as a significant decrease in Tb.Sp and Po(tot), which implied a protective effect on maintaining the stabilization of tibial SCB microstructure. Furthermore, there was also a down-regulated inflammatory cytokines and upregulated anti-inflammatory cytokine IL-10 in HA+LZ-SMS group. Finally, 64 shared targets from 37 active compounds in LZ-SMS related to the core genes for the development of OA. LZ-SMS has a putative role in regulating inflammatory circumstance through influencing the MAPK signaling pathway. Conclusion Our study elucidated a protective effect of HA-gel ​+ ​LZ-SMS in mitigating cartilage degradation and putative interaction with targets and signaling pathway for the development of traumatic OA. The translational potential of this article Our results provide a biological rationale for the use of LZ-SMS as a potential candidate for OA treatment.

Inflammatory bowel disease (IBD) is a chronic intestinal disease with painful clinical manifestations and high risks of cancerization. With no curative therapy for IBD at present, the development of effective therapeutics is highly advocated. Drug delivery systems have been extensively studied to transmit therapeutics to inflamed colon sites through the enhanced permeability and retention (EPR) effect caused by the inflammation. However, the drug still could not achieve effective concentration value that merely utilized on EPR effect and display better therapeutic efficacy in the inflamed region because of nontargeted drug release. Substantial researches have shown that some specific receptors and cell adhesion molecules highly expresses on the surface of colonic endothelial and/or immune cells when IBD occurs, ligand-modified drug delivery systems targeting such receptors and cell adhesion molecules can specifically deliver drug into inflamed sites and obtain great curative effects. This review introduces the overexpressed receptors and cell adhesion molecules in inflamed colon sites and retrospects the drug delivery systems functionalized by related ligands. Finally, challenges and future directions in this field are presented to advance the development of the receptor-mediated targeted drug delivery systems for the therapy of IBD., Graphical abstract When inflammatory bowel disease occurs, some specific receptors and cell adhesion molecules, like mannose receptor, CD98, CD44 and ICAM-1, are overexpressed on the colonic epithelial cells and/or immune cells. Drug delivery systems superficially modified with related ligands can specifically bind to receptors on inflamed cells and deliver drug into target area.Image 1

Localized delivery, comparing to systemic drug administration, offers a unique alternative to enhance efficacy, lower dosage, and minimize systemic tissue toxicity by releasing therapeutics locally and specifically to the site of interests. Herein, a localized drug delivery platform (“plum‒pudding” structure) with controlled release and long-acting features is developed through an injectable hydrogel (“pudding”) crosslinked via self-assembled triblock polymeric micelles (“plum”) to help reduce renal interstitial fibrosis. This strategy achieves controlled and prolonged release of model therapeutics in the kidney for up to three weeks in mice. Following a single injection, local treatments containing either anti-inflammatory small molecule celastrol or anti-TGFβ antibody effectively minimize inflammation while alleviating fibrosis via inhibiting NF-κB signaling pathway or neutralizing TGF-β1 locally. Importantly, the micelle-hydrogel hybrid based localized therapy shows enhanced efficacy without local or systemic toxicity, which may represent a clinically relevant delivery platform in the management of renal interstitial fibrosis., Graphical abstract Schematic representation of the “plum‒pudding” system consisting of hyaluronic acid (HA)-derived hydrogel crosslinked via self-assembled triblock micelles, which can serve as a reservoir for hydrophobic solutes to achieve controlled and prolonged release.Image 1

Trabeculectomy is the mainstay of surgical glaucoma treatment, while the success rate was unsatisfying due to postoperative scarring of the filtering blebs. Clinical countermeasures for scar prevention are intraoperative intervention or repeated subconjunctival injections. Herein, we designed a co-delivery system capable of transporting fluorouracil and anti-TGF-β2 oligonucleotide to synergistically inhibit fibroblast proliferation via topical instillation. This co-delivery system was built based on a cationic dendrimer core (PAMAM), which encapsulated fluorouracil within hydrophobic cavity and condensed oligonucleotide with surface amino groups, and was further modified with hyaluronic acid and cell-penetrating peptide penetratin. The co-delivery system was self-assembled into nanoscale complexes with increased cellular uptake and enabled efficient inhibition on proliferation of fibroblast cells. In vivo studies on rabbit trabeculectomy models further confirmed the anti-fibrosis efficiency of the complexes, which prolonged survival time of filtering blebs and maintained their height and extent during wound healing process, exhibiting an equivalent effect on scar prevention compared to intraoperative infiltration with fluorouracil. Qualitative observation by immunohistochemistry staining and quantitative analysis by Western blotting both suggested that TGF-β2 expression was inhibited by the co-delivery complexes. Our study provided a potential approach promising to guarantee success rate of trabeculectomy and prolong survival time of filtering blebs., Graphical abstract A cationic dendrimer poly(amidoamine) (PAMAM) was used for co-loading of fluorouracil and anti-TGF-β2 oligonucleotide, which further self-assembled with hyaluronic acid and cell-penetrating peptide penetratin to form the co-delivery complexes. The complexes could efficiently inhibit fibroblast proliferation via topical instillation, which could improve success rate of trabeculectomy.Image 1

Graphical abstract Comparison of delivery efficiency of insertion-responsive microneedles and coated microneedles after insertion into a dog’s hairy ear. (a, a’) Vaccine-coated microneedle array patch (MAP) with magnified image and vaccine-coated insertion-responsive microneedles (IRMN) with magnified image. (b, b’) Administration of MAP and IRMN, respectively. (c, c’) Images of MAP and IRMN with magnified image after removal from skin. Scale bar in magnified image is 150 μm. IRMN can provide quick, painless, and convenient drug delivery into hairy animals., Highlights • IRMN are the first microneedle system to deliver a canine vaccine successfully into a hairy dog without removal of the dog’s hair. • The use of IRMN can provide both convenience and compliance for both the dog and the owner. • A canine influenza vaccine was administered through a dog’s ears using IRMN successfully without removing the dog’s hair. • IRMN required only a few seconds of administration time without use of patch. • Vaccine-coated IRMN induced the same level of antibody titer as that induced by intramuscular administration of the vaccine. • IRMN are a potential vaccine administration system for use with hairy dog., Microneedles provide the advantages of convenience and compliance by avoiding the pain and fear of needles that animals often experience. Insertion-responsive microneedles (IRMN) were used for administration to a hairy dog without removing the dog’s hair. Canine H3N2 vaccine was administered with IRMN attached to the dog’s ears ex vivo and the conventional microneedle system (MN) was administered for 15 min to compare puncture performance and delivery efficiency. The vaccine was also administered to compare antibody formation using IRMN with the use of intramuscular injection. The veterinarian observed the behavior of the dog during the course of the administration and compared the response to IRMN with that of intramuscular administration. The tips of IRMN were separated from the base and delivered into the hairy skin successfully. Puncture performance of IRMN were the same as that of coated microneedles (95%), but delivery efficiency of IRMN were 95% compared to less than 1% for coated microneedles. The H3N2 vaccine inoculated into the dog's ears showed the same antibody formation as the intramuscular injection. The dog appeared to be more comfortable with IRMN administration compared to syringe administration. IRMN are the first microneedle system to deliver a canine vaccine successfully into a hairy dog without removal of the dog’s hair. The use of IRMN can provide both convenience and compliance for both the dog and the owner.

The breast cancer is one of the most common cancer affecting millions of lives worldwide. Though the prevalence of breast cancer is worldwide; however, the developing nations are having a comparatively higher percentage of breast cancer cases and associated complications. The molecular etiology behind breast cancer is complex and involves several regulatory molecules and their downstream signaling. Studies have demonstrated that the CD44 remains one of the major molecule associated not only in breast cancer but also several other kinds of tumors. The complex structure and functioning of CD44 posed a challenge to develop and deliver precise anti-cancerous drugs against targeted tissue. There are more than 20 isoforms of CD44 reported till date associated with several kinds of tumor in the using breast cancer. The success of any anti-cancerous therapy largely depends on the precise drug delivery system, and in modern days nanotechnology-based drug delivery vehicles are the first choice not only for cancer but several other chronic diseases as well. The Carbon nanotubes (CNTs) have shown tremendous scope in delivering the drug by targeting a particular receptor and molecules. Functionalized CNTs including both SWCNTs and MWCNTs are a pioneer in drug delivery with higher efficacy. The present work emphasized mainly on the potential of CNTs including both SWCNTs and MWCNTs in drug delivery for anti-cancerous therapy. The review provides a comprehensive overview of the development of various CNTs and their validation for effective drug delivery. The work focus on drug delivery approaches for breast cancer, precisely targeting CD44 molecule. Keywords: Anti-cancerous therapy, Breast cancer, CD44, Delivery, Drug, Multiwalled carbon nanotubes

Introduction: Clinical outcomes after the implantation of allogenic human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs) in osteoarthritic knees have been rarely reported. Our study aimed to investigate clinical outcomes of osteoarthritic patients who underwent hUCB-MSC implantation. Methods: In this case series (level of evidence: 4), from January 2014 to December 2015, 128 patients with full-thickness cartilage lesions (International Cartilage Repair Society grade 4 and Kellgren–Lawrence grade ≤3) who underwent hUCB-MSC implantation were retrospectively evaluated with a minimum of 2-year follow-up. After removing the sclerotic subchondral bone with an arthroscopic burr, 4-mm-diameter holes were created at 2-mm intervals, and hyaluronic acid and hUCB-MSCs were subsequently mixed and implanted in the holes and other articular defect sites.Clinical outcomes were evaluated preoperatively, 1 year postoperatively, and 2 years postoperatively (minimum) using visual analog scale (VAS), Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and International Knee Documentation Committee (IKDC) scores. To assess clinical outcomes, patients were divided into two or three groups according to the lesion size, lesion location, number of lesions, body mass index, and age; statistical analyses were performed using these data. Results: The mean (±standard deviation) VAS, WOMAC, and IKDC scores at 1 and 2 years after surgery including hUCB-MSC implantation improved significantly compared to the preoperative scores (P

Objective The magnitude of the therapeutic effects of intra-articular injection of platelet-rich plasma (PRP) on osteoarthritis (OA) is still under debate. The goal of this study that was a systematic review of randomised controlled trials ​of PRP injections for the treatment of OA was to elucidate the therapeutic efficacy of PRP. Methods Electronic databases of PubMed, CENTRAL, EMBASE, EBSCO, ClinicalTrials.gov, and International Clinical Trials Registry Platform ​were searched from inception to June 2018 for RCTs that compared PRP injections to controls in patients with OA. A random-effects approach was used to compile data and subgroups according to trial size (large trials versus small trials), patient profile (age and gender), and PRP preparation method was performed. Results Thirty trials met the inclusion criteria and were analysed. All results had unexplained statistical heterogeneity. Patients treated with PRP compared with control showed statistically relevant pain relief and function improvement at short term (standardised mean difference [SMD] ​= ​−0.62, 95% confidence interval [CI]: −0.98 to −0.27, P ​= ​0.0006, SMD ​= ​−0.74, 95% CI: −1.11 to 0.36, P ​= ​0.0001, respectively), medium term (SMD ​= ​−0.53, 95% CI: −0.83 to −0.23, P ​= ​0.0006, SMD ​= ​−0.50, 95% CI: −0.75 to −0.25, P ​= ​0.0006), and long term (SMD ​= ​−0.69, 95% CI: −1.08 to −0.30, P ​= ​0.0006, SMD ​= ​−0.68, 95% CI: −0.1.09 to −0.27, P ​= ​0.001, respectively). A subgroup analysis of the data from large trials and from trials composed of less than 50% female patients revealed that therapeutic effects of the treatment are insignificant. Conclusions According to the currently available data, PRP injections are beneficial for pain relief and function improvement in patients with OA. This meta-analysis, however, demonstrated that the efficacy of PRP is related to sample size and gender composition. Thus, more randomised controlled trials of high quality and larger patient size, also including gender aspects, are required to understand this phenomenon. The translational potential of this article The translation potential of this meta-analysis is that provided another perspective to analyse the treatment effect of PRP for OA. In future research, phenotypes subpopulation and gender difference of OA patient should be considered for PRP treatment.

Purpose: High fibular osteotomy (HFO) is a simple surgical technique to reduce pain and improve function in patients with osteoarthritis via fibular osteotomy. We report short-term results of HFO and mesenchymal cell induced chondrogenesis (MCIC) for the treatment of osteoarthritis of knee with varus deformity. Patients and methods: 45 symptomatic patients with 14 males and 31 females age ranging from 40 to 75 years were treated by HFO and MCIC. Main lesions involved medial compartment of knee and lateral compartment with normal to mild lesions of lateral meniscus and articular cartilage, amenable to treatment via partial meniscectomy or observation. Results: Knee injury and Osteoarthritis Outcome score and Lysholm showed a statistically significant increase and VAS, varus angle in X-ray showed a statistically significant decrease. A statistically significant difference between preoperative and postoperative scores was detected in male and female patients without any sexual differences. Conclusion: High fibular osteotomy and mesenchymal cell induced chondrogenesis can be considered as a good treatment option for medial compartment osteoarthritis of knee with varus deformity. Keywords: High fibular osteotomy, Osteoarthritis, Varus deformity, Knee, Mesenchymal cell induced chondrogenesis (MCIC)

Introduction To investigate the efficacy of the transplantation of autologous bone marrow-derived mesenchymal stem cells (BMSCs) under arthroscopy with microfracture (MFX) compared with microfracture alone. Methods Eleven patients with a symptomatic articular cartilage defect of the knee were included in the study. They were randomized to receive BMSCs with MFX (cell-T group, n=7) or MFX alone (control group, n=4). Clinical results were evaluated using International Knee Documentation committee (IKDC) knee evaluation questionnaires and the Knee Injury and Osteoarthritis Outcome Score (KOOS) before and 48 weeks after surgery. Quantitative and qualitative assessments of repair tissue were carried out at 48 weeks by T2 mapping of magnetic resonance images (MRIs) and the magnetic resonance observation of cartilage repair tissue (MOCART) scoring system with follow-up MRI. Results No significant differences between preoperative and postoperative IKDC and KOOS were observed in the cell-T or control group. However, forty-eight weeks after surgery, the cell-T group showed a trend for a greater KOOS QOL score compared with the control group (79.4 vs. 39.1, respectively; P=0.07). The T2 value did not differ significantly between the two groups, but the mean MOCART score was significantly higher in the cell-T group than in the control group (P=0.02). Conclusions Compared with MFX alone, BMSC transplantation with MFX resulted in better postoperative healing of the cartilage and subchondral bone as determined by the MOCART score. Clinically, BMSC transplantation with MFX gave a higher KOOS QOL score after 48 weeks., Highlights • This is the first prospective randomized clinical trial between BMSCs with MFX and MFX alone. • BMSCs with MFX showed a trend for a greater KOOS QOL score compared with MFX alone. • BMSCs with MFX resulted in better healing of the cartilage by the MOCART score.

The need for long-term treatments of chronic diseases has motivated the widespread development of long-acting parenteral formulations (LAPFs) with the aim of improving drug pharmacokinetics and therapeutic efficacy. LAPFs have been proven to extend the half-life of therapeutics, as well as to improve patient adherence; consequently, this enhances the outcome of therapy positively. Over past decades, considerable progress has been made in designing effective LAPFs in both preclinical and clinical settings. Here we review the latest advances of LAPFs in preclinical and clinical stages, focusing on the strategies and underlying mechanisms for achieving long acting. Existing strategies are classified into manipulation of in vivo clearance and manipulation of drug release from delivery systems, respectively. And the current challenges and prospects of each strategy are discussed. In addition, we also briefly discuss the design principles of LAPFs and provide future perspectives of the rational design of more effective LAPFs for their further clinical translation., Graphical abstract This review introduces the latest advances of long-acting parenteral formulations in preclinical and clinical stages, focusing on the strategies and underlying mechanisms for achieving long-acting effect.Image 1

Background & Aims Primary sclerosing cholangitis (PSC) is a progressive liver disease characterised by fluctuating liver biochemistries and highly variable disease progression. The Enhanced Liver Fibrosis (ELF®) test and liver stiffness measurements (LSMs) reflect fibrosis and predict clinical outcomes in PSC; however, longitudinal assessments are missing. We aimed to characterise the systematic change in ELF and LSM over time in a prospective cohort of patients with PSC, along with their longitudinal relationship to alkaline phosphatase (ALP) and bilirubin. Methods We included 113 non-transplant PSC patients (86 males [76.1%]; mean age 43.3 ± 15.7 years) with annual study visits between 2013 and 2019 at 2 Norwegian centres. ELF test, LSM, clinical data, liver biochemistries, and revised Mayo risk score were measured. We used linear mixed-effects models to estimate change over time, intraclass correlations (ICCs), and their relationship with ALP and bilirubin. Results At baseline, the median (range) ELF test was 9.3 (7.5–12.9) and median LSM 1.26 m/s (0.66–3.04 m/s). ELF and LSM increased over time (0.09 point/year, 95% CI [0.03, 0.15], p = 0.005, vs. 0.12 point/year, 95% CI [0.03, 0.21], p = 0.009). Between-patient effects explained 78% of ELF variation (ICC 0.78) and 56% of LSM variation (ICC 0.56). ALP also increased and showed the highest ICC (0.86). Conclusions ELF and LSM increased over a 5-year period. Longitudinal analyses demonstrated differences regarding within- and between-patient effects, suggesting that the ELF test may have superior reliability for risk stratification compared with LSM in PSC. Lay summary Primary sclerosing cholangitis (PSC) is characterised by substantial disease variability between patients and fluctuating liver biochemistries. Hence, new biomarkers are needed to identify individuals with an increased risk of developing end-stage liver disease. We explore the change over time of 2 putative prognostic biomarkers in PSC, the serum Enhanced Liver Fibrosis (ELF®) test and LSMs by ultrasound, demonstrating differences that may reflect differing abilities to discriminate risk., Graphical abstract, Highlights • ELF and LSM increased in patients with PSC, but only in patients with ALP >1.5× ULN. • ELF may be more reliable for PSC risk stratification (low within-patient variation). • A subgroup showed concomitant spontaneous reduction in ALP, ELF, and LSM.

Inflammation, a common feature of many diseases, is an essential immune response that enables survival and maintains tissue homeostasis. However, in some conditions, the inflammatory process becomes detrimental, contributing to the pathogenesis of a disease. Targeting inflammation by using nanomedicines (i.e. nanoparticles loaded with a therapeutic active principle), either through the recognition of molecules overexpressed onto the surface of activated macrophages or endothelial cells, or through enhanced vasculature permeability, or even through biomimicry, offers a promising solution for the treatment of inflammatory diseases. After providing a brief insight on the pathophysiology of inflammation and current therapeutic strategies, the review will discuss, at a pre-clinical stage, the main innovative nanomedicine approaches that have been proposed in the past five years for the resolution of inflammatory disorders, finally focusing on those currently in clinical trials., Graphical Abstract Unlabelled Image, Highlights • Inflammation is an essential immune response that enables survival and maintains tissue homeostasis. • Sometimes the inflammatory process becomes detrimental, contributing to a disease development. • Conventional pharmacological treatments may result in off-target side effects and toxicity. • Innovative nanomedicines show significant therapeutic improvements in pre-clinical models. • Clinical translation remains limited due to the complexity of both inflammatory diseases and nanomedicines development.

The popularity of dermal hyaluronic acid (HA) fillers has grown rapidly in the recent decade as they offer rejuvenation and nonsurgical cosmetic treatments for the correction of contour deformities and facial rhytids. Filler injections are performed with rapid recovery and little discomfort. Although various filler agents are available, the ideal filler has not yet been discovered, as all fillers are may cause complications.1, 2 Fillers can be classified in various ways. One classification is by the duration of its effect: temporary or permanent.1 This classification depends on bioavailability, chemical composition, and degradation. Quickly biodegradable agents, such as HA, may induce complications that generally disappear spontaneously within few months.2 Other types of permanent fillers such as silicone may induce complications that occur years after the procedure.2 These complications may include lumps, allergic skin reactions, edema, migration, scarring, skin necrosis, retinal artery occlusion, paralysis in the face, skin discoloration, and xanthelasma-like reaction.2, 3 These reactions can be associated with significant cosmetic morbidity and may result in the treating physician ordering unnecessary radiologic examinations and performing surgery in attempt to identify the etiology. Consequently, the surgeon should obtain a detailed history of possible soft tissue filler injections in the past, as nonbiodegradable material may persist for years. The patient often does not provide this information and may not recall which product was injected.2, 4, 5 We describe a patient who presented with an orbital mass secondary to filler injection and underwent orbitotomy. This case report adheres to the principles of the Declaration of Helsinki.

The extracellular matrix (ECM) is critical for mammary ductal development and differentiation, but how mammary fibroblasts regulate ECM remodeling remains to be elucidated. Herein, we used a mouse genetic model to activate platelet derived growth factor receptor-alpha (PDGFRα) specifically in the stroma. Hyperactivation of PDGFRα in the mammary stroma severely hindered pubertal mammary ductal morphogenesis, but did not interrupt the lobuloalveolar differentiation program. Increased stromal PDGFRα signaling induced mammary fat pad fibrosis with a corresponding increase in interstitial hyaluronic acid (HA) and collagen deposition. Mammary fibroblasts with PDGFRα hyperactivation also decreased hydraulic permeability of a collagen substrate in an in vitro microfluidic device assay, which was mitigated by inhibition of either PDGFRα or HA. Fibrosis seen in this model significantly increased the overall stiffness of the mammary gland as measured by atomic force microscopy. Further, mammary tumor cells injected orthotopically in the fat pads of mice with stromal activation of PDGFRα grew larger tumors compared to controls. Taken together, our data establish that aberrant stromal PDGFRα signaling disrupts ECM homeostasis during mammary gland development, resulting in increased mammary stiffness and increased potential for tumor growth.

Introduction Peroxisome proliferator–activated receptor (PPAR) subfamily play an important role in chondrogenesis. Previous study has reported that mixture of GW0742 (PPAR-δ agonist), hyaluronic acid (HA) and mesenchymal stem cells (MSCs) enhance chondrogenesis. The purpose of this study is to compare with efficacies of commercially available HA and demonstrate correlation of PPAR-γ and PPAR-δ. Methods In this experimental study, MSCs were cultured with chondrogenic media and clinical HA gels (Euflexxa®, Synvisc®, Orthovisc® and Supartz®) using micormass culture method. Expression of type Ⅰ, Ⅱ collagen and matrix metalloprotease-13 (MMP-13) was measured by immunoblotting. MSCs were cultured with chondrogenic media and/or HA and/or GW0742 and/or rosiglitazone (PPAR-γ agonist) and/or human osteoarthritis synovial fluid. Immunoblotting was used to measure expression of type Ⅱ collagen and PPAR-γ. To identify the effective dose for chondrogenesis and adipogenesis, either 0.1, 1, 5 or 10 μM of rosiglitazone was added to MSCs in chondrogenic media or adipogenic media. Results Clinical HA gels inhibited expression of type Ⅰ collagen and enhanced the expression of MMP-13. Type Ⅱ collagen expression was significantly elevated in all treatment groups except Supartz®. GW0742 decreased the expression of PPAR-γ with/without inflammation condition. Rosiglitazone enhanced adipogenesis in a dose-dependent manner and enhanced the expression of type Ⅱ collagen under inflammation condition. Otherwise, the expression of type Ⅱ collagen and formation of chondrocyte spheroids showed a dose-dependent manner with a peak at 1 μM of rosiglitazone. Conclusions PPAR-γ has a considerable anti-inflammatory effect and a strong pro-adipogenic effect, which inhibits the chondrogenic effect. PPAR-γ is related with PPAR-δ and shows a chondrogenic effect at lower concentrations. And clinical HA gels shows various efficacy of chondrogenesis. This study suggested that PPAR-γ and PPAR-δ are key regulatory factors of chondrogenesis., Graphical abstract Image 1

Purpose: To evaluate skin biocompatibility of a nighttime hydrating eyelid gel and possible ocular surface effects in contact lens users (CLU) and non-contact lens users (NCLU). The formulation is registered as a medical device as Tridocosahexaenoine-AOX® (TDHA-AOX) (a concentrated DHA triglyceride), containing also hyaluronic acid (HA). Methods: A prospective, randomized, masked clinical trial was performed with 62 participants of both sexes, aged 20–70 years, split into: (1) CLU (n = 30) and (2) NCLU (n = 32). All participants were instructed to apply a single dose of the moisturizing gel (containing TDHA-AOX and HA) nightly to the upper and inner eyelids of their right eye (RE) only, and during 2 consecutive weeks. Personal interviews, questionnaires, ophthalmic examinations and reflex tear collection were performed. Ophthalmological parameters included ocular surface response and contact lens status. Levels of satisfaction/adverse events were also recorded. Biochemical parameters included basal and final determination of pro-inflammatory mediator molecules in tear samples by multiplex analyses. Statistics were done by the SPSS 24.0 program. Results: The CLU group had higher OS dysfunction than NCLU, but overall clinical parameters (corneal staining, and Schirmer/FBUT tests) and OSDI scores showed significant improvement in CLU individuals as compared to the NCLU participants, at the end of study. CLDEQ-8 scores pinpointed significant amelioration in initial risk of developing DEs by applying eyelid gel. Multiplex analyses demonstrated significantly lower VEGF expression levels (p

Background & aims Analysis of volatile organic compounds (VOCs) in exhaled breath, ‘volatomics’, provides opportunities for non-invasive biomarker discovery and novel mechanistic insights into a variety of diseases. The purpose of this pilot study was to compare breath VOCs in an initial cohort of patients with non-alcoholic fatty liver disease (NAFLD) and healthy controls. Methods Breath samples were collected from 15 participants with Child-Pugh class A NAFLD cirrhosis, 14 with non-cirrhotic NAFLD, and 14 healthy volunteers. Exhaled breath samples were collected using an established methodology and VOC profiles were analysed by gas chromatography-mass spectrometry. The levels of 19 VOCs previously associated with cirrhosis were assessed. Peaks of the VOCs were confirmed and integrated using Xcalibur® software, normalised to an internal standard. Receiver-operating characteristic (ROC) curves were used to determine the diagnostic accuracy of the candidate VOCs. Results Terpinene, dimethyl sulfide, and D-limonene provided the highest predictive accuracy to discriminate between study groups. Combining dimethyl sulfide with D-limonene led to even better discrimination of patients with NAFLD cirrhosis from healthy volunteers (AUROC 0.98; 95% CI 0.93–1.00; p, Graphical abstract, Highlights • Metabolic dysfunction in liver disease is reflected in the biocomposition of exhaled breath. • Specific volatile organic compounds can be measured in breath samples (volatomics) and have diagnostic potential in chronic liver disease. • Levels of alfa-terpinene, dimethyl sulfide, and D-limonene in exhaled breath can be used to stratify patients with non-alcoholic fatty liver disease.

Graphical abstract, Highlights • Pathogenesis and characteristics of idiopathic pulmonary fibrosis (IPF) are presented. • The history and current situation of traditional Chinese medicine (TCM) in treating lung diseases are introduced. • Therapeutic mechanisms of different TCM to treat IPF are summarized. • Advantages and types of pulmonary drug delivery systems (PDDS) are emphasized. • Combining TCM with PDDS is a potential strategy to treat IPF., Idiopathic pulmonary fibrosis (IPF) is a progressive pulmonary interstitial inflammatory disease of unknown etiology, and is also a sequela in severe patients with the Coronavirus Disease 2019 (COVID-19). Nintedanib and pirfenidone are the only two known drugs which are conditionally recommended for the treatment of IPF by the FDA. However, these drugs pose some adverse side effects such as nausea and diarrhoea during clinical applications. Therefore, it is of great value and significance to identify effective and safe therapeutic drugs to solve the clinical problems associated with intake of western medicine. As a unique medical treatment, Traditional Chinese Medicine (TCM) has gradually exerted its advantages in the treatment of IPF worldwide through a multi-level and multi-target approach. Further, to overcome the current clinical problems of oral and injectable intakes of TCM, pulmonary drug delivery system (PDDS) could be designed to reduce the systemic metabolism and adverse reactions of the drug and to improve the bioavailability of drugs. Through PubMed, Google Scholar, Web of Science, and CNKI, we retrieved articles published in related fields in recent years, and this paper has summarized twenty-seven Chinese compound prescriptions, ten single TCM, and ten active ingredients for effective prevention and treatment of IPF. We also introduce three kinds of inhaling PDDS, which supports further research of TCM combined with PDDS to treat IPF.

Highlights • Hyaluronidase1 (HYAL1) is N-glycosylated at Asn99, Asn216, and Asn350. • N-glycosylation regulates secretion of HYAL1. • N-glycosylation is important for enzymatic activity of HYAL1., Hyaluronidase1 (HYAL1) is a hydrolytic enzyme that degrades hyaluronic acid (HA) and has three predicted N-glycosylation sites at Asn99, Asn216, and Asn350. In this report, we show the functional significance of N-glycosylation on HYAL1 functions. Using mass spectrometry, we demonstrated that HYAL1 was N-glycosylated at the three asparagine residues. N-glycosylation of HYAL1 is important for secretion of HYAL1, as demonstrated by site-directed mutation. Moreover, a defect of N-glycosylation attenuated the enzymatic activity of HYAL1. Thus, HYAL1 is N-glycosylated at the three asparagine residues, and its secretion and enzymatic activity are regulated by N-glycosylation.

Introduction The purpose of this study was to assess the direct injection of bone marrow-derived mesenchymal stem cells (BMSCs) suspended in hyaluronic acid (HA) combined with drilling as a treatment for chondral defects in a canine model. Methods Tibial bone marrow was aspirated, and BMSCs were isolated and cultured. One 8.0-mm diameter chondral defect was created in the femoral groove, and nine 0.9-mm diameter holes were drilled into the defect. BMSCs (2.14 × 107 cells) suspended in HA were injected into the defect. HA alone was injected into a similar defect on the contralateral knee as a control. Animals were sacrificed at 3 and 6 months. Results Although the percentage of coverage assessed macroscopically was significantly better at 6 months than at 3 months in both the BMSC (p = 0.02) and control (p = 0.001) groups, there were no significant differences in the International Cartilage Repair Society grades. The Wakitani histological score was significantly better at 6 months than at 3 months in the BMSC and control groups. While the control defects were mostly filled with fibrocartilage, several of the defects in the BMSC group contained hyaline-like cartilage. The mean Wakitani scores of the BMSC group improved from 7.0 ± 1.0 at 3 months to 4.6 ± 0.9 at 6 months, and those of the control group improved from 9.4 ± 1.2 to 6.0 ± 0.6. The BMSC group showed significantly better regeneration than the control group at 3 months (p = 0.04), but the difference at 6 months was not significant (p = 0.06). Conclusions The direct injection of BMSCs in HA combined with drilling enhanced cartilage regeneration., Highlights • Direct injection of BMSCs with HA and drilling was tested for chondral defects. • HA alone was injected into a similar defect on the contralateral knee as a control. • Macroscopic coverage and histology indicated better healing at 6 than at 3 months. • The BMSC group healed significantly better than the control group at 3 months.

Highlights • Oxidative stress in the arthritis joint is involved in generating mediators for inflammation. • Oxidative stress-induced expression of Cox-2 was mediated by MAPKs and NF-κB. • ROS-induced MAPKs and NF-κB were attenuated by inhibition of MAPKKK TAK1. • Inhibition of TAK1 activity resulted in reduced expression of Cox-2 and PGE2. • ROS-induced TAK1 activation and Cox-2 expression was inhibited by antioxidants N-acetyl cysteamine and hyaluronic acid., Oxidative stress within the arthritis joint has been indicated to be involved in generating mediators for tissue degeneration and inflammation. COX-2 is a mediator in inflammatory action, pain and some catabolic reactions in inflamed tissues. Here, we demonstrated a direct relationship between oxidative stress and Cox-2 expression in the bovine synovial fibroblasts. Furthermore, we elucidated a novel mechanism, in which oxidative stress induced phosphorylation of MAPKs and NF-κB through TAK1 activation and resulted in increased Cox-2 and prostaglandin E2 expression. Finally, we demonstrated that ROS-induced Cox-2 expression was inhibited by supplementation of an antioxidant such as N-acetyl cysteamine and hyaluronic acid in vitro and in vivo. From these results, we conclude that oxidative stress is an important factor for generation of Cox-2 in synovial fibroblasts and thus its neutralization may be an effective strategy in palliative therapy for chronic joint diseases.