Repurposing of SARS-CoV-2 compounds against Marburg Virus using MD simulation, mm/GBSA, PCA analysis, and free energy landscape.

The significant mortality rate associated with Marburg virus infection made it the greatest hazard among infectious diseases. Drug repurposing using in silico methods has been crucial in identifying potential compounds that could prevent viral replication by targeting the virus's primary proteins. This study aimed at repurposing the drugs of SARS-CoV-2 for identifying potential candidates against the matrix protein VP40 of the Marburg virus. Virtual screening was performed where the control compound, Nilotinib, showed a binding score of -9.99 kcal/mol. Based on binding scores, hit compounds 9549298, 11960895, 44545852, 51039094, and 89670174 were selected that had a lower binding score than the control. Subsequent molecular dynamics (MD) simulation revealed that compound 9549298 consistently formed a hydrogen bond with the residue Gln290. This was observed both in molecular docking and MD simulation poses, indicating a strong and significant interaction with the protein. 11960895 had the most stable and consistent RMSD pattern exhibited in 100 ns simulation, while 9549298 had the most identical RMSD plot compared to the control molecule. MM/PBSA analysis showed that the binding free energy (ΔG) of 9549298 and 11960895 was lower than the control, with -30.84 and -38.86 kcal/mol, respectively. It was observed by the PCA (principal component analysis) and FEL (free energy landscape) analysis that compounds 9549298 and 11960895 had lesser conformational variation. Overall, this study proposed 9549298 and 11960895 as potential binders of VP40 MARV that can cause its inhibition, however it inherently lacks experimental validation. Furthermore, the study proposes in-vitro experiments as the next step to validate these computational findings, offering a practical approach to further explore these compounds' potential as antiviral agents.Communicated by Ramaswamy H. Sarma.

AI-driven estimation of O6 methylguanine-DNA-methyltransferase (MGMT) promoter methylation in glioblastoma patients: a systematic review with bias analysis.

BACKGROUND: Accurate and non-invasive estimation of MGMT promoter methylation status in glioblastoma (GBM) patients is of paramount clinical importance, as it is a predictive biomarker associated with improved overall survival (OS). In response to the clinical need, recent studies have focused on the development of non-invasive artificial intelligence (AI)-based methods for MGMT estimation. In this systematic review, we not only delve into the technical aspects of these AI-driven MGMT estimation methods but also emphasize their profound clinical implications. Specifically, we explore the potential impact of accurate non-invasive MGMT estimation on GBM patient care and treatment decisions. METHODS: Employing a PRISMA search strategy, we identified 33 relevant studies from reputable databases, including PubMed, ScienceDirect, Google Scholar, and IEEE Explore. These studies were comprehensively assessed using 21 diverse attributes, encompassing factors such as types of imaging modalities, machine learning (ML) methods, and cohort sizes, with clear rationales for attribute scoring. Subsequently, we ranked these studies and established a cutoff value to categorize them into low-bias and high-bias groups. RESULTS: By analyzing the 'cumulative plot of mean score' and the 'frequency plot curve' of the studies, we determined a cutoff value of 6.00. A higher mean score indicated a lower risk of bias, with studies scoring above the cutoff mark categorized as low-bias (73%), while 27% fell into the high-bias category. CONCLUSION: Our findings underscore the immense potential of AI-based machine learning (ML) and deep learning (DL) methods in non-invasively determining MGMT promoter methylation status. Importantly, the clinical significance of these AI-driven advancements lies in their capacity to transform GBM patient care by providing accurate and timely information for treatment decisions. However, the translation of these technical advancements into clinical practice presents challenges, including the need for large multi-institutional cohorts and the integration of diverse data types. Addressing these challenges will be critical in realizing the full potential of AI in improving the reliability and accessibility of MGMT estimation while lowering the risk of bias in clinical decision-making.

Harvesting marine plastic pollutants-derived renewable energy: A comprehensive review on applied energy and sustainable approach.

The inevitable use of plastics in the existing standard of life makes its way to ecosystems, predominantly into the marine ecosystem. Recent research on energy recycling from marine discarded plastics through biological, chemical, and thermal processes is summarized, which degrade plastic debris and transform it into energy-efficient products. In a system-oriented approach, different boundaries like carbon efficiency, global warming potential, cumulative energy demand, and cost of the product have been evaluated. Even these technologies may successfully reduce the yearly volume of marine plastics by up to 89% while reducing greenhouse gas emissions by 30%. Conversely, recycling a ton of marine discarded plastics may save 915 cubic feet of landfill space, 6500 kWh of energy, and barrels of oil. Energy may be recovered up to 79% from waste plastics using various techniques. Up to 84% liquid fuel had been generated, with a maximum calorific power of 45 MJ/kg. It has been shown that in Asian countries, the power generation capacity of throw-away facemask wastes regularly varies from 2256 kWh/day to 18.52 million kWh/day. Hence, the conversion of marine plastics into biofuel, syngas, biochar, hydrocarbons, electricity, and value-added functional materials by various biotechnological and chemical processes like biodegradation, pyrolysis, gasification, methanolysis, and hydrolysis should be improvised as a source of alternative energy in the immediate future. Our review signifies the potential benefits of energy harvesting technologies from marine plastics pollutants to overcome the growing challenge of energy demands and provide a long-term solution to underdeveloped and developing countries as a sustainable source of energy. Endorsing current strategies to harvest energy from marine plastic wastes that enhance power generation technologies will help in building a more sustainable and greener environment that imparts a healthy and circular economy while shielding natural resources.

Clinical Spectrum and Trajectory of Innovative Therapeutic Interventions for Insomnia: A Perspective.

Increasing incidences of insomnia in adults, as well as the aging population, have been reported for their negative impact on the quality of life. Insomnia episodes may be associated with neurocognitive, musculoskeletal, cardiovascular, gastrointestinal, renal, hepatic, and metabolic disorders. Epidemiological evidence also revealed the association of insomnia with oncologic and asthmatic complications, which has been indicated as bidirectional. Two therapeutic approaches including cognitive behavioral therapy (CBT) and drugs-based therapies are being practiced for a long time. However, the adverse events associated with drugs limit their wide and long-term application. Further, Traditional Chinese medicine, acupressure, and pulsed magnetic field therapy may also provide therapeutic relief. Notably, the recently introduced cryotherapy has been demonstrated as a potential candidate for insomnia which could reduce pain, by suppressing oxidative stress and inflammation. It seems that the synergistic therapeutic approach of cryotherapy and the above-mentioned approaches might offer promising prospects to further improve efficacy and safety. Considering these facts, this perspective presents a comprehensive summary of recent advances in pathological aetiologies of insomnia including COVID-19, and its therapeutic management with a greater emphasis on cryotherapy.

CRISPR/Cas9 system in breast cancer therapy: advancement, limitations and future scope.

Cancer is one of the major causes of mortality worldwide, therefore it is considered a major health concern. Breast cancer is the most frequent type of cancer which affects women on a global scale. Various current treatment strategies have been implicated for breast cancer therapy that includes surgical removal, radiation therapy, hormonal therapy, chemotherapy, and targeted biological therapy. However, constant effort is being made to introduce novel therapies with minimal toxicity. Gene therapy is one of the promising tools, to rectify defective genes and cure various cancers. In recent years, a novel genome engineering technology, namely the clustered regularly interspaced short palindromic repeat (CRISPR)-associated protein-9 (Cas9) has emerged as a gene-editing tool and transformed genome-editing techniques in a wide range of biological domains including human cancer research and gene therapy. This could be attributed to its versatile characteristics such as high specificity, precision, time-saving and cost-effective methodologies with minimal risk. In the present review, we highlight the role of CRISPR/Cas9 as a targeted therapy to tackle drug resistance, improve immunotherapy for breast cancer.

Multiple roles for basement membrane proteins in cancer progression and EMT.

Metastasis or the progression of malignancy poses a major challenge in cancer therapy and is the principal reason for increased mortality. The epithelial-mesenchymal transition (EMT) of the basement membrane (BM) allows cells of epithelial phenotype to transform into a mesenchymal-like (quasi-mesenchymal) phenotype and metastasize via the lymphovascular system through a metastatic cascade by intravasation and extravasation. This helps in the progression of carcinoma from the primary site to distant organs. Collagen, laminin, and integrin are the prime components of BM and help in tumor cell metastasis, which makes them ideal cancer drug targets. Further, recent studies have shown that collagen, laminin, and integrin can be used as a biomarker for metastatic cells. In this review, we have summarized the current knowledge of such therapeutics, which are either currently in preclinical or clinical stages and could be promising cancer therapeutics. DATA AVAILABILITY: Not applicable.

Differential Transcriptome Profiling Unveils Novel Deregulated Gene Signatures Involved in Pathogenesis of Alzheimer's Disease.

Alzheimer's disease (AD) is a neurodegenerative disorder that is characterized by a progressive loss of cognitive functions at a higher level than normal aging. Although the apolipoprotein (APOE) gene is a major risk factor in developing AD, other genes have also been reported to be linked with complex phenotypes. Therefore, this genome-wide expression study explored differentially expressed genes as possible novel biomarkers involved in AD. The mRNA expression dataset, GSE28146, containing 15 sample data composed of 7 AD cases from the hippocampus region with age-matched control (n = 8, >80 years), was analyzed. Using "affy" R-package, mRNA expression was calculated, while pathway enrichment analysis was performed to determine related biological processes. Of 58 differentially expressed genes, 44 downregulated and 14 upregulated genes were found to be significantly (p < 0.001) altered. The pathway enrichment analysis revealed two altered genes, i.e., dynein light chain 1 (DYNLL1) and kalirin (KLRN), associated with AD in the elderly population. The majority of genes were associated with retrograde endocannabinoid as well as vascular endothelial growth factors affecting the complex phenotypes. The DYNLL1 and KLRN genes may be involved with AD and Huntington's disease (HD) phenotypes and represent a common genetic basis of these diseases. However, the hallmark of AD is dementia, while the classic motor sign of HD includes chorea. Our data warrant further investigation to identify the role of these genes in disease pathogenesis.

Melatonin rescues cerebral ischemic events through upregulated tunneling nanotube-mediated mitochondrial transfer and downregulated mitochondrial oxidative stress in rat brain.

BACKGROUND: Cerebral ischemic events, comprising of excitotoxicity, reactive oxygen production, and inflammation, adversely impact the metabolic-redox circuit in highly active neuronal metabolic profile which maintains energy-dependent brain activities. Therefore, we investigated neuro-regenerative potential of melatonin (Mel), a natural biomaterial secreted by pineal gland. METHODS: We specifically determined whether Mel could influence tunneling nanotubes (TNTs)-mediated transfer of functional mitochondria (Mito) which in turn may alter membrane potential, oxidative stress and apoptotic factors. In vitro studies assessed the effects of Mito on levels of cytochrome C, mitochondrial transfer, reactive oxygen species, membrane potential and mass, which were all further enhanced by Mel pre-treatment, whereas in vivo studies examined brain infarct area (BIA), neurological function, inflammation, brain edema and integrity of neurons and myelin sheath in control, ischemia stroke (IS), IS + Mito and IS + Mel-Mito group rats. RESULTS: Results showed that Mel pre-treatment significantly increased mitochondrial transfer and antioxidants, and inhibited apoptosis. Mel-pretreated Mito also significantly reduced BIA with improved neurological function. Apoptotic, oxidative-stress, autophagic, mitochondrial/DNA-damaged biomarkers indices were also improved. CONCLUSION: Conclusively, Mel is a potent biomaterial which could potentially impart neurogenesis through repairing impaired metabolic-redox circuit via enhanced TNT-mediated mitochondrial transfer, anti-oxidation, and anti-apoptotic activities in ischemia.

Platelet-derived biomaterials-mediated improvement of bone injury through migratory ability of embryonic fibroblasts: in vitro and in vivo evidence.

Bony injuries lead to compromised skeletal functional ability which further increase in aging population due to decreased bone mineral density. Therefore, we aimed to investigate the therapeutic potential of platelet-derived biomaterials (PDB) against bone injury. Specifically, we assessed the impact of PDB on osteo-inductive characteristics and migration of mouse embryonic fibroblasts (MEFs). Osteogenic lineage, matrix mineralization and cell migration were determined by gene markers (RUNX2, OPN and OCN), alizarin Red S staining, and migration markers (FAK, pFAK and Src) and EMT markers, respectively. The therapeutic impact of TGF-ß1, a key component of PDB, was confirmed by employing inhibitor of TGF-ß receptor I (Ti). Molecular imaging-based in vivo cellular migration in mice was determined by establishing bone injury at right femurs. Results showed that PDB markedly increased expression of osteogenic markers, matrix mineralization, migration and EMT markers, revealing higher osteogenic and migratory potential of PDB-treated MEFs. In vivo cell migration was manifested by expression of migratory factors, SDF-1 and CXCR4. Compared to control, PDB-treated mice exhibited higher bone density and volume. Ti treatment inhibited both migration and osteogenic potential of MEFs, affirming impact of TGF-ß1. Collectively, our study clearly indicated PDB-rescued bone injury through enhancing migratory potential of MEFs and osteogenesis.

The Novel Herbal Cocktail AGA Alleviates Oral Cancer through Inducing Apoptosis, Inhibited Migration and Promotion of Cell Cycle Arrest at SubG1 Phase.

Traditional Chinese medicines Antler's extract (A) and Ganoderma lucidum (G) and Antrodia Camphorata (A) have been known to individually contain a plethora of bioactive factors including triterpenoids, polysaccharides etc., exerting various curative impacts such as anti-inflammatory, anti-oxidative, anti-atherosclerotic and anti-viral activities. However, their combinatorial therapeutic efficacy for oral cancer has not been investigated. Hence, we synthesized a robust cocktail called AGA and investigated its anti-oral cancer potential in vitro and in vivo. An MTT assay revealed the IC50 of AGA to be about 15 mg at 72 h. Therefore, 10 mg and 20 mg doses were selected to study the effect of AGA. The AGA significantly inhibited proliferation of oral cancer cells (HSC3, SAS, and OECM-1) in a dose- and time-dependent manner. AGA retarded cell cycle regulators (CDK4, CDK6, cyclin A, B1, D1 and E2) and apoptosis inhibitory protein Bcl-2, but enhanced pro-apoptotic protein Bax and a higher percentage of cells in Sub-G1 phase. Mechanistically, AGA suppressed all EMT markers; consequently, it decreased the migration ability of cancer cells. AGA significantly reduced xenograft tumor growth in nude mice with no adverse events in liver and renal toxicity. Conclusively, AGA strongly inhibited oral cancer through inducing apoptosis and inhibiting the migration and promotion of cell cycle arrest at subG1 phase, which may be mediated primarily via cocktail-contained triterpenoids and polysaccharides.

Modulating redox homeostasis and cellular reprogramming through inhibited methylenetetrahydrofolate dehydrogenase 2 enzymatic activities in lung cancer.

Recent reports have indicated the role of highly expressed methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) enzyme in cancers, showing poor survival; however, detailed mechanistic insight of metabolic functions of MTHFD2 have not been well-defined. Therefore, we aimed to examine the metabolic functions and cellular reprograming potential of MTHFD2 in lung cancer (LCa). In this study, we initially confirmed the expression levels of MTHFD2 in LCa not only in tissue and OncomineTM database, but also at molecular levels. Further, we reprogrammed metabolic activities in these cells through MTHFD2 gene knockdown via lentiviral transduction, and assessed their viability, transformation and self-renewal ability. In vivo tumorigenicity was also evaluated in NOD/SCID mice. Results showed that MTHFD2 was highly expressed in stage-dependent LCa tissues as well in cell lines, A549, H1299 and H441. Cellular viability, transformation and self-renewal abilities were significantly inhibited in MTHFD2-knockdown LCa cell lines. These cells also showed suppressed tumor-initiating ability and reduced tumor size compared to vector controls. Under low oxygen tension, MTHFD2-knockdown groups showed no significant increase in sphere formation, and hence the stemness. Conclusively, the suppressed levels of MTHFD2 is essential for cellular metabolic reprogramming leading to inhibited LCa growth and tumor aggressiveness.

Amelioration of Nicotine-Induced Osteoarthritis by Platelet-Derived Biomaterials Through Modulating IGF-1/AKT/IRS-1 Signaling Axis.

Besides inhalation, a few studies have indicated that the uptake of nicotine through air or clothing may be a significant pathway of its exposure among passive smokers. Nicotine is well known to exert various physiological impacts, including stimulating sympathetic nervous system, causing vascular disturbances, and inducing cell death. Therefore, we aimed to establish whether exposure of nicotine could induce articular cartilage degeneration in a mouse model of osteoarthritis (OA). We specifically assessed dose-dependent effect of nicotine in vitro to mimic its accumulation. Further, during the in vivo studies, mice subcutaneously administered with nicotine was examined for OA-associated pathologic changes. We found that nicotine significantly suppressed chondrocytes and chondrogenic markers (Sox, Col II, and aggrecan). Nicotine-treated mice also showed altered knee joint ultrastructure with reduced Col II and proteoglycans. After corroborating nicotine-induced OA characteristics, we treated this pathologic condition through employing platelet-derived biomaterial (PDB)-based regenerative therapy. The PDB significantly suppressed OA-like pathophysiological characteristics by 4 weeks. The mechanistic insight underlying this therapy demonstrated that PDB significantly restored levels of insulin-like growth factor 1 (IGF-1) signaling pathway proteins, especially pIGF-1 R, pAKT, and IRS-1, regulating extracellular matrix synthesis by chondrocytes. Taken together, the PDB exerts regenerative and reparative activities in nicotine-mediated initiation and progression of OA, through modulating IGF-1/AKT/IRS-1 signaling axis.

Highly Expressed FOXF1 Inhibit Non-Small-Cell Lung Cancer Growth via Inducing Tumor Suppressor and G1-Phase Cell-Cycle Arrest.

Cancer pathogenesis results from genetic alteration-induced high or low transcriptional programs, which become highly dependent on regulators of gene expression. However, their role in progressive regulation of non-small-cell lung cancer (NSCLC) and how these dependencies may offer opportunities for novel therapeutic options remain to be understood. Previously, we identified forkhead box F1 (FOXF1) as a reprogramming mediator which leads to stemnesss when mesenchymal stem cells fuse with lung cancer cells, and we now examine its effect on lung cancer through establishing lowly and highly expressing FOXF1 NSCLC engineered cell lines. Higher expression of FOXF1 was enabled in cell lines through lentiviral transduction, and their viability, proliferation, and anchorage-dependent growth was assessed. Flow cytometry and Western blot were used to analyze cellular percentage in cell-cycle phases and levels of cellular cyclins, respectively. In mice, tumorigenic behavior of FOXF1 was investigated. We found that FOXF1 was downregulated in lung cancer tissues and cancer cell lines. Cell proliferation and ability of migration, anchorage-independent growth, and transformation were inhibited in H441-FOXF1H and H1299-FOXF1H, with upregulated tumor suppressor p21 and suppressed cellular cyclins, leading to cell-cycle arrest at the gap 1 (G1) phase. H441-FOXF1H and H1299-FOXF1H injected mice showed reduced tumor size. Conclusively, highly expressing FOXF1 inhibited NSCLC growth via activating tumor suppressor p21 and G1 cell-cycle arrest, thus offering a potentially novel therapeutic strategy for lung cancer.

Adipose-derived Stem Cells Attenuates Diabetic Osteoarthritis via Inhibition of Glycation-mediated Inflammatory Cascade.

Diabetes mellitus (DM) is well-known to exert complications such as retinopathy, cardiomyopathy and neuropathy. However, in recent years, an elevated osteoarthritis (OA) complaints among diabetics have been observed, portending the risk of diabetic OA. Since formation of advanced glycation end products (AGE) is believed to be the etiology of various diseases under hyperglycemic conditions, we firstly established that streptozotocin-induced DM could potentiate the development of OA in C57BL/6J mouse model, and further explored the intra-articularly administered adipose-derived stem cell (ADSC) therapy focusing on underlying AGE-associated mechanism. Our results demonstrated that hyperglycemic mice exhibited OA-like structural impairments including a proteoglycan loss and articular cartilage fibrillations in knee joint. Highly expressed levels of carboxymethyl lysine (CML), an AGE and their receptors (RAGE), which are hallmarks of hyperglycemic microenvironment were manifested. The elevated oxidative stress in diabetic OA knee-joint was revealed through increased levels of malondialdehyde (MDA). Further, oxidative stress-activated nuclear factor kappa B (NF-κB), the marker of proinflammatory signalling pathway was also accrued; and levels of matrix metalloproteinase-1 and 13 were upregulated. However, ADSC treatment attenuated all OA-like changes by 4 weeks, and dampened levels of CML, RAGE, MDA, NF-κB, MMP-1 and 13. These results suggest that during repair and regeneration, ADSCs inhibited glycation-mediated inflammatory cascade and rejuvenated cartilaginous tissue, thereby promoting knee-joint integrity in diabetic milieu.

Cerebro- and renoprotective activities through platelet-derived biomaterials against cerebrorenal syndrome in rat model.

Though the cross-induction of either acute kidney (AKI) injury to ischemic stroke (IS) or IS to AKI might not be encountered in the early stages of cerebrorenal syndrome (CRS), both pathologies coexist in late stages. Therefore, we firstly established a late stage CRS rat model by simultaneous induction of both diseases, and further, cerebro and reno-protective activities of human platelet-rich plasma (hPRP), a blood-derived tissue engineering biomaterial, were tested in this pathology. hPRP was administrated via left common carotid artery and abdominal aorta 2 h post-sham procedure in Sprague-Dawley rats. Circulatory inflammatory markers (TNF-α/MPO/IL-6/Ly6G/CD11b/c), histopathologic cerebro and renal changes and oxidative stress were determined. Inflammation, infarct size, brain-associated inflammatory/DNA and mitochondrial damage and oxidative-stress with reduced neurons and neurological function were manifested in CRS group compared to other groups. CRS group also demonstrated declined renal function, accelerated renal collagen deposition, fibrosis and compromised glomerular podocyte components (podocin/ZO-1/fibronectin/synaptopodin). However, hPRP simultaneously suppressed all the inflammatory, cerebral and renal pathologic characteristics. hPRP also inhibited the expression of brain-associated inflammatory/DNA/mitochondrial damage and oxidative-stress biomarkers. These findings imply that hPRP may effectively exert cerebro- and renoprotective activities in late stage CRS through anti-oxidative, anti-inflammatory, anti-DNA and anti-mitochochondrial damaging activities.

Time- and Kellgren⁻Lawrence Grade-Dependent Changes in Intra-Articularly Transplanted Stromal Vascular Fraction in Osteoarthritic Patients.

Knee osteoarthritis (OA) is one of the most prevalent disorders in elderly population. Among various therapeutic alternatives, we employed stromal vascular fraction (SVF), a heterogeneous cell population, to regenerate damaged knee cartilage. OA patients were classified on the basis of age, gender, body mass index (BMI), and x-ray-derived Kellgren-Lawrence (KL) grade. They were treated with SVF and followed-up for 24 months. Visual analogue scale (VAS) and Western Ontario and McMaster Universities Osteoarthritis (WOMAC) Index were used to determine treatment efficacy. Cartilage healing was assessed using the MRI-based Outerbridge score (OS) and evaluation of bone marrow edema (BME) lesions, while a placebo group was used as a control. Time- and KL-dependent changes were also monitored. We observed a decreasing trend in VAS score and WOMAC index in the SVF-treated group up to 24 months, as compared with the placebo group. Besides, a significant increase and decrease in Lysholm and OS, respectively, were observed in the treatment group. Compared with the values before treatment, the greatly reduced WOMAC scores of KL3 than KL2 groups at 24 months, indicate more improvement in the KL3 group. Highly decreased BME in the treated group was also noted. In conclusion, the SVF therapy is effective in the recovery of OA patients of KL3 grade in 24 months.

Neuronal nitric oxide synthase activity mediates Lycium barbarum polysaccharides-enhanced sexual performance without stimulating noncontact erection in rats.

RATIONALE: Lycium barbarum polysaccharide (LBP) is known to promote reproductive functions. However, its role in noncontact erection (NCE) of penis initiated by brain regions including medial preoptic area (MPOA) and paraventricular nucleus (PVN) regions responsible for sexual behavior has not been investigated. OBJECTIVES: Therefore, this study initially investigated the effects of LBP on male sexual function, and subsequently, the mechanistic insight was investigated through assessing the expression of neuronal nitric oxide synthase (nNOS) in the MPOA and PVN. METHODS: The adult male rats were treated with 100 mg/kg of LBP or vehicle by oral gavage. Before and after 14 days of treatment, copulatory behavior and noncontact erection (NCE) were recorded. After the last behavioral test, the brain was isolated to measure nNOS expression in the MPOA and PVN. RESULTS: Data showed that LBP treatment significantly increased both the frequencies of intromission as well as ejaculation, compared to the control group. Whereas, a reduced post-ejaculatory interval was observed compared to same group on day 0. Furthermore, the treatment led to an increased intromission ratio, inter-intromission interval, and the number of MPOA nNOS-immunoreactive cells (nNOS-ir). Additionally, a significantly positive correlation between ejaculation frequency and MPOA nNOS-ir cells was recorded. Of note, LBP treatment had no effects on NCE and PVN nNOS-ir expression. CONCLUSION: These findings suggest that LBP enhances sexual behavior through increased nNOS expression in the MPOA in male rats.

Mechanistic insight into hyaluronic acid and platelet-rich plasma-mediated anti-inflammatory and anti-apoptotic activities in osteoarthritic mice.

Osteoarthritis (OA) poses a major clinical challenges owing to limited regenerative ability of diseased or traumatized chondrocytes in articular cartilage. Previous studies have determined the individual therapeutic efficacies of hyaluronic acid (HA) and platelet-rich plasma (PRP) on OA; however, the underlying mechanism is still lacking. Therefore, we investigated mechanistic approach of HA+PRP therapy on chondrocyte apoptosis in IL-1ß+TNF-α (I+T) treated in vitro OA model, in addition to in vivo anterior cruciate ligament transection-OA mice model. MTT assay showed an enhanced chondrocyte proliferation and viability in HA+PRP-treated group, compared to I+T, I+T/HA, I+T/PRP, I+T/HA+PRP groups. Further, HA+PRP also significantly suppressed ROS, apoptotic cleaved caspase-3 and PARP, p53 and p21 and MMP-1; whereas, cell cycle modulatory proteins including p-ERK, cyclin B1, D1, and E2 were upregulated. The sub-G1 population and TUNEL assay confirmed the higher abundance of healthy chondrocytes in HA+PRP group. A significantly decreased ARS staining in HA+PRP group was also noted, indicating reduced cartilaginous matrix mineralization compared to other groups. Conclusively, compared to HA or PRP, the combined HA+PRP might be a promising therapy for articular cartilage regeneration in osteoarthritic pathology, possibly via augmented anti-inflammatory, anti-oxidative chondrocyte proliferation and inhibited MMP-1 activity and matrix calcification.

Correction: Evaluation of a novel biodegradable thermosensitive keto-hydrogel for improving postoperative pain in a rat model.

[This corrects the article DOI: 10.1371/journal.pone.0186784.].

Tumor-Targeted Immunotherapy by Using Primary Adipose-Derived Stem Cells and an Antigen-Specific Protein Vaccine.

Cancer is a leading cause of mortality and a major public health problem worldwide. For biological therapy against cancer, we previously developed a unique immunotherapeutic platform by combining mesenchymal stem cells with an antigen-specific protein vaccine. However, this system possesses a few limitations, such as improperly immortalized mesenchymal stem cells (MSCs) along with transfected oncogenic antigens in them. To overcome the limitations of this platform for future clinical application, we freshly prepared primary adipose-derived stem cells (ADSCs) and modified the E7' antigen (E7') as a non-oncogenic protein. Either subcutaneously co-inoculated with cancer cells or systemically administered after tumor growth, ADSC labeled with enhanced green fluorescent protein (eGFP) and combined with modified E7' (ADSC-E7'-eGFP) cells showed significant antitumor activity when combined with the protein vaccine in both colon and lung cancer in mice. Specifically, this combined therapy inhibited tumor through inducing cell apoptosis. The significantly reduced endothelial cell markers, CD31 and vascular endothelial growth factor (VEGF), indicated strongly inhibited tumor angiogenesis. The activated immune system was demonstrated through the response of CD4+ T and natural killer (NK) cells, and a notable antitumor activity might be contributed by CD8+ T cells. Conclusively, these evidences imply that this promising immunotherapeutic platform might be a potential candidate for the future clinical application against cancer.