IRE1 signaling regulates chondrocyte apoptosis and death fate in the osteoarthritis.

IRE1 is an important central regulator of unfolded protein response (UPR) in the endoplasmic reticulum (ER) because of its ability to regulate cell fate as a function of stress sensing. When misfolded proteins accumulated in chondrocytes ER, IRE1 disintegrates with BIP/GRP78 and undergoes dimer/oligomerization and transautophosphorylation. These two processes are mediated through an enzyme activity of IRE1 to activate endoribonuclease and generates XBP1 by unconventional splicing of XBP1 messenger RNA. Thereby promoting the transcription of UPR target genes and apoptosis. The deficiency of inositol-requiring enzyme 1α (IRE1α) in chondrocytes downregulates prosurvival factors XBP1S and Bcl-2, which enhances the apoptosis of chondrocytes through increasing proapoptotic factors caspase-3, p-JNK, and CHOP. Meanwhile, the activation of IRE1α increases chondrocyte viability and reduces cell apoptosis. However, the understanding of IRE1 responses and cell death fate remains controversial. This review provides updated data about the role IRE1 plays in chondrocytes and new insights about the potential efficacy of IRE1 regulation in cartilage repair and osteoarthritis treatment.

Exhaustion and over-activation of immune cells in COVID-19: Challenges and therapeutic opportunities.

Exhaustion of immune cells in COVID-19 remains a serious concern for infection management and therapeutic interventions. As reported, immune cells such as T effector cells (Teff), T regulatory cells (Tregs), natural killer cells (NKs), and antigen-presenting cells (APCs) exhibit uncontrolled functions in COVID-19. Unfortunately, the mechanisms that orchestrate immune cell functionality and virus interaction are still unknown. Recent studies linked adaptive immune cell exhaustion to underlying epigenetic mechanisms that regulate the epigenetic transcription of inhibitory immune checkpoint receptors (ICs). Further to that, the over-activation of T cells accompanied by the dysfunctionality of DCs and Tregs may enhance uncontrollable alveoli inflammation and cytokine storm in COVID-19. This might explain the reasons behind the failure of DC-based vaccines in inducing sufficient anti-viral responses. This review explains the processes behind the over-activation and exhaustion of innate and adaptive immune cells in COVID-19, which may contribute to developing novel immune intervention strategies.

ANLN and UBE2T are prognostic biomarkers associated with immune regulation in breast cancer: a bioinformatics analysis.

OBJECTIVES: To screen and verify differential genes affecting the prognosis of breast cancer. METHODS: Breast cancer gene expression datasets were downloaded from the GEO database, and original data were analyzed in R. The TIMER database was used to analyze the relationship between ANLN and UBE2T and immune cell infiltration. RESULTS: Ten hub-key genes were identified, and survival analysis showed that UBE2T and ANLN were upregulated in breast cancer and their upregulation was associated with a poor prognosis. ANLN and UBE2T upregulation was associated with the prevalence of Th1 and Th2 cells, shifting the Th1/Th2 balance to Th2 in Basal and Luminal-B breast cancers, which indicates a poor prognosis (P < 0.05). CONCLUSION: ANLN and UBE2T are potential biomarkers for predicting the prognosis of breast cancer.

Forecasting sensitive targets of the kynurenine pathway in pancreatic adenocarcinoma using mathematical modeling.

In this study, a new mathematical model was established and validated to forecast and define sensitive targets in the kynurenine pathway (Kynp) in pancreatic adenocarcinoma (PDAC). Using the Panc-1 cell line, genetic profiles of Kynp molecules were tested. qPCR data were implemented in the algorithm programming (fmincon and lsqnonlin function) to estimate 35 parameters of Kynp variables by Matlab 2017b. All tested parameters were defined as non-negative and bounded. Then, based on experimental data, the function of the fmincon equation was employed to estimate the approximate range of each parameter. These calculations were confirmed by qPCR and Western blot. The correlation coefficient (R) between model simulation and experimental data (72 hours, in intervals of 6 hours) of every variable was >0.988. The analysis of reliability and predictive accuracy depending on qPCR and Western blot data showed high predictive accuracy of the model; R was >0.988. Using the model calculations, kynurenine (x3, a6), GPR35 (x4, a8), NF-kßp105 (x7, a16), and NF-kßp65 (x8, a18) were recognized as sensitive targets in the Kynp. These predicted targets were confirmed by testing gene and protein expression responses. Therefore, this study provides new interdisciplinary evidence for Kynp-sensitive targets in the treatment of PDAC.

Potential efficacy of dendritic cell immunomodulation in the treatment of osteoarthritis.

Dendritic cells (DCs) are a cluster of heterogeneous antigen-presenting cells that play a pivotal role in both innate and adaptive immune responses. Rare reports have discussed their role in OA immunopathogenesis. Recently, DCs derived from the synovial fluid of OA mice were shown to have increased expression of toll-like receptors. Moreover, from in vitro studies it was concluded that DCs derived from OA patients had secreted high levels of inflammatory cytokines. Likewise, a significant increase in CD123+BDCA-2 plasmacytoid DCs has been observed in the synovial fluid of OA patients. Furthermore, DCs have a peripheral tolerance potential and can become regulatory under specific circumstances. This could be exploited as a promising tool to eliminate immunoinflammatory manifestations in OA disease. In this review, the potential roles DCs could play in OA pathogenesis have been described. In addition, suggestions for the development of new immunotherapeutic strategies involving intra-articular injections of tolerogenic plasmacytoid DCs for treating OA inflammations have been made.

Intra-articular injection of hUC-MSCs expressing miR-140-5p induces cartilage self-repairing in the rat osteoarthritis.

INTRODUCTION: Currently, osteoarthritis (OA) receives global increasing attention because it associates severe joint pain and serious disability. Stem cells intra-articular injection therapy showed a potential therapeutic superiority to reduce OA development and to improve treating outputs. However, the long-term effect of stem cells intra-articular injection on the cartilage regeneration remains unclear. Recently, miR-140-5p was confirmed as a critical positive regulator in chondrogenesis. We hypothesized that hUC-MSCs overexpressing miR-140-5p have better therapeutic effect on osteoarthritis. MATERIALS AND METHODS: To enhance stem cell chondrogenic differentiation, we have transfected human umbilical cord mesenchymal stem cells (hUC-MSCs) with miR-140-5p mimics and miR-140-5p lentivirus to overexpress miR-140-5p in a short term or a long term accordingly. Thereafter, MSCs proliferation, chondrogenic genes expression and extracellular matrix were assessed. Destabilization of the medial meniscus (DMM) surgery was performed on the knee joints of SD rats as an OA model, and then intra-articular injection of hUC-MSCs or hUC-MSCs transfected with miR-140-5p lentivirus was carried to evaluate the cartilage healing effect with histological staining and OARSI scores. The localization of hUC-MSCs after intra-articular injection was further confirmed by immunohistochemical staining. RESULTS: Significant induction of chondrogenic differentiation in the miR-140-5p-hUC-MSCs (140-MSCs), while its proliferation was not influenced. Interestingly, intra-articular injection of 140-MSCs significantly enhanced articular cartilage self-repairing in comparison to normal hUC-MSCs. Moreover, we noticed that intra-articular injection of high 140-MSCs numbers reinforces cells assembling on the impaired cartilage surface and subsequently differentiated into chondrocytes. CONCLUSIONS: In conclusion, these results indicate therapeutic superiority of hUC-MSCs overexpressing miR-140-5p to treat OA using intra-articular injection.

Inhibition of RM-1 prostate carcinoma and eliciting robust immune responses in the mouse model by using VEGF-M2-GnRH3-hinge-MVP vaccine.

GnRH and VEGF have been investigated as prostate carcinoma enhancers that support tumor spread and progression. Although both have documented roles in prostate carcinoma and many cancer types, the weak immunogenicity of these peptides has remained a major challenge for use in immunotherapy. Here, we describe a novel strategy to inhibit GnRH and VEGF production and assess the effect on the immune responses against these hormones using the RM-1 prostate cancer model. We designed a novel recombinant fusion protein which combined GnRH and VEGF as a vaccine against this tumor. The newly constructed fusion protein hVEGF121-M2-GnRH3-hinge-MVP contains the human vascular endothelial growth factor (hVEGF121) and three copies of GnRH in sequential linear alignment and T helper epitope MVP as an immunogenic vaccine. The effectiveness of the vaccine in eliciting an immune response and attenuating the prostate tumor growth was evaluated. Results showed that administration of a new vaccine effectively elicited humoral and cellular immune responses. We found that, a novel fusion protein, hVEGF121-M2-GnRH3-hinge-MVP, effectively inhibited growth of RM-1 prostate model and effectively promoted immune response. In conclusion, hVEGF121-M2-GnRH3-hinge-MVP is an effective dual mechanism tumor vaccine that limits RM-1 prostate growth. This vaccine may be a promising strategy for the treatment of hormone refractory prostate malignancies.

Up-regulation of miR-210 induced by a hypoxic microenvironment promotes breast cancer stem cells metastasis, proliferation, and self-renewal by targeting E-cadherin.

Breast cancer stem cells (BCSCs), a small subset of breast cancer cells with stem cell-like properties, are essential in tumor formation, metastasis, resistance to anticancer therapies, and cancer recurrence. MicroRNAs (miRNAs) are involved in tumorigenicity by regulating specific oncogenes and tumor-suppressor genes, and their roles in BCSCs are becoming apparent. A novel, 3-dimensional (3D), semisolid culture system was established to culture MCF-7 spheroid cells with high percentage of BCSCs. The differences in miRNA expression among the MCF-7 parental cells, BCSC-enriched MCF-7 spheroid cells, and CD44+/CD24- MCF-7 cells were evaluated by miRNA microarray, and the high expression of miR-210 in MCF-7 spheroid cells and CD44+/CD24- MCF-7 cells was verified by quantitative RT-PCR. MCF-7 cells were cultured in a hypoxic chamber to detect the effect of hypoxia on miR-210 expression and the stemness of the cells. The 3-(4,5-dimethylthiazol-2- yl)-2,5-diphenyl tetrazolium bromide (MTT), transwell, and sphere-formation assays were performed to detect the proliferation, migration, and self-renewal ability of miR-210-overexpressed MCF-7 cells and MCF-7 spheroid cells with miR-210 knocked down. The target of miR-210 was validated with a dual-luciferase reporter assay and Western blotting. In vivo xenograft assay and metastasis assay were performed to study the effects of miR-210 targeting E-cadherin on BCSCs growth and lung metastasis, and the tumors were assessed by immunohistochemistry and immunofluorescence. We developed a novel 3D, semisolid culture system to culture MCF-7 spheroid cells, which are enriched in BCSCs, and found, by performing miRNAs expression profiling, miR-210 was up-regulated in those cells compared with MCF-7 parental cells. High miR-210 expression was also detected in CD44+/CD24- MCF-7 cells and human CD44+/CD24- breast cancer cells, which was demonstrated to be partially due to the hypoxic microenvironment around BCSCs in MCF-7 spheroids or solid tumors. Ectopic expression of miR-210 in MCF-7 cells promoted their migration, invasion, proliferation, and self-renewal in both in vitro and in vivo studies. We further reported that miR-210 suppressed E-cadherin expression by targeting the open reading frame region of E-cadherin mRNA and by up-regulation of E-cadherin transcription repressor, Snail. Accordingly, E-cadherin overexpression compromises the migration, invasion, proliferation, and self-renewal ability of miR-210-overexpressed MCF-7 both in vitro and in vivo. These findings reveal a novel regulatory pathway centered on hypoxia-mediated miR-210 targeting of E-cadherin, which contributes to the properties and breast tumorigenesis of BCSCs.-Tang, T., Yang, Z., Zhu, Q., Wu, Y., Sun, K., Alahdal, M., Zhang, Y., Xing, Y., Shen, Y., Xia, T., Xi, T., Pan, Y., Jin, L. Up-regulation of miR-210 induced by a hypoxic microenvironment promotes breast cancer stem cells metastasis, proliferation, and self-renewal by targeting E-cadherin.

Novel mutant P277 peptide VP to ameliorate atherogenic side-effects and to preserve anti-diabetic effects in NOD mice.

P277 is a 24 amino-acids peptide, residues 437-460 of human heat shock protein 60 (HSP60). P277 or sequence repeated 6 × P277 was previously found showing potency preventive and therapeutic anti-diabetes functions in NOD mice, but aroused atherosclerosis due to the induction of anti-HSP65 autoantibodies as reported. To determine the intrinsic B epitope sequence, we screened P277 with pepscan method and then proved by detection of sera IgG from peptide fragments vaccinated mouse and rabbits. Results indicated HSP60 443-448 (ALLRCI) is potential intrinsic B epitope sequence of P277. We modified P277 by deleting the former three amino acids of ALLRCI (VP) or replacing these six with alanine (AP). The detection of serum lipid parameter in NOD mice and aorta endothelial damage levels in high-cholesterol diets fed rabbits demonstrated that VP induced higher anti-diabetes efficacy and caused less arteriosclerosis-liked diseases separately. With less TLR2/4 activation of dendritic cells and macrophages, VP treatment reduced Th1 related P277 specific pro-inflammatory cytokines production and increased regulatory immune responses both in vivo and in vitro. These results indicated that optimized VP peptide might serve as a promising candidate for mouse type 1 diabetes therapy.

Overexpression of ClC-3 Chloride Channel in Chondrosarcoma: An In Vivo Immunohistochemical Study with Tissue Microarray.

BACKGROUND Recently, ClC-3 chloride channel expression has been noted to be high in some tumors. In chondrosarcoma, which is a malignant tumor with a high incidence in the bone, there has been no previous literature regarding ClC-3 chloride channel expression. Here we evaluated the expression of ClC-3 chloride channel in chondrosarcoma and explored its clinical significance. MATERIAL AND METHODS In this study, 75 chondrosarcoma and 5 normal cartilage tissues were collected. Thereafter, tissue microarray was performed. Immunohistochemistry was also used to observe the level of ClC-3 chloride channel expression between normal and chondrosarcoma tissues. RESULTS Results showed that the expression of ClC-3 chloride channel in the normal chondrocyte was thinner, since it showed distinct differentiation among chondrosarcoma specimens. Interestingly, we noticed that the moderately-differentiated chondrosarcoma (MDC) and the poorly-differentiated chondrosarcoma (PDC) exhibited 94.44% of ClC-3 chloride channel. Besides, the subcellular localization of ClC-3 chloride channel was changed in association with malignant degree changes. The subcellular localization of ClC-3 chloride channel in the MDC and PDC tissue was localized in the cytoplasm and both nucleus and cytoplasm: 83.33% (5 out of 6 cases) and 91.66% (11 out of 12 cases) respectively. On the other hand, we noticed that patient age and gender could have a relation with ClC-3 chloride channel expression; 30- to 60-year-old males showed more expression. CONCLUSIONS These results demonstrated a high frequency of ClC-3 chloride channel overexpression and subcellular localization differences in MDC and PDC tissue, suggesting a specific role of ClC-3 chloride channel in the pathogenesis of chondrosarcoma.

Pharmacological Effects of EGLP-1, a Novel Analog of Glucagon-Like Peptide-1, on Carbohydrate and Lipid Metabolism.

BACKGROUND/AIMS: Abnormal glucose metabolism and lipid metabolism are two key issues in Type 1 diabetes mellitus (T1DM). Insulin can control carbohydrate metabolism adequately, but cannot regulate lipid metabolism well in patients with T1DM. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have cured type 2 diabetes mellitus in clinical trials and have improved T1DM glycemic control in preclinical studies. However, previous studies have not reported whether GLP-1 can lower the serum concentration of non-esterified fatty acids (NEFAs). In this study, we examine whether GLP-1 can affect serum NEFA levels. METHODS: The bioactivity of EGLP-1 (a novel GLP-1 analog) in vitro was analyzed in CG-HEK293 cells and with high-performance liquid chromatography. An intraperitoneal glucose tolerance test (IPGTT) was used to analyze the acute and sustained hypoglycemic effects of EGLP-1 in normal C57BL/6J mice. Streptozotocin-induced hyperglycemic mice were used to study the effects of EGLP-1 on blood glucose and NEFAs as well as its mechanism. RESULTS: EGLP-1 activated GLP-1R and resisted dipeptidyl peptidase-IV digestion in vitro. Additionally, EGLP-1 had an insulinotropic action in vivo that lasted for approximately 6 h. In Streptozotocin-induced hyperglycemic mice, EGLP-1 improved hyperglycemia, inhibited food intake, and increased ß-cell area. Serum physiological indexes showed that insulin and C-peptide levels were increased, while NEFA and triacylglycerol concentrations were decreased. Western blot analysis revealed that EGLP-1 significantly reduced phosphorylated-hormone sensitive lipase (pHSL) levels in white adipose tissue. CONCLUSIONS: EGLP-1 can improve hyperglycemia by increasing islet ß-cell area and improving ß-cell function, possibly due to reduced NEFA content in serum by lowering pHSL levels.

PGLP-1, a novel long-acting dual-function GLP-1 analog, ameliorates streptozotocin-induced hyperglycemia and inhibits body weight loss.

It is well known that glucagon-like peptide 1 (GLP-1) has antidiabetic action. It has 2 distinct functions, an insulinotropic effect dependent on GLP-1 receptor (GLP-1R) and an insulinomimetic effect independent of GLP-1R. However, use of GLP-1 in vivo is limited by its short half-life. Therefore, our lab designed PGLP-1, a novel 2-function candidate peptide as a potential substitute. Using a streptozotocin-induced hyperglycemic mouse model, we demonstrated in vitro and in vivo that PGLP-1 had insulinotropic actions dependent on GLP-1R and insulinomimetic functions independent of GLP-1R. PGLP-1 treatment increased islet ß-cell mass, plasma insulin, and C-peptide levels and Ki-67-immunoreactive ß-cell numbers, verifying that PGLP-1 can work as a short GLP-1R agonist, similar to commercially available exendin-4. Additionally, PGLP-1 improved insulin sensitivity, inhibited gluconeogenesis by increasing expression of AMPK and receptor subfamily 0, group B, member 2 (SHP), and inhibited body weight loss by inhibiting ß-oxidation, suggesting that PGLP-1 had insulinomimetic action. Taken together, these data indicated that PGLP-1, as a dual-function peptide, improved glycemic control and inhibited body weight loss, suggesting it could be useful for type 1 diabetes mellitus patients as an adjunctive therapy to insulin.-Gao, H., Zhao, Q., Song, Z., Yang, Z., Wu, Y., Tang, S., Alahdal, M., Zhang, Y., Jin, L. PGLP-1, a novel long-acting dual-function GLP-1 analog, ameliorates streptozotocin-induced hyperglycemia and inhibits body weight loss.

α-Ketoglutarate Promotes Pancreatic Progenitor-Like Cell Proliferation.

A major source of ß cell generation is pancreatic progenitor-like cell differentiation. Multiple studies have confirmed that stem cell metabolism plays important roles in self-renewal and proliferation. In the absence of glucose, glutamine provides the energy for cell division and growth. Furthermore, α-ketoglutarate (αKG), a precursor for glutamine synthesis, is sufficient for enabling glutamine-independent cell proliferation. We have demonstrated that αKG contributes to the large-scale proliferation of pancreatic progenitor-like cells that can provide an ample amount of clinically relevant ß cells. We compared the mRNA expression of a subset of genes, the abundance of ATP, reactive oxide species, mitochondrial number, and the colony-forming frequency between mouse pancreatic CD133⁺ and CD133- cells. We employed Real-Time PCR, immunostaining and passage assays to investigate self-renewal and proliferation of pancreatic progenitor-like cells in a 3D culture system in the presence and absence of αKG. The energy metabolism of CD133⁺ cells was more prone to oxidative phosphorylation. However, in the 3D culture system, when αKG was supplemented to the culture medium, the proliferation of the pancreatic progenitor-like cells was significantly elevated. We confirmed that the presence of αKG correlated with the up-regulation of Ten-Eleven Translocation (Tet). αKG can promote the proliferation of pancreatic progenitor-like cells via the up-regulation of Tet.

Non-coding RNAs in cancer immunotherapy: Predictive biomarkers and targets.

BACKGROUND: To date, standardising clinical predictive biomarkers for assessing the response to immunotherapy remains challenging due to variations in personal genetic signatures, tumour microenvironment complexities and epigenetic onco-mechanisms. MAIN BODY: Early monitoring of key non-coding RNA (ncRNA) biomarkers may help in predicting the clinical efficacy of cancer immunotherapy and come up with standard predictive ncRNA biomarkers. For instance, reduced miR-125b-5p level in the plasma of non-small cell lung cancer patients treated with anti-PD-1 predicts a positive outcome. The level of miR-153 in the plasma of colorectal cancer patients treated with chimeric antigen receptor T lymphocyte (CAR-T) cell therapy may indicate the activation of T-cell killing activity. miR-148a-3p and miR-375 levels may forecast favourable responses to CAR-T-cell therapy in B-cell acute lymphoblastic leukaemia. In cancer patients treated with the GPC3 peptide vaccine, serum levels of miR-1228-5p, miR-193a-5p and miR-375-3p were reported as predictive biomarkers of good response and improved overall survival. Therefore, there is a critical need for further studies to elaborate on the key ncRNA biomarkers that have the potential to predict early clinical responses to immunotherapy. CONCLUSION: This review summarises important predictive ncRNA biomarkers that were reported in cancer patients treated with different immunotherapeutic modalities, including monoclonal antibodies, small molecule inhibitors, cancer vaccines and CAR-T cells. In addition, a concise discussion on forthcoming perspectives is provided, outlining technical approaches for the optimal utilisation of immunomodulatory ncRNA biomarkers as predictive tools and therapeutic targets.

Exosomes loaded with chondrogenic stimuli agents combined with 3D bioprinting hydrogel in the treatment of osteoarthritis and cartilage degeneration.

Osteoarthritis (OA) is a challenging joint inflammatory disease that often leads to disability. Immunoregulatory Exosomes (Exos) have shown promise in OA and cartilage degeneration treatment. Engineering Exos to deliver therapeutic agents like Kartogenin (KGN) has displayed potential for restoring cartilage regeneration. However, challenges include the uneven distribution of Exos at the injury site and the release of Exos cargo out of chondrocytes. Hydrogel-loaded uMSC-Exo has demonstrated significant therapeutic effects in wound healing and tissue regeneration. Recently, a new version of three-dimensional (3D) bioprinting of hydrogel significantly restored cartilage regeneration in OA joints. Combining immune regulatory Exos with 3D bioprinting hydrogel (3D-BPH-Exos) holds the potential for immunomodulating cartilage tissue and treatment of OA. It can reduce intracellular inflammasome formation and the release of inflammatory agents like IL-1ß, TNF-α, and INF-γ, while also preventing chondrocyte apoptosis by restoring mitochondrial functions and enhancing chondrogenesis in synovial MSCs, osteoprogenitor cells, and osteoclasts. Loading Exos with chondrogenic stimuli agents in the 3D-BPH-Exos approach may offer a faster and safer strategy for cartilage repair while better inhibiting joint inflammation than high doses of anti-inflammatory drugs and cell-based therapies. This review provides a comprehensive overview of hydrogel bioprinting and exosome-based therapy in OA. It emphasizes the potential of 3D-BPH-Exos loaded with chondrogenic stimuli agents for OA treatment, serving as a basis for further research.

Role of exosomal ncRNAs released by M2 macrophages in tumor progression of gastrointestinal cancers.

Macrophages (MΦs) type 2 (M2) play crucial roles in the pathogenesis of gastrointestinal cancers (GIC) by enhancing tumor progression, invasion, and metastasis. Polarized M2 has been linked to the increase of GIC tumorigenesis and drug resistance. Several studies reported that M2-derived exosomal non-coding RNAs (Exos-ncRNAs) play pivotal roles in the modulation of the GIC tumor microenvironment (TME) and mostly promote drug resistance and immunosuppression. The impact of M2-Exos-ncRNAs is attributed to altered signaling pathways, enhancement of immunoregulatory mechanisms, and post-transcriptional modulation. Recent studies described novel targets in M2-TAMs-derived Exos-ncRNAs and potential promising clinical outcomes such as inhibiting tumor formation, invasion, and metastasis. Highlighting current knowledge of M2-Exos-ncRNAs involved in GIC pathogenesis and immunomodulation would thus be a significant contribution to improving clinical outcomes. In this review, we summarize recent updates on the role of M2-TAMs-Exos-ncRNAs in GIC pathogenesis, immunosuppression, and drug resistance. A deep understanding of M2-TAMs-derived Exos-ncRNAs could help to identify potential biomarkers and therapeutic targets.

Current advances of liquid biopsies in prostate cancer: Molecular biomarkers.

Prostate cancer (PCa) incidence is increasing and endangers men's lives. Early detection of PCa could improve overall survival (OS) by preventing metastasis. The prostate-specific antigen (PSA) test is a popular screening method. Several advisory groups, however, warn against using the PSA test due to its high false positive rate, unsupported outcome, and limited benefit. The number of disease-related biopsies performed annually far outweighs the number of diagnoses. Thus, there is an urgent need to develop accurate diagnostic biomarkers to detect PCa and distinguish between aggressive and indolent cancers. Recently, non-coding RNA (ncRNA), circulating tumor DNA (ctDNA)/ctRNA, exosomes, and metabolomic biomarkers in the liquid biopsies (LBs) of patients with PCa showed significant differences and clinical benefits in diagnosis, prognosis, and monitoring response to therapy. The analysis of urinary exosomal ncRNA presented a substantial correlation among Exos-miR-375 downregulation, clinical T stage, and bone metastases of PCa. Furthermore, the expression of miR-532-5p in urine samples was a vital predictive biomarker of PCa progression. Thus, this review focuses on promising molecular and metabolomic biomarkers in LBs from patients with PCa. We thoroughly addressed the most recent clinical findings of LB biomarker use in diagnosing and monitoring PCa in early and advanced stages.

Promising use of immune cell-derived exosomes in the treatment of SARS-CoV-2 infections.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is persistently threatening the lives of thousands of individuals globally. It triggers pulmonary oedema, driving to dyspnoea and lung failure. Viral infectivity of coronavirus disease 2019 (COVID-19) is a genuine challenge due to the mutagenic genome and mysterious immune-pathophysiology. Early reports highlighted that extracellular vesicles (exosomes, Exos) work to enhance COVID-19 progression by mediating viral transmission, replication and mutations. Furthermore, recent studies revealed that Exos derived from immune cells play an essential role in the promotion of immune cell exhaustion by transferring regulatory lncRNAs and miRNAs from exhausted cells to the active cells. Fortunately, there are great chances to modulate the immune functions of Exos towards a sustained repression of COVID-19. Engineered Exos hold promising immunotherapeutic opportunities for remodelling cytotoxic T cells' function. Immune cell-derived Exos may trigger a stable epigenetic repression of viral infectivity, restore functional cytokine-producing T cells and rebalance immune response in severe infections by inducing functional T regulatory cells (Tregs). This review introduces a view on the current outcomes of immunopathology, and immunotherapeutic applications of immune cell-derived Exos in COVID-19, besides new perspectives to develop novel patterns of engineered Exos triggering novel anti-SARS-CoV-2 immune responses.

The Homeostasis of Cartilage Matrix Remodeling and the Regulation of Volume-Sensitive Ion Channel.

Degenerative joint diseases of the hips and knees are common and are accompanied by severe pain and movement disorders. At the microscopic level, the main characteristics of osteoarthritis are the continuous destruction and degeneration of cartilage, increased cartilage extracellular matrix catabolism, decreased anabolism, increased synovial fluid, and decreased osmotic pressure. Cell volume stability is mainly regulated by ion channels, many of which are expressed in chondrocytes. These ion channels are closely related to pain regulation, volume regulation, the inflammatory response, cell proliferation, apoptosis, and cell differentiation. In this review, we focus on the important role of volume control-related ion channels in cartilage matrix remodeling and summarize current views. In addition, the potential mechanism of the volume-sensitive anion channel LRRC8A in the early occurrence of osteoarthritis is discussed.