Viral infections are known as one of the major factors causing death. Ginseng is a medicinal plant that demonstrated a wide range of antiviral potential, and saponins are the major bioactive ingredients in the genus Panax with vast therapeutic potential. Studies focusing on the antiviral activity of the genus Panax plant-derived agents (extracts and saponins) and their mechanisms were identified and summarized, including contributions mainly from January 2016 until January 2022. P. ginseng, P. notoginseng, and P. quinquefolius were included in the review as valuable medicinal herbs against infections with 14 types of viruses. Reports from 9 extracts and 12 bioactive saponins were included, with 6 types of protopanaxadiol (PPD) ginsenosides and 6 types of protopanaxatriol (PPT) ginsenosides. The mechanisms mainly involved the inhibition of viral attachment and replication, the modulation of immune response by regulating signaling pathways, including the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway, cystathionine γ-lyase (CSE)/hydrogen sulfide (H2S) pathway, phosphoinositide-dependent kinase-1 (PDK1)/ protein kinase B (Akt) signaling pathway, c-Jun N-terminal kinase (JNK)/activator protein-1 (AP-1) pathway, and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway. This review includes detailed information about the mentioned antiviral effects of the genus Panax extracts and saponins in vitro and in vivo, and in human clinical trials, which provides a scientific basis for ginseng as an adjunctive therapeutic drug or nutraceutical.

Glycolipid metabolism disorder are major threats to human health and life. Genetic, environmental, psychological, cellular, and molecular factors contribute to their pathogenesis. Several studies demonstrated that neuroendocrine axis dysfunction, insulin resistance, oxidative stress, chronic inflammatory response, and gut microbiota dysbiosis are core pathological links associated with it. However, the underlying molecular mechanisms and therapeutic targets of glycolipid metabolism disorder remain to be elucidated. Progress in high-throughput technologies has helped clarify the pathophysiology of glycolipid metabolism disorder. In the present review, we explored the ways and means by which genomics, transcriptomics, proteomics, metabolomics, and gut microbiomics could help identify novel candidate biomarkers for the clinical management of glycolipid metabolism disorder. We also discuss the limitations and recommended future research directions of multi-omics studies on these diseases.

Because immune checkpoint inhibitors (ICIs) are effective for a subset of melanoma patients, identification of melanoma subtypes responsive to ICIs is crucial. We performed clustering analyses to identify immune subtypes of melanoma based on the enrichment levels of 28 immune cells using transcriptome datasets for six melanoma cohorts, including four cohorts not treated with ICIs and two cohorts treated with ICIs. We identified three immune subtypes (Im-H, Im-M, and Im-L), reproducible in these cohorts. Im-H displayed strong immune signatures, low stemness and proliferation potential, genomic stability, high immunotherapy response rate, and favorable prognosis. Im-L showed weak immune signatures, high stemness and proliferation potential, genomic instability, low immunotherapy response rate, and unfavorable prognosis. The pathways highly enriched in Im-H included immune, MAPK, apoptosis, calcium, VEGF, cell adhesion molecules, focal adhesion, gap junction, and PPAR. The pathways highly enriched in Im-L included Hippo, cell cycle, and ErbB. Copy number alterations correlated inversely with immune signatures in melanoma, while tumor mutation burden showed no significant correlation. The molecular features correlated with favorable immunotherapy response included immune-promoting signatures and pathways of PPAR, MAPK, VEGF, calcium, and glycolysis/gluconeogenesis. Our data recapture the immunological heterogeneity in melanoma and provide clinical implications for the immunotherapy of melanoma.

The initiation and development of major inflammatory diseases, i.e., cancer, vascular inflammation, and some autoimmune diseases are closely linked to the immune system. Biologics-based immunotherapy is exerting a critical role against these diseases, whereas the usage of the immunomodulators is always limited by various factors such as susceptibility to digestion by enzymes in vivo, poor penetration across biological barriers, and rapid clearance by the reticuloendothelial system. Drug delivery strategies are potent to promote their delivery. Herein, we reviewed the potential targets for immunotherapy against the major inflammatory diseases, discussed the biologics and drug delivery systems involved in the immunotherapy, particularly highlighted the approved therapy tactics, and finally offer perspectives in this field.

Metabolic profiling in COVID-19 patients has been associated with disease severity, but there is no report on sex-specific metabolic changes in discharged survivors. Herein we used an integrated approach of LC-MS-and GC-MS-based untargeted metabolomics to analyze plasma metabolic characteristics in men and women with non-severe COVID-19 at both acute period and 30 days after discharge. The results demonstrate that metabolic alterations in plasma of COVID-19 patients during the recovery and rehabilitation process were presented in a sex specific manner. Overall, the levels of most metabolites were increased in COVID-19 patients after the cure relative to acute period. The major plasma metabolic changes were identified including fatty acids in men and glycerophosphocholines and carbohydrates in women. In addition, we found that women had shorter length of hospitalization than men and metabolic characteristics may contribute to predict the duration from positive to negative in non-severe COVID-19 patients. Collectively, this study shed light on sex-specific metabolic shifts in non-severe COVID-19 patients during the recovery process, suggesting a sex bias in prognostic and therapeutic evaluations based on metabolic profiling.

The Hedgehog (HH) signaling pathway plays important roles in gastrointestinal carcinogenesis and the gastrointestinal tumor microenvironment (TME). Aberrant HH signaling activation may accelerate the growth of gastrointestinal tumors and lead to tumor immune tolerance and drug resistance. The interaction between HH signaling and the TME is intimately involved in these processes, for example, tumor growth, tumor immune tolerance, inflammation, and drug resistance. Evidence indicates that inflammatory factors in the TME, such as interleukin 6 (IL-6) and interferon-γ (IFN-γ), macrophages, and T cell-dependent immune responses, play a vital role in tumor growth by affecting the HH signaling pathway. Moreover, inhibition of proliferating cancer-associated fibroblasts (CAFs) and inflammatory factors can normalize the TME by suppressing HH signaling. Furthermore, aberrant HH signaling activation is favorable to both the proliferation of cancer stem cells (CSCs) and the drug resistance of gastrointestinal tumors. This review discusses the current understanding of the role and mechanism of aberrant HH signaling activation in gastrointestinal carcinogenesis, the gastrointestinal TME, tumor immune tolerance and drug resistance and highlights the underlying therapeutic opportunities.

OBJECTIVE: Immune checkpoint blockade (ICB) has been approved for treatment of hepatocellular carcinoma (HCC). However, many patients with advanced HCC are non-responders to ICB monotherapy. Cytotoxic chemotherapy has been proposed to modulate the tumor microenvironment (TME) and sensitize tumors to ICB. Thus, we aimed to study the combination of cytotoxic chemotherapy and ICB in an orthotopic HCC model.
METHODS: Preclinical orthotopic HCC mouse models were used to elucidate the efficacy of 5-fluorouracil (5-FU) and ICB. The mice were intrahepatically injected with RIL-175 or Hepa1-6 cells, followed by treatment with 5-FU and anti-programmed cell death ligand 1 (PD-L1) antibody. Myeloid-derived suppressor cells (MDSCs) were depleted to validate their role in attenuating sensitivity to immunotherapy. Flow cytometry-based immune profiling and immunofluorescence staining were performed in mice and patient samples, respectively.
RESULTS: 5-FU could induce intratumoral MDSC accumulation to counteract the infiltration of T lymphocytes and natural killer cells, thus abrogating the anti-tumor efficacy of PD-L1 blockade. In clinical samples, MDSCs accumulated and CD8+ T cell numbers decreased following transarterial chemoembolization.
CONCLUSIONS: 5-FU can trigger the accumulation of immunosuppressive MDSCs, impairing the response to PD-L1 blockade in HCC. Our data suggest that the combination of specific chemotherapy and ICB may impair anti-tumor immune responses, warranting further study in preclinical models and consideration in clinical settings.
BACKGROUND: Our findings suggest that some chemotherapies may impair the anti-tumor efficacy of immunotherapy. Further studies are required to uncover the specific effects of different chemotherapies on the immunological profile of tumors. This data will be critical for the rational design of combination immunotherapy strategies for patients with hepatocellular carcinoma.

Extracellular nucleotides, including ATP, are essential regulators of liver function and serve as danger signals that trigger inflammation upon injury. Ectonucleotidases, which are expressed by liver-resident cells and recruited immune cells sequentially hydrolyse nucleotides to adenosine. The nucleotide/nucleoside balance orchestrates liver homeostasis, tissue repair, and functional restoration by regulating the crosstalk between liver-resident cells and recruited immune cells. In this review, we discuss our current knowledge on the role of purinergic signals in liver homeostasis, restriction of inflammation, stimulation of liver regeneration, modulation of fibrogenesis, and regulation of carcinogenesis. Moreover, we discuss potential targeted therapeutic strategies for liver diseases based on purinergic signals involving blockade of nucleotide receptors, enhancement of ectonucleoside triphosphate diphosphohydrolase activity, and activation of adenosine receptors.

UNASSIGNED: Human mesenchymal stromal cells (MSCs) phenotypically share their positive expression of the International Society for Cell and Gene Therapy (ISCT) markers CD73, CD90 and CD105 with fibroblasts. Fibroblasts are often co-isolated as an unwanted by-product from biopsy and they can rapidly overgrow the MSCs in culture. Indeed, many other surface markers have been proposed, though no unique MSC specific marker has been identified yet. Quantitative PCR (qPCR) is a precise, efficient and rapid method for gene expression analysis. To identify a marker suitable for accurate MSC characterisation, qPCR was exploited.
UNASSIGNED: Two commercially obtained bone marrow (BM) derived MSCs and an hTERT immortalised BM-MSC line (MSC-TERT) have been cultured for different days and at different oxygen levels before RNA extraction. Together with RNA samples previous extracted from umbilical cord derived MSCs and MSC-TERT cells cultured in 2D or 3D, this heterogeneous sample set was quantitatively analysed for the expression levels of 18 candidate MSC marker genes. The expression levels in MSCs were compared with the expression levels in fibroblasts to verify the differentiation capability of these genes between MSCs and fibroblasts. None of the ISCT markers could differentiate between fibroblasts and MSCs. A total of six other genes (ALCAM, CLIC1, EDIL3, EPHA2, NECTIN2, and TMEM47) were identified as possible biomarkers for accurate identification of MSCs.
UNASSIGNED: Justified by considerations on expression level, reliability and specificity, Activated-Leukocyte Cell Adhesion Molecule (ALCAM) was the best candidate for improving the biomarker set of MSC identification.

Although immunotherapy has emerged as an effective therapeutic strategy for various cancers including head and neck squamous cell carcinomas (HNSCCs), only a subset of patients can benefit from such therapy. Hence, it is pressing to discover predictive biomarkers for cancer immunotherapy response. TP53 and HRAS mutations frequently occur in HNSCC and correlate with a worse prognosis in HNSCC. We extensively characterized the associations of TP53 mutations and HRAS mutations with HNSCC immunity based on multiple cancer genomics datasets. We compared the enrichment levels of 20 immune signatures between TP53-mutated and TP53-wildtype HNSCCs, and between HRAS-mutated and HRAS-wildtype HNSCCs, and found that TP53 mutations were associated with depressed immune signatures while HRAS mutations were associated with enhanced immune signatures in HNSCC. Moreover, we found multiple p53- and RAS-mediated pathways showing significant correlations with HNSCC immunity. Furthermore, we demonstrated that the association between TP53 mutation and tumor immunity was independent of the human papillomavirus (HPV) infection and smoking status in HNSCC. These data suggest that p53 and RAS may play important roles in regulating HNSCC immunity and that the TP53 and HRAS mutation status could be useful biomarkers for stratifying HNSCC patients responsive to immunotherapy.