Natural products reverse cisplatin resistance in the hypoxic tumor microenvironment.

Cisplatin is one of the most commonly used drugs for cancer treatment. Despite much progress in improving patient outcomes, many patients are resistant to cisplatin-based treatments, leading to limited treatment efficacy and increased treatment failure. The fact that solid tumors suffer from hypoxia and an inadequate blood supply in the tumor microenvironment has been widely accepted for decades. Numerous studies have shown that a hypoxic microenvironment significantly reduces the sensitivity of tumor cells to cisplatin. Therefore, understanding how hypoxia empowers tumor cells with cisplatin resistance is essential. In the fight against tumors, developing innovative strategies for overcoming drug resistance has attracted widespread interest. Natural products have historically made major contributions to anticancer drug research due to their obvious efficacy and abundant candidate resources. Intriguingly, natural products show the potential to reverse chemoresistance, which provides new insights into cisplatin resistance in the hypoxic tumor microenvironment. In this review, we describe the role of cisplatin in tumor therapy and the mechanisms by which tumor cells generate cisplatin resistance. Subsequently, we call attention to the linkage between the hypoxic microenvironment and cisplatin resistance. Furthermore, we summarize known and potential natural products that target the hypoxic tumor microenvironment to overcome cisplatin resistance. Finally, we discuss the current challenges that limit the clinical application of natural products. Understanding the link between hypoxia and cisplatin resistance is the key to unlocking the full potential of natural products, which will serve as new therapeutic strategies capable of overcoming resistance.

Activation of AMPK inhibits cervical cancer growth by hyperacetylation of H3K9 through PCAF.

BACKGROUND: Dysregulation in histone acetylation, a significant epigenetic alteration closely associated with major pathologies including cancer, promotes tumorigenesis, inactivating tumor-suppressor genes and activating oncogenic pathways. AMP-activated protein kinase (AMPK) is a cellular energy sensor that regulates a multitude of biological processes. Although a number of studies have identified the mechanisms by which AMPK regulates cancer growth, the underlying epigenetic mechanisms remain unknown. METHODS: The impact of metformin, an AMPK activator, on cervical cancer was evaluated through assessments of cell viability, tumor xenograft model, pan-acetylation analysis, and the role of the AMPK-PCAF-H3K9ac signaling pathway. Using label-free quantitative acetylproteomics and chromatin immunoprecipitation-sequencing (ChIP) technology, the activation of AMPK-induced H3K9 acetylation was further investigated. RESULTS: In this study, we found that metformin, acting as an AMPK agonist, activates AMPK, thereby inhibiting the proliferation of cervical cancer both in vitro and in vivo. Mechanistically, AMPK activation induces H3K9 acetylation at epigenetic level, leading to chromatin remodeling in cervical cancer. This also enhances the binding of H3K9ac to the promoter regions of multiple tumor suppressor genes, thereby promoting their transcriptional activation. Furthermore, the absence of PCAF renders AMPK activation incapable of inducing H3K9 acetylation. CONCLUSIONS: In conclusion, our findings demonstrate that AMPK mediates the inhibition of cervical cancer growth through PCAF-dependent H3K9 acetylation. This discovery not only facilitates the clinical application of metformin but also underscores the essential role of PCAF in AMPK activation-induced H3K9 hyperacetylation.

Prevotella copri exhausts intrinsic indole-3-pyruvic acid in the host to promote breast cancer progression: inactivation of AMPK via UHRF1-mediated negative regulation.

Emerging evidence has revealed the novel role of gut microbiota in the development of cancer. The characteristics of function and composition in the gut microbiota of patients with breast cancer patients has been reported, however the detailed causation between gut microbiota and breast cancer remains uncertain. In the present study, 16S rRNA sequencing revealed that Prevotella, particularly the dominant species Prevotella copri, is significantly enriched and prevalent in gut microbiota of breast cancer patients. Prior-oral administration of P. copri could promote breast cancer growth in specific pathogen-free mice and germ-free mice, accompanied with sharp reduction of indole-3-pyruvic acid (IPyA). Mechanistically, the present of excessive P. copri consumed a large amount of tryptophan (Trp), thus hampering the physiological accumulation of IPyA in the host. Our results revealed that IPyA is an intrinsic anti-cancer reagent in the host at physiological level. Briefly, IPyA directly suppressed the transcription of UHRF1, following by the declined UHRF1 and PP2A C in nucleus, thus inhibiting the phosphorylation of AMPK, which is just opposite to the cancer promoting effect of P. copri. Therefore, the exhaustion of IPyA by excessive P. copri strengthens the UHRF1-mediated negative control to inactivated the energy-controlling AMPK signaling pathway to promote tumor growth, which was indicated by the alternation in pattern of protein expression and DNA methylation. Our findings, for the first time, highlighted P. copri as a risk factor for the progression of breast cancer.

Small-molecule agents for cancer immunotherapy.

Cancer immunotherapy, exemplified by the remarkable clinical benefits of the immune checkpoint blockade and chimeric antigen receptor T-cell therapy, is revolutionizing cancer therapy. They induce long-term tumor regression and overall survival benefit in many types of cancer. With the advances in our knowledge about the tumor immune microenvironment, remarkable progress has been made in the development of small-molecule drugs for immunotherapy. Small molecules targeting PRR-associated pathways, immune checkpoints, oncogenic signaling, metabolic pathways, cytokine/chemokine signaling, and immune-related kinases have been extensively investigated. Monotherapy of small-molecule immunotherapeutic drugs and their combinations with other antitumor modalities are under active clinical investigations to overcome immune tolerance and circumvent immune checkpoint inhibitor resistance. Here, we review the latest development of small-molecule agents for cancer immunotherapy by targeting defined pathways and highlighting their progress in recent clinical investigations.

Apigenin promotes apoptosis of 4T1 cells through PI3K/AKT/Nrf2 pathway and improves tumor immune microenvironment in vivo.

The 2022 US Cancer Statistics show that breast cancer is one of the most common cancers in women. Epidemiology has shown that adding flavonoids to the diet inhibits cancers that arise in particular women, such as cervical cancer, ovarian cancer, and breast cancer. Although there have been research reports on apigenin (API) and breast cancer, its anti-tumor effect and potential mechanism on breast cancer have not yet been clarified. Therefore, in this study, we used 4T1 cells and a 4T1 xenograft tumor mouse model to investigate the antitumor effect of API on breast cancer and its underlying mechanism. In vitro, we used MTT, transwell, staining, and western blotting to investigate the inhibitory effect of apigenin on 4T1 and the underlying molecular mechanism. In vivo by establishing a xenograft tumor model, using immunohistochemistry, and flow cytometry to study the inhibitory effect of apigenin on solid breast tumors and its effect on the tumor immune microenvironment. The results showed that API can induce breast cancer cell apoptosis through the PI3K/AKT/Nrf2 pathway and can improve the tumor immune microenvironment in mice with breast tumors, thereby inhibiting the growth of breast cancer. Thus, API may be a promising agent for breast cancer treatment.

Biology and function of exosomes in tumor immunotherapy.

Exosomes are nano-scale extracellular vesicles that are found widely in various biological fluids. As messengers, exosomes deliver characteristic biological information from donor cells, facilitating their accumulation and subsequent transfer of information to tumor immune cells. Immunotherapy is a cutting-edge strategy for cancer therapy, but it has not yet reached its full potential owing to severe side effects and limited efficacy. Exosomes possess antigens and immunostimulatory molecules and can serve as cell-free vaccines to induce antitumor immunity. In addition, given their stability, low immunogenicity, and targeting ability, exosomes represent ideal drug delivery systems in tumor immunotherapy by delivering cargoes, including non-coding ribonucleic acids (RNAs), membrane proteins, chemotherapeutic agents, and immune cell death inducers. Exosomes can also be engineered to precisely target tumor cells. However, as a rising star in tumor immunotherapy, exosomes are also impeded by some challenges, including the lack of uniform technical standards for their isolation and purification, the need to improve exosomal cargo loading for efficient exosome delivery, and the expansion of clinical trials, which are currently in their infancy. Long-term, multi-center, and large-scale clinical trials are needed to evaluate the performance of exosomes in the future. Nonetheless, exosomes have demonstrated encouraging performance in tumor immunotherapy. In this review, we summarize the potential and challenges of exosomes in tumor immunotherapy, with the aim to shed light on exosomes as new-era tumor immunotherapy tools.

The strategies to cure cancer patients by eradicating cancer stem-like cells.

Cancer stem-like cells (CSCs), a subpopulation of cancer cells, possess remarkable capability in proliferation, self-renewal, and differentiation. Their presence is recognized as a crucial factor contributing to tumor progression and metastasis. CSCs have garnered significant attention as a therapeutic focus and an etiologic root of treatment-resistant cells. Increasing evidence indicated that specific biomarkers, aberrant activated pathways, immunosuppressive tumor microenvironment (TME), and immunoevasion are considered the culprits in the occurrence of CSCs and the maintenance of CSCs properties including multi-directional differentiation. Targeting CSC biomarkers, stemness-associated pathways, TME, immunoevasion and inducing CSCs differentiation improve CSCs eradication and, therefore, cancer treatment. This review comprehensively summarized these targeted therapies, along with their current status in clinical trials. By exploring and implementing strategies aimed at eradicating CSCs, researchers aim to improve cancer treatment outcomes and overcome the challenges posed by CSC-mediated therapy resistance.

The role of gut microbiota and drug interactions in the development of colorectal cancer.

The human gut microbiota is a complex ecosystem regulating the host's environmental interaction. The same functional food or drug may have varying bioavailability and distinct effects on different individuals. Drugs such as antibiotics can alter the intestinal flora, thus affecting health. However, the relationship between intestinal flora and non-antibiotic drugs is bidirectional: it is not only affected by drugs; nevertheless, it can alter the drug structure through enzymes and change the bioavailability, biological activity, or toxicity of drugs to improve their efficacy and safety. This review summarizes the roles and mechanisms of antibiotics, antihypertensive drugs, nonsteroidal anti-inflammatory drugs, lipid-lowering drugs, hypoglycemic drugs, virus-associated therapies, metabolites, and dietary in modulating the colorectal cancer gut microbiota. It provides a reference for future antitumor therapy targeting intestinal microorganisms.

A universal all-in-one RPA-Cas12a strategy with de novo autodesigner and its application in on-site ultrasensitive detection of DNA and RNA viruses.

Revolutionary all-in-one RPA-CRISPR assays are rapidly becoming the most sought-after tools for point-of-care testing (POCT) due to their high sensitivity and ease of use. Despite the availability of one-pot methods for specific targets, the development of more efficient methods for new targets remains a significant challenge. In this study, we present a rapid and universal approach to establishing an all-in-one RPA-Cas12a method CORDSv2 based on rational balancing amplification and Cas12a cleavage, which achieves ultrasensitive detection of several targets, including SARS-CoV-2, ASFV, HPV16, and HPV18. CORDSv2 demonstrates a limit of detection (LOD) of 0.6 cp/µL and 100% sensitivity for SARS-CoV-2, comparable to qPCR. Combining with our portable device(hippo-CORDS), it has a visual detection LOD of 6 cp/µL and a sensitivity up to 100% for SARS-CoV-2 and 97% for Ct<35 ASFV samples, surpassing most one-pot visual methods. To simplify and accelerate the process for new targets, we also develop a de novo autodesigner by which the optimal couples of primers and crRNA can be selected rapidly. As a universal all-in-one RPA-CRISPR method for on-site testing, CORDSv2 becomes an attractive choice for rapid and accurate diagnosis in resource-limited settings.

Potassium channels, tumorigenesis and targeted drugs.

Potassium channels play an important role in human physiological function. Recently, various molecular mechanisms have implicated abnormal functioning of potassium channels in the proliferation, migration, invasion, apoptosis, and cancer stem cell phenotype formation. Potassium channels also mediate the association of tumor cells with the tumor microenvironment. Meanwhile, potassium channels are important targets for cancer chemotherapy. A variety of drugs exert anti-cancer effects by modulating potassium channels in tumor cells. Therefore, there is a need to understand how potassium channels participate in tumor development and progression, which could reveal new, novel targets for cancer diagnosis and treatment. This review summarizes the roles of voltage-gated potassium channels, calcium-activated potassium channels, inwardly rectifying potassium channels, and two-pore domain potassium channels in tumorigenesis and the underlying mechanism of potassium channel-targeted drugs. Therefore, the study lays the foundation for rational and effective drug design and individualized clinical therapeutics.

CD39/CD73/A2AR pathway and cancer immunotherapy.

Cancer development is closely associated with immunosuppressive tumor microenvironment (TME) that attenuates antitumor immune responses and promotes tumor cell immunologic escape. The sequential conversion of extracellular ATP into adenosine by two important cell-surface ectonucleosidases CD39 and CD73 play critical roles in reshaping an immunosuppressive TME. The accumulated extracellular adenosine mediates its regulatory functions by binding to one of four adenosine receptors (A1R, A2AR, A2BR and A3R). The A2AR elicits its profound immunosuppressive function via regulating cAMP signaling. The increasing evidence suggests that CD39, CD73 and A2AR could be used as novel therapeutic targets for manipulating the antitumor immunity. In recent years, monoclonal antibodies or small molecule inhibitors targeting the CD39/CD73/A2AR pathway have been investigated in clinical trials as single agents or in combination with anti-PD-1/PD-L1 therapies. In this review, we provide an updated summary about the pathophysiological function of the adenosinergic pathway in cancer development, metastasis and drug resistance. The targeting of one or more components of the adenosinergic pathway for cancer therapy and circumvention of immunotherapy resistance are also discussed. Emerging biomarkers that may be used to guide the selection of CD39/CD73/A2AR-targeting treatment strategies for individual cancer patients is also deliberated.

Human microbiomes in cancer development and therapy.

Colonies formed by bacteria, archaea, fungi, and viral groups and their genomes, metabolites, and expressed proteins constitute complex human microbiomes. An increasing evidences showed that carcinogenesis and disease progression were link to microbiomes. Different organ sources, their microbial species, and their metabolites are different; the mechanisms of carcinogenic or procancerous are also different. Here, we summarize how microbiomes contribute to carcinogenesis and disease progression in cancers of the skin, mouth, esophagus, lung, gastrointestinal, genital, blood, and lymph malignancy. We also insight into the molecular mechanisms of triggering, promoting, or inhibiting carcinogenesis and disease progress induced by microbiomes or/and their secretions of bioactive metabolites. And then, the strategies of application of microorganisms in cancer treatment were discussed in detail. However, the mechanisms by which human microbiomes function are still poorly understood. The bidirectional interactions between microbiotas and endocrine systems need to be clarified. Probiotics and prebiotics are believed to benefit human health via a variety of mechanisms, in particular, in tumor inhibition. It is largely unknown how microbial agents cause cancer or how cancer progresses. We expect this review may open new perspectives on possible therapeutic approaches of patients with cancer.

Herbal formula Jiawei Xiaochengqi decoction prevents postoperative abdominal adhesion in a rat model through inhibition of CXCL2-CXCR2 pathway.

BACKGROUND: Postoperative abdominal adhesion (PAA) is the most common complication after abdominal surgeries, which can lead to intestinal obstruction, chronic abdominal pain or female infertility. Jiawei Xiaochengqi decoction (JWXCQ) is a hospital preparation widely used for PAA treatment in Nanfang Hospital of Southern Medical University for more than twenty years. PURPOSE: This study aimed to investigate the therapeutic effects and potential mechanism of JWXCQ against PAA and provide beneficial information for its clinical application. METHODS: The main active components of JWXCQ were identified using ultra high performance liquid chromatography (UHPLC) combined with standard substance comparison. The efficacy and underlying mechanism of JWXCQ were evaluated through in vivo experiments with a postsurgical-induced peritoneal adhesion rat model, and in vitro studies with LPS-stimulated Raw 264.7 macrophages and primary fibroblasts. H&E and Masson staining were performed to assess histopathological changes. The levels of cytokines/proteins-associated with inflammation and degradation of extracellular matrix as well as CXCL2-CXCR2 pathway-related proteins were determined by ELISA, qRT-PCR, western blot assays or immunohistochemistry, respectively. Furthermore, siCXCR2 transfection was used to validate the mechanism of action of JWXCQ. RESULTS: JWXCQ treatment significantly reduced the formation of PAA, inhibited the inflammation and collagen deposition, and facilitated the secretion of MMP9, decreased the levels of IL-1ß, IL-6, TIMP1, COL-1, and suppressed the CXCL2-CXCR2 pathway in PAA rats. Furthermore, JWXCQ inhibited its downstream pathways, the JAK2-STAT3 and PI3K-AKT signaling, as indicated by the suppression of the phosphorylation levels of STAT3 and AKT. In vitro cell experiments revealed that JWXCQ reduced IL-1ß and IL-6 secretion in Raw 264.7 macrophages and COL-1 in primary fibroblasts. The CXCL2-CXCR2, JAK2-STAT3 and PI3K-AKT pathways were also inhibited after JWXCQ treatment, which were consistent with the in vivo results. More importantly, silence of CXCR2 eliminated the regulatory effects of JWXCQ. CONCLUSION: JWXCQ could effectively prevent the PAA formation by alleviating inflammation and collagen deposition, which was associated with the inhibition of CXCL2-CXCR2 pathway. This study investigated the relevant pharmacological mechanisms of JWXCQ, providing further evidence for the application of JWXCQ in clinical PAA treatment.

Label-free-based quantitative proteomic analysis of the inhibition of cisplatin-resistant ovarian cancer cell proliferation by cucurbitacin B.

BACKGROUND: Ovarian cancer is a serious threat to women's health, and resistance to chemotherapeutic drugs constitutes one of the principal reasons for ovarian cancer recurrence and the low overall survival rate. Therefore, it is of paramount importance to develop additional and more-effective drugs to combat resistance to chemotherapeutic drugs. Cucurbitacin B (CuB) is a natural compound found in food plants such as bitter gourd and pumpkin, and it manifests favorable antitumor effects on a variety of malignant tumors. PURPOSE: The present study aimed to determine the mechanism effects of CuB overcomes tumor-drug resistance in ovarian cancer. METHODS: We used CCK-8, Edu, flow cytometric assays and cisplatin-resistant ovarian cancer xenograft mouse model to evaluate the cellular proliferation, cellular apoptosis.and tumor growth. We subsequently applied a pharmacoproteomic approach to analyze the molecular mechanisms by which CuB inhibited the proliferation of cisplatin-resistant ovarian cancer cells. We also employed western blot and molecular docking experiments to verify elements of PI3K/Akt/mTOR pathway expression. RESULTS: We found that CuB inhibited cellular proliferation and promoted apoptosis in cisplatin-resistant ovarian cancer cell lines. We discerned that CuB inhibited tumor growth of xenograft mouse tumors. We ascertained that treatment of A2780-DDP cells with CuB resulted in the differential expression of 305 proteins, with 202 proteins downregulated and 103 proteins upregulated. Of these proteins, the mTOR protein was significantly downregulated in the drug-treated group. We also found that CuB inhibited PI3K, Akt, and mTOR and that it activated cGAS expression upstream of PI3K and inhibited ATR expression. Molecular docking experiments revealed that CuB was hydrogen-bonded to mTOR proteins at Gly (2142) and Thr (2207), with a binding force of -10.2 kcal/mol. CONCLUSION: Our study confirmed that cucurbitacin B inhibits the PI3K/Akt/mTOR signaling pathway, targets mTOR, suppresses the proliferation of cisplatin-resistant ovarian cancer cells.And we also found that cucurbitacin B induces DNA damage, activates cGASA and recruits IKBα,playing a crucial role in eliciting anti-tumor immunity. We herein uncovered a new use for CuB in inhibiting tumor-drug resistance, providing a novel approach to overcoming chemotherapeutic drug resistance in ovarian cancer.

Role of microbes in colorectal cancer therapy: Cross-talk between the microbiome and tumor microenvironment.

The human gut microbiota is associated with the development and progression of colorectal cancer, and manipulation of the gut microbiota is a novel strategy for the prevention and treatment of colorectal cancer. Some bacteria have antitumor activity against colorectal cancer, where specific bacteria can improve the tumor microenvironment, activate immune cells including dendritic cells, helper T cells, natural killer cells, and cytotoxic T cells, and upregulate the secretion of pro-tumor immune cytokines such as interleukin-2 and interferon. In this paper, we summarize some bacteria with potential benefits in colorectal cancer and describe their roles in the tumor microenvironment, demonstrate the application of gut microbes in combination with immunosuppressive agents, and provide suggestions for further experimental studies and clinical practice applications.

Adagrasib, a KRAS G12C inhibitor, reverses the multidrug resistance mediated by ABCB1 in vitro and in vivo.

BACKGROUND: Multidrug resistance (MDR) is a complex phenomenon that frequently leads to chemotherapy failure during cancer treatment. The overexpression of ATP-binding cassette (ABC) transporters represents the major mechanism contributing to MDR. To date, no effective MDR modulator has been applied in clinic. Adagrasib (MRTX849), a specific inhibitor targeting KRAS G12C mutant, is currently under investigation in clinical trials for the treatment of non-small cell lung cancer (NSCLC). This study focused on investigating the circumvention of MDR by MRTX849. METHODS: The cytotoxicity and MDR reversal effect of MRTX849 were assessed by MTT assay. Drug accumulation and drug efflux were evaluated by flow cytometry. The MDR reversal by MRTX849 in vivo was investigated in two ABCB1-overexpressing tumor xenograft models in nude mice. The interaction between MRTX849 and ABCB1 substrate binding sites was studied by the [125I]-IAAP-photoaffinity labeling assay. The vanadate-sensitive ATPase assay was performed to identify whether MRTX849 would change ABCB1 ATPase activity. The effect of MRTX849 on expression of ABCB1 and PI3K/AKT signaling molecules was examined by flow cytometry, Western blot and Quantitative Real-time PCR analyses. RESULTS: MRTX849 was shown to enhance the anticancer efficacy of ABCB1 substrate drugs in the transporter-overexpressing cells both in vitro and in vivo. The MDR reversal effect was specific against ABCB1 because no similar effect was observed in the parental sensitive cells or in ABCG2-mediated MDR cells. Mechanistically, MRTX849 increased the cellular accumulation of ABCB1 substrates including doxorubicin (Dox) and rhodamine 123 (Rho123) in ABCB1-overexpressing MDR cells by suppressing ABCB1 efflux activity. Additionally, MRTX849 stimulated ABCB1 ATPase activity and competed with [125I]-IAAP for photolabeling of ABCB1 in a concentration-dependent manner. However, MRTX849 did not alter ABCB1 expression or phosphorylation of AKT/ERK at the effective MDR reversal drug concentrations. CONCLUSIONS: In summary, MRTX849 was found to overcome ABCB1-mediated MDR both in vitro and in vivo by specifically attenuating ABCB1 efflux activity in drug-resistant cancer cells. Further studies are warranted to translate the combination of MRTX849 and conventional chemotherapy to clinical application for circumvention of MDR. Video Abstract.

Natural Products in Preventing Tumor Drug Resistance and Related Signaling Pathways.

Drug resistance is still an obstacle in cancer therapy, leading to the failure of tumor treatment. The emergence of tumor drug resistance has always been a main concern of oncologists. Therefore, overcoming tumor drug resistance and looking for new strategies for tumor treatment is a major focus in the field of tumor research. Natural products serve as effective substances against drug resistance because of their diverse chemical structures and pharmacological effects. We reviewed the signaling pathways involved in the development of tumor drug resistance, including Epidermal growth factor receptor (EGFR), Renin-angiotensin system (Ras), Phosphatidylinositol-3-kinase/protein kinase B (PI3K/Akt), Wnt, Notch, Transforming growth factor-beta (TGF-ß), and their specific signaling pathway inhibitors derived from natural products. This can provide new ideas for the prevention of drug resistance in cancer therapy.

Far infrared irradiation suppresses experimental arthritis in rats by down-regulation of genes involved inflammatory response and autoimmunity.

Introduction: Far-infrared radiation (FIR) is widely used in the treatment of various diseases such as insomnia and cardiovascular risk. Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease in which the therapeutic potential of FIR in RA is unclear. Objectives: To determine the therapeutic potential and mechanistic actions of FIR in treatment of RA. Methods: Adjuvant-induced arthritis (AIA) rat models were established to assess the therapeutic potency of FIR in RA treatment. The scoring parameters such as arthritis score, swelling of the hind paw, spleen and thymus indices, micro-CT analysis indices were adopted to estimate the beneficial effects of FIR during RA treatment in AIA model. PCR gene expression arrays were used to analyze inflammatory and autoimmune genes expression profiles in rat synovium. The inflammatory and immunity genes profiling was further analyzed through transcription factor prediction using PROMO. A signaling network map of possible molecular circuits connecting the identified differential genes to the RA's pathogenesis was constructed based on extensive literature reviews, and the major signaling pathways were validated by Western blotting. Results: Thirty minutes of FIR treatment significantly improved the symptoms of AIA in rats. Gene expression profiling indicated that 27 out of 370 genes were down-regulated by FIR. AP-1, CEBPα, CEBPß, c-Fos, GR, HNF-3ß, USF-1, and USF-2 were predicted as key transcription factors that regulated the identified differential genes. In addition, MAPK, PI3K-Akt, and NF-κB signaling are the major molecular pathways down-regulated by FIR treatment. Conclusion: FIR may provide beneficial effects on the AIA rat model of arthritis by suppression of the MAPK, PI3K-Akt and NF-κB signaling pathways. Therefore, we believe that FIR may provide an alternative non-pharmacological and non-surgical therapeutic approach for the treatment of RA.

Traditional Patchouli essential oil modulates the host's immune responses and gut microbiota and exhibits potent anti-cancer effects in ApcMin /+ mice.

Patchouli Essential Oil (PEO) has been used as a scent for various healing purposes since the ancient Egyptian period. The primary source of the oil is Pogostemon cablin (PC), a medicinal plant for treating gastrointestinal symptoms. However, the pharmacological function has not been addressed. Here, we report the cancer prevention and gut microbiota (GM) modulating property of PEO and its derivatives patchouli alcohol (PA) and pogostone (PO) in the ApcMin /+ colorectal cancer mice model. We found that PEO, PA, and PO significantly reduced the tumor burden. At the same time, it strengthened the epithelial barrier, evidenced by substantially increasing the number of the goblet and Paneth cells and upregulation of tight junction and adhesion molecules. In addition, PEO, PA, and PO shifted M1 to M2 macrophage phenotypes and remodeled the inflammatory milieu of ApcMin /+ mice. We also found suppression of CD4+CD25+ and stimulation CD4+ CD8+ cells in the spleen, blood, mesenteric lymph nodes (MLNs), and Peyer's patches (PPs) of the treated mice. The composition of the gut microbiome of the drug-treated mice was distinct from the control mice. The drugs stimulated the short-chain fatty acids (SCFAs)-producers and the key SCFA-sensing receptors (GPR41, GPR43, and GPR109a). The activation of SCFAs/GPSs also triggered the alterations of PPAR-γ, PYY, and HSDCs signaling mediators in the treated mice. Our work showed that PEO and its derivatives exert potent anti-cancer effects by modulating gut microbiota and improving the intestinal microenvironment of the ApcMmin /+ mice.