Pitavastatin sensitizes the EGFR-TKI associated resistance in lung cancer by inhibiting YAP/AKT/BAD-BCL-2 pathway.

BACKGROUND: Despite effective strategies, resistance in EGFR mutated lung cancer remains a challenge. Metabolic reprogramming is one of the main mechanisms of tumor drug resistance. A class of drugs known as "statins" inhibit lipid cholesterol metabolism and are widely used in patients with cardiovascular diseases. Previous studies have also documented its ability to improve the therapeutic impact in lung cancer patients who receive EGFR-TKI therapy. Therefore, the effect of statins on targeted drug resistance to lung cancer remains to be investigated. METHODS: Prolonged exposure to gefitinib resulted in the emergence of a resistant lung cancer cell line (PC9GR) from the parental sensitive cell line (PC9), which exhibited a traditional EGFR mutation. The CCK-8 assay was employed to assess the impact of various concentrations of pitavastatin on cellular proliferation. RNA sequencing was conducted to detect differentially expressed genes and their correlated pathways. For the detection of protein expression, Western blot was performed. The antitumor activity of pitavastatin was evaluated in vivo via a xenograft mouse model. RESULTS: PC9 gefitinib resistant strains were induced by low-dose maintenance. Cell culture and animal-related studies validated that the application of pitavastatin inhibited the proliferation of lung cancer cells, promoted cell apoptosis, and restrained the acquired resistance to EGFR-TKIs. KEGG pathway analysis showed that the hippo/YAP signaling pathway was activated in PC9GR cells relative to PC9 cells, and the YAP expression was inhibited by pitavastatin administration. With YAP RNA interference, pAKT, pBAD and BCL-2 expression was decreased, while BAX expression as increased. Accordingly, YAP down-regulated significantly increased apoptosis and decreased the survival rate of gefitinib-resistant lung cancer cells. After pAKT was increased by SC79, apoptosis of YAP down-regulated cells induced by gefitinib was decreased, and the cell survival rate was increased. Mechanistically, these effects of pitavastatin are associated with the YAP pathway, thereby inhibiting the downstream AKT/BAD-BCL-2 signaling pathway. CONCLUSION: Our study provides a molecular basis for the clinical application of the lipid-lowering drug pitavastatin enhances the susceptibility of lung cancer to EGFR-TKI drugs and alleviates drug resistance.

Metabolic reprogramming by traditional Chinese medicine and its role in effective cancer therapy.

Metabolic reprogramming, characterized by alterations of cellular metabolic patterns, is fundamentally important in supporting the malignant behaviors of cancer cells. It is considered as a promising therapeutic target against cancer. Traditional Chinese medicine (TCM) and its bioactive components have been used in cancer therapy for an extended period, and they are well-known for their multi-target pharmacological functions and fewer side effects. However, the detailed and advanced mechanisms underlying the anticancer activities of TCM remain obscure. In this review, we summarized the critical processes of cancer cell metabolic reprogramming, including glycolysis, mitochondrial oxidative phosphorylation, glutaminolysis, and fatty acid biosynthesis. Moreover, we systemically reviewed the regulatory effects of TCM and its bioactive ingredients on metabolic enzymes and/or signal pathways that may impede cancer progress. A total of 46 kinds of TCMs was reported to exert antitumor effects and/or act as chemosensitizers via regulating metabolic processes of cancer cells, and multiple targets and signaling pathways were revealed to contribute to the metabolic-modulating functions of TCM. In conclusion, TCM has its advantages in ameliorating cancer cell metabolic reprogramming by its poly-pharmacological actions. This review may shed some new light on the explicit recognition of the mechanisms of anticancer actions of TCM, leading to the development of natural antitumor drugs based on reshaping cancer cell metabolism.

Ultra-weak photon emission in healthy subjects and patients with type 2 diabetes: evidence for a non-invasive diagnostic tool.

BACKGROUND: Spontaneous ultra-weak photon emission (UPE) is a common phenomenon in biological systems and has been linked to pathological states. Researchers have always considered ultra-weak photon emission a potential non-invasive diagnostic tool, but its application in the medical field is stagnant due to the lack of relevant data for pathological states. METHODS: Ultra-weak photon signals from five body sites (forehead, neck, heart, stomach, and navel) in fifty patients with type 2 diabetes and sixty age-matched healthy subjects were measured using a moveable whole-body biophoton detection system. Photon signal is measured for 10 min and detected in bins of 50 ms by a photomultiplier with a range of 290-630 nm. Each signal is a time series of 12 000 elements. Various parameters including photon intensity, Q value, squeezed state parameters (|α|, θ, ø, r) and SSI were analyzed. RESULTS AND CONCLUSION: we found significant differences in the abovementioned parameters between groups, and all subjects could be clustered into two groups according to the results obtained by principal component analysis. Methods and results from this study could be useful for constructing a UPE database for a range of diseases, which would promote the application of UPE in clinical diagnosis in the future.

Correlation between the different therapeutic properties of Chinese medicinal herbs and delayed luminescence.

In the practice and principle of Chinese medicine, herbal materials are classified according to their therapeutic properties. 'Cold' and 'heat' are the most important classes of Chinese medicinal herbs according to the theory of traditional Chinese medicine (TCM). In this work, delayed luminescence (DL) was measured for different samples of Chinese medicinal herbs using a sensitive photon multiplier detection system. A comparison of DL parameters, including mean intensity and statistic entropy, was undertaken to discriminate between the 'cold' and 'heat' properties of Chinese medicinal herbs. The results suggest that there are significant differences in mean intensity and statistic entropy and using this method combined with statistical analysis may provide novel parameters for the characterization of Chinese medicinal herbs in relation to their energetic properties.

Classification of Chinese herbs based on the cluster analysis of delayed luminescence.

Traditional Chinese material medica are an important component of the Chinese pharmacopeia. According to the traditional Chinese medicinal concept, Chinese herbal medicines are classified into different categories based on their therapeutic effects, however, the bioactive principles cannot be solely explained by chemical analysis. The aim of this study is to classify different Chinese herbs based on their therapeutic effects by using delayed luminescence (DL). The DL of 56 Chinese herbs was measured using an ultra-sensitive luminescence detection system. The different DL parameters were used to classify Chinese herbs according to a hierarchical cluster analysis. The samples were divided into two groups based on their DL kinetic parameters. Interestingly, the DL classification results were quite consistent with classification according to the Chinese medicinal concepts of 'cold' and 'heat' properties. In this paper, we show for the first time that by using DL technology, it is possible to classify Chinese herbs according to the Chinese medicinal concept and it may even be possible to predict their therapeutic properties.

The impact of bolus on clinical outcomes for post-mastectomy breast cancer patients treated with IMRT: data from China.

PURPOSE: This study aims to investigate the effects of chest wall bolus in intensity-modulated radiotherapy (IMRT) technology on clinical outcomes for post-mastectomy breast cancer patients. MATERIALS AND METHODS: This retrospective study included patients with invasive carcinoma ((y)pT0-4, (y)pN0-3) who received photon IMRT after mastectomy at the Affiliated Hospital of Qingdao University from 2014 to 2019. The patients were divided into two groups based on whether they received daily bolus application or not, and the baseline characteristics were matched using propensity score matching (PSM). Cumulative incidence (CI) of local recurrence (LR), locoregional recurrence (LRR), overall survival (OS) and disease-free survival (DFS) were evaluated with a log-rank test. Acute skin toxicity and late radiation pneumonia was analyzed using chi-square test. RESULTS: A total of 529 patients were included in this study, among whom 254 (48%) patients received bolus application. The median follow-up time was 60 months. After matching, 175 well-paired patients were selected. The adjusted 5-year outcomes (95% confidence interval) in patients treated with and without bolus were, respectively: CI of LR 2.42% (0.04-4.74) versus 2.38% (0.05-4.65), CI of LRR 2.42% (0.04-4.74) versus 3.59% (0.73-6.37), DFS 88.12% (83.35-93.18) versus 84.69% (79.42-90.30), OS 94.21% (90.79-97.76) versus 95.86% (92.91-98.91). No correlation between bolus application and skin toxicity (P = 0.555) and late pneumonia (P = 0.333) was observed. CONCLUSIONS: The study revealed a low recurrence rate using IMRT technology. The daily used 5 mm chest wall bolus was not associated with improved clinical outcomes.

Polyene phosphatidylcholine enhances the therapeutic response of oxaliplatin in gastric cancer through Nrf2/HMOX1 mediated ferroptosis.

Oxaliplatin (OXA)-based chemotherapy is one of the first-line treatments for advanced gastric cancer. However, the potential risk for chemotherapy-induced hepatic injury can hinder its effectiveness. Polyene phosphatidylcholine (PPC) is often used as a hepatoprotective agent to counter OXA-induced hepatic injury; however, its impact on the antitumour effectiveness of OXA remains uncertain. Our retrospective study examined 98 patients with stage IV gastric cancer to assess the impact of PPC on progression-free survival (PFS) and disease control rate (DCR). Furthermore, in vitro and in vivo assays were conducted to elucidate the combined biological effects of OXA and PPC (OXA+PPC) on gastric cancer. RNA sequencing, luciferase reporter assays, live/dead cell assays, immunofluorescence, and western blotting were used to identify the activated signalling pathways and downstream factors post OXA+PPC treatment. The findings indicated that PPC served as an independent prognostic factor, correlating with prolonged PFS and improved DCR in patients with gastric cancer. The combination of OXA and PPC significantly inhibited tumour cell growth both in vitro and in vivo. RNA sequencing revealed that OXA+PPC treatment amplified reactive oxygen species and ferroptosis signalling pathways. Mechanistically, OXA+PPC upregulated the expression of haem oxygenase-1 by promoting the nuclear migration of nuclear factor erythroid 2-related factor (Nrf2), thereby enhancing its transcriptional activity. Drug-molecule docking analysis demonstrated that PPC competitively bound to the peptide structural domains of both Nrf2 and Kelch-like ECH-associated protein 1 (KEAP1), accounting for the increased translocation of Nrf2. In conclusion, our study reveals the synergistic antitumour potential of PPC and OXA while protecting patients against hepatic injury. This suggests a promising combined treatment approach for patients with advanced gastric cancer.

The association of dietary patterns with incident chronic kidney disease and kidney function decline among middle-aged Korean adults: a cohort study.

OBJECTIVES: This study assessed the association of dietary patterns with the incidence of chronic kidney disease (CKD) and kidney function decline among Korean adults. METHODS: Data were collected from the records of 20,147 men and 39,857 women who participated in the Health Examinees study. Principal component analysis was used to identify 3 dietary patterns (prudent, flour-based food and meat, and white rice-based), and CKD risk was defined using the Epidemiology Collaboration equation for estimated glomerular filtration rate: (eGFR) <60 mL/min/1.73 m2. A kidney function decline was defined as a >25% decrease in eGFR from baseline. RESULTS: During the 4.2-year follow-up, 978 participants developed CKD and 971 had a 25% decline in kidney function. After adjusting for potential impact variables, compared with the lowest quartile of the prudent dietary pattern, participants in the highest quartile had a 37% lower risk of kidney function decline among men (hazard ratio [HR], 0.63; 95% confidence interval [CI], 0.47 to 0.85); while higher adherence to the flour-based food and meat dietary pattern was associated with an increased risk of CKD in both men (HR, 1.63; 95% CI, 1.22 to 2.19) and women (HR, 1.47; 95% CI, 1.05 to 2.05) as well as a decline in kidney function in both men (HR, 1.49; 95% CI, 1.07 to 2.07) and women (HR, 1.77; 95% CI, 1.33 to 2.35). CONCLUSIONS: Although a higher adherence to the prudent dietary pattern was inversely associated with the risk of kidney function decline in men, there was no association with CKD risk. In addition, a higher adherence to the flour-based food and meat dietary pattern increased the risk of CKD and kidney function decline. Further clinical trials are needed to confirm these associations.

Dietary patterns and risk of non-alcoholic fatty liver disease in Korean adults: a prospective cohort study.

OBJECTIVES: Dietary patterns can holistically provide insights into the association of food groups and nutrients with the disease. Several studies have evaluated the association of dietary patterns with the risk of non-alcoholic fatty liver disease (NAFLD) in Western populations. However, few studies focused on this topic were conducted on Korean adults. Therefore, in this cohort study, we aimed to investigate the association between dietary patterns and the risk of NAFLD among middle-aged Koreans. DESIGN: The survey was performed at general hospitals and health examination centres in Korea. Dietary intake was assessed using a validated Food Frequency Questionnaire. The dietary patterns were identified using principal component analysis. The HR and 95% CI for NAFLD for each of the quartiles of the three dietary patterns were estimated using a Cox proportional hazards model. SETTING: South Korean Community. PARTICIPANTS: 44 460 healthy Koreans (aged 40-69 years) who completed a follow-up survey from 2012 to 2016 in the Health Examinees study were included. RESULTS: Men and women following a prudent pattern showed a 22% and 36% lower NAFLD risk, respectively (men: HR=0.78; women: HR=0.64). Men and women who highly adhered to the flour-based food and meat pattern had a 29% and 55% higher NAFLD risk, respectively (men: HR=1.29; women: HR=1.55). CONCLUSION: The prudent pattern induced a lower NAFLD risk, whereas the flour-based food and meat pattern induced a higher NAFLD risk. No significant difference was found between the white rice pattern and NAFLD risk.

Association of food groups and dietary pattern with breast cancer risk: A systematic review and meta-analysis.

BACKGROUND & AIMS: We conducted a systematic review and meta-analysis of current evidence for the association between food groups, dietary patterns, and breast cancer risk among the Asian population. METHODS: This systematic review and meta-analysis followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. We performed a systematic literature search up to December 2022 in English in the PubMed, Web of Science, Embase, and Cochrane databases. Risk ratios (RRs) with 95% confidence intervals (CIs) were extracted as effect sizes. Publication bias was estimated by two different funnel plot methods. RESULTS: We collected the data from 15 cohort studies and 34 case-control studies meeting the search criteria. The meta-analysis found that the consumption of fruits and, likewise, vegetables were associated with a 29% lower risk of breast cancer, respectively [RR = 0.71 (0.55, 0.93); RR = 0.71 (0.53, 0.95)]. By contrast, no significance was found between meat, soy foods, and green tea consumption and breast cancer risk (P > 0.05). However, soy protein and isoflavone intake could lower breast cancer risk by 35% and 32%, respectively [RR = 0.65 (0.51, 0.83); RR = 0.68 (0.55, 0.82)]. As for the dietary pattern, high adherence to a healthy dietary pattern and, similarly, to a healthy eating index was associated with a 38% and 51% reduction in breast cancer risk, respectively [RR = 0.62 (0.44, 0.88; RR = 0.49 (0.27, 0.87)], while high adherence to an unhealthy dietary pattern was associated with a 44% increased risk [RR = 1.44 (1.06, 1.96)]. Considering alcohol consumption, a 75% increased risk of breast cancer was found [RR = 1.75 (1.33, 2.30)]. CONCLUSION: The present meta-analysis found that high intakes of fruits, vegetables, soy protein, and soy isoflavone significantly reduced the risk of breast cancer, while high intake of alcohol had a significantly increased risk. Meat, soy food, and green tea consumption were not significantly associated with breast cancer risk. Considering dietary patterns, high adherence to a healthy eating index and a healthy dietary pattern may reduce breast cancer risk. Conversely, adherence to unhealthy dietary patterns may increase breast cancer risk. However, further studies are needed to confirm the associations between dietary patterns and breast cancer in the Asian population.

Corrigendum: A biophoton method for identifying the quality states of fresh Chinese herbs.

[This corrects the article DOI: 10.3389/fphar.2023.1140117.].

Targeting Ferroptosis in Cancer by Natural Products: An Updated Review.

Ferroptosis is a new cell death process characterized by massive iron accumulation and lipid peroxidation. Emerging evidence demonstrates that ferroptosis plays a crucial role in the development and progression of tumorigenesis. Targeting it is a potentially effective cancer prevention and treatment strategy in the clinic. A comprehensive review of molecular mechanisms of targeting ferroptosis in cancer by natural products needs to be re-summarized and updated due to the advances in research. We searched and reviewed relevant literature through the database Web of Science, mainly focusing on the regulatory effects of natural products and their active compounds in treating or preventing cancer by regulating ferroptosis. A total of 62 kinds of natural products and their active compounds were reported to exert antitumor effects via causing ferroptosis of cancer cells by regulating the System Xc--GPX4 axis and lipid, mitochondrial, and iron metabolism. Natural products have advantages in improving chemotherapy's therapeutic effects by causing cancer cell ferroptosis through their polypharmacological actions. These molecular mechanisms of ferroptosis regulation by natural products will pave the way for developing natural antitumor drugs based on regulating ferroptosis.

A biophoton method for identifying the quality states of fresh Chinese herbs.

Introduction: The quality of Chinese herbs is the basis for ensuring their safety and efficacy. However, the quality evaluation system is imperfect. In particular, there is a lack of quality evaluation methods for fresh Chinese herbs during growth. The biophoton is a common phenomenon and provides complete information about the interior of the living system, which is consistent with the holistic concept of traditional Chinese medicine. Therefore, we aim to correlate the biophoton characteristics with the quality states to find the biophoton parameters that can characterize the quality states of fresh Chinese herbs. Methods: The biophoton characteristics of motherwort and safflower were measured and characterized by the counts per second (CPS) in the steady state and the initial intensity (I0) and coherent time (T) of delayed luminescence. The active ingredient content was measured by ultra-high-performance liquid chromatography (UPLC). The pigment content of motherwort leaves was measured by UV spectrophotometry. The t-test and correlation analysis were performed on the experimental results. Results: The CPS and I0 of motherwort and I0 of safflower showed a significant downward trend during the growth process, and their active ingredient content showed a trend that increased and then decreased. The CPS, I0, and the content of active ingredients and pigments in a healthy state were significantly higher than those in a poor state, while T showed the opposite results. The CPS and I0 were all significantly and positively correlated with the content of active ingredients and pigments, while the T of motherwort showed the opposite results. Conclusion: It is feasible to identify the quality states of fresh Chinese herbs by using their biophoton characteristics. Both CPS and I0 have better correlations with the quality states and can be considered characteristic parameters of the quality of fresh Chinese herbs.

Ultra-weak photon emission as a potential tool for evaluating the therapeutic effect of traditional Chinese medicine in patients with type 2 diabetes.

Background: Traditional Chinese medicine (TCM) has been used to prevent and treat type 2 diabetes (T2DM) for thousands of years. The holistic view of TCM and the "multitarget" characteristics of Chinese medicine have unique advantages in the prevention and treatment of T2DM. TCM syndrome differentiation and treatment are effective for T2DM; however, currently, the therapeutic effect of TCM is generally evaluated by asking for patients' subjective feelings, or by checking the changes in relevant indicators. The main problems are that the patient's descriptions are unclear and subjective, and although the self-reported symptoms may have improved significantly, the relevant indicators are sometimes not obvious, which cannot truly reflect the therapeutic effect of TCM. Therefore, it is urgent to develop a novel, sensitive, and noninvasive method to quantitatively evaluate the therapeutic effect of TCM. Methods: In this study, ultra-weak photon emission (UPE) was measured at four sites of hands of T2DM patients with Qi-Yin deficiency before treatment and after 1 and 2 weeks of treatment with TCM. The UPE intensity and spectral distribution were calculated and analyzed using the results measured at these four sites. Spearman's correlation coefficient was used to quantify the correlation between the UPE parameters and the syndrome scores of TCM. Results: The UPE intensity of T2DM patients with Qi-Yin deficiency decreased gradually with the course of the treatment and was significantly lower than that before the treatment. The ratio of photon counts between the wavelength ranges of 495-550 nm and 550-610 nm after the treatment was higher than that before the treatment and negatively correlated with the corresponding syndrome scores so that the degree of symptoms improvement could be characterized by the ratio (495-550 nm/550-610 nm). Conclusions: The therapeutic effect of TCM in T2DM patients with Qi-Yin deficiency can be shown at the level of UPE. UPE is a potential and noninvasive tool for evaluating the therapeutic effect of TCM in patients with T2DM.

HDGF promotes gefitinib resistance by activating the PI3K/AKT and MEK/ERK signaling pathways in non-small cell lung cancer.

Hepatoma-derived growth factor (HDGF) expression is associated with poor prognosis in non-small cell lung cancer (NSCLC); however, whether HDGF affects gefitinib resistance in NSCLC remains unknown. This study aimed to explore the role of HDGF in gefitinib resistance in NSCLC and to discover the underlying mechanisms. Stable HDGF knockout or overexpression cell lines were generated to perform experiments in vitro and in vivo. HDGF concentrations were determined using an ELISA kit. HDGF overexpression exacerbated the malignant phenotype of NSCLC cells, while HDGF knockdown exerted the opposite effects. Furthermore, PC-9 cells, which were initially gefitinib-sensitive, became resistant to gefitinib treatment after HDGF overexpression, whereas HDGF knockdown enhanced gefitinib sensitivity in H1975 cells, which were initially gefitinib-resistant. Higher levels of HDGF in plasma or tumor tissue also indicated gefitinib resistance. The effects of HDGF on promoting the gefitinib resistance were largely attenuated by MK2206 (Akt inhibitor) or U0126 (ERK inhibitor). Mechanistically, gefitinib treatment provoked HDGF expression and activated the Akt and ERK pathways, which were independent of EGFR phosphorylation. In summary, HDGF contributes to gefitinib resistance by activating the Akt and ERK signaling pathways. The higher HDGF levels may predict poor efficacy for TKI treatment, thus it has the potential to serve as a new target for overcoming tyrosine kinase inhibitor resistance in combating NSCLC.

Immunogenic cell death mediation patterns reveal novel paradigm for characterizing the immune microenvironment and immunotherapeutic responses in bladder cancer.

Background: Immunogenic cell death (ICD) plays an important role in several malignancies. However, the role of ICD-mediated patterns in bladder cancer (BCA) remains unknown. Methods: For assessing the ICD-mediated patterns based on the expression of IRGs, 4 large BCA cohorts were obtained. The ICD-mediated patterns of individual samples were quantified as an ICD score by principal component analysis. The correlations of the ICD-mediated patterns with the tumor immune microenvironment (TIME) and responses to immunotherapy were comprehensively evaluated. The IRGs with predictive prognostic values were further validated by in vitro loss of function assays. Results: Two distinct ICD-mediated patterns were established, showing distinct clinical features and immune microenvironment features. Although ICD cluster A was associated with a poor prognosis with a high ICD score, it showed an immune activation state with a more favorable response to immunotherapy and treatment that induced ICD. The ICD-related gene, CALR, was significantly upregulated in the T24 BCA cell line relative to the control SV-HUC-1 cells. Knocking down CALR suppressed T24 cell viability and caused ER stress. Conclusion: We identified the existence of distinct ICD-mediated patterns in BCA closely associated with the remodeling of the TIME. Further in-depth examination of ICD-related features is warranted to obtain a broader prospect for therapeutic innovations and improved prognosis of BCA.

Association between the mediterranean diet and cognitive health among healthy adults: A systematic review and meta-analysis.

Background: An increasing prevalence of cognitive disorders warrants comprehensive systematic reviews on the effect of diet on cognitive health. Studies have suggested that the Mediterranean (MeDi) diet has protective effects against metabolic diseases. However, comprehensive systematic reviews on the effect of the MeDi diet on the cognitive decline are limited. We investigated whether adherence to the MeDi diet could lower the risk of the cognitive disorder or improve cognitive function in older adults. Methods: In this systematic review and meta-analysis, PubMed, Web of Science, PsycINFO, Scopus, and Cochrane databases were searched from inception to June 2021. Cohort studies and randomized controlled trials (RCTs) were included. The effect sizes were estimated as log risk ratios and standard mean differences (SMDs) with 95% confidence intervals (CIs). The Newcastle-Ottawa score and Cochrane Collaboration's tool were used to assess the risk of bias in cohort studies and RCTs, respectively. Results: Of the 1,687 screened studies, 31 cohort studies and five RCTs met the eligibility criteria for qualitative analysis; 26 cohort studies and two RCTs were included in the meta-analysis. In the cohort studies, high adherence to the MeDi diet was associated with lower risk of mild cognitive impairment (MCI) [risk ratio (RR) = 0.75 (0.66-0.86)], and Alzheimer's disease (AD) [RR = 0.71 (0.56-0.89)]. In the RCTs, high adherence to the MeDi diet was associated with better episodic [SMD = 0.20 (0.09-0.30)] and working memories [SMD = 0.17 (0.01-0.32)] than lowest group. Conclusion: Adherence to the MeDi diet may reduce the risk of MCI and AD. However, other associations with cognitive outcomes (global cognition, working memory, and episodic memory) remain open to interpretation. Overall, the MeDi diet is recommended to prevent or delay cognitive disorders and improve cognitive function. Further, long-term RCTs are warranted to strengthen the evidence. Systematic review registration: [https://www.crd.york.ac.uk], identifier [CRD42021276801].

Treatment of progressive nodular histiocytosis: a case report.

Background: Progressive nodular histiocytosis (PNH) is an extremely rare type of non-Langerhans cell histiocytosis, characterized by the emergence of hundreds small to large cutaneous papulonodules without spontaneous remission. It can be life-threatening if pharyngeal and laryngeal mucosa were involved, just as we reported in this case. Disfigurement and disabling are common, whereas current treatment options are of limited efficacy. At present, about 20 reported cases can be found through a PubMed search, fewer with treatment options. In this article, we report a unique case of a patient diagnosed with PNH, in whom regorafenib had a remarkably curative effect. Case Presentation: We present the case of a 21-year-old man who developed lesions on his face, trunk, limbs, and exceptionally in the pharyngeal and laryngeal mucosa. Immunohistochemistry showed diffuse CD68 positivity and scattered S-100 positivity, while CD1α, smooth muscle actin (SMA) and B-Raf proto-oncogene, serine/threonine kinase (BRAF) were negative. Histopathological and biochemical examinations confirmed the diagnosis of PNH. The patient underwent facial lesion resections; however, the lesions recurred rapidly within 1 month. In December 2019, treatment with a small multi-kinase inhibitor, regorafenib (120 mg daily for 3 weeks on, and 1 week off), was initiated, and the patient's progress was monitored. After 10 days of administration, the patient's facial lesions began to gradually alleviate, and after 1 month, the lesions in the trunk, limb, and especially the face continued to subside even further. In 2021, the regorafenib dose was subsequently adjusted to 40 mg daily, with intermittent administration. No abnormalities were observed in the routine blood tests, liver, and kidney function results during the follow-ups to date. Presently, the patient's overall condition is good, the lesions are gradually improving, and the patient has returned to normal life and work. Conclusions: This clinical report supports the future exploration of regorafenib treatment in patients with PNH.

K Value: An Indicator that can Characterize the Cold and Hot Properties of Traditional Chinese Medicines.

Aims: The cold and hot properties of Chinese medicines are an important concept to represent the function of drugs, and are also a unique classification method of traditional Chinese medicine (TCM). The method reflects an herb's therapeutic properties and guides reasonable clinical prescription. However, the present key problem is the lack of an objective and quantitative evaluation index for the cold and hot properties of Chinese herbs. Delayed luminescence (DL) is the long-term afterglow of biological systems after illumination with light, which can reflect differences in herbal materials prepared under different conditions. We aim to use S. obliquus as an indicator organism to characterize the differences between the cold and hot properties of Chinese herbs. Methods: Scenedesmus obliquus (S. obliquus) was used as an indicator organism to characterize the differences between the cold and hot properties of Chinese herbs. The decoction solution of different properties of Chinese herbs was added to S. obliquus culture medium; then, the delayed luminescence (DL) of S. obliquus after the addition of decoctions of different properties of Chinese herbs was measured to obtain information on the effect of different properties of Chinese herbs on S. obliquus. Many DL parameters were calculated, and ROC curve analysis was applied with the aim of finding a suitable parameter that can characterize the differences in cold and hot properties of Chinese herbs. Results: Our results show that the K value is a sensitive parameter that can reflect the differences of cold and hot properties of Chinese herbs, thus providing new insights into the cold and hot properties of Chinese herbs. Conclusions: DL measurement of S. obliquus after addition of different properties of Chinese herbs could be a novel and promising method to study the cold and hot properties of Chinese herbs.

Marsdenia tenacissima extract disturbs the interaction between tumor-associated macrophages and non-small cell lung cancer cells by targeting HDGF.

ETHNOPHARMACOLOGICAL RELEVANCE: Marsdenia tenacissima (Roxb.) Wight et Arn. is a traditional Chinese herbal medicine, and its water-soluble ingredient Marsdenia tenacissima extract (MTE), was widely used for cancer treatment. The multi-pharmacological efficacies and mechanisms of MTE in directly inhibiting tumor cells have been extensively studied. However, the anti-tumor effects of MTE in the tumor-associated macrophages (TAMs) microenvironment remain unclear. AIM OF THE STUDY: To uncover the role of hepatoma-derived growth factor (HDGF) in the interaction between TAMs and non-small cell lung cancer (NSCLC) cells. To evaluate the anti-tumor effects of MTE on the vicious crosstalk between TAMs and NSCLC by targeting HDGF. MATERIALS AND METHODS: HDGF-overexpression PC-9 and H292 NSCLC cell lines were constructed and verified. RNA-sequencing (RNA-seq) was performed in HDGF-overexpression PC-9 cells to probe the differential expression of genes. THP-1-derived macrophages were characterized using specific markers after stimulation with phorbol-12-myristate 13-acetate (PMA) and rhIL-4 or rhHDGF. The role of HDGF both in NSCLC cells and TAMs was determined using approaches like Western blot, qRT-PCR, ELISA, and flow cytometry. The interaction between tumor cells and TAMs were assessed by indirect co-culture H1975, PC-9 cells with M2 type macrophages. The effects of MTE on anti-tumor and macrophage polarization were evaluated in vitro and in vivo. RESULTS: RNA-seq results identified IL-4 as a critical response to HDGF in NSCLC. HDGF induced macrophages polarizing toward M2 type, and promoted NSCLC cells proliferation, migration and invasion in vitro. On the one hand, HDGF dose-dependently promoted IL-4 expression in NSCLC cells. On the other hand, HDGF induced M2 macrophage polarization through the IL-4/JAK1/STAT3 signaling pathway. MTE treatment significantly decreased the expression and secretion of HDGF in NSCLC cells. Meanwhile, MTE treatment led to M2 macrophage repolarization, as evidenced by decreased expression of M2 markers and increased levels of M1 markers. Importantly, MTE treatment significantly suppressed tumor development in C57BL/6 mice bearing Lewis lung cancer (LLC) cells in vivo, accompanied by decreased plasma HDGF levels, reduced M2 macrophages infiltration and increased M1 macrophages proportion in mice tumor tissues. CONCLUSIONS: HDGF upregulated IL-4 expression in NSCLC cells, and promoted M2 polarization by the IL-4/JAK1/STAT3 signaling pathway in macrophages. MTE disturbed the interaction between NSCLC and TAMs in vitro, and inhibited tumor growth in vivo, at least in part, by suppressing HDGF. Therefore, our present study revealed a novel anti-tumor mechanism of MTE through inhibiting HDGF expression and enhancing macrophage polarization from M2 to M1 phenotype.