Opportunities and challenges of traditional Chinese medicine doctors in the era of artificial intelligence.

With the exponential advancement of artificial intelligence (AI) technology, the realm of medicine is experiencing a paradigm shift, engendering a multitude of prospects and trials for healthcare practitioners, encompassing those devoted to the practice of traditional Chinese medicine (TCM). This study explores the evolving landscape for TCM practitioners in the AI era, emphasizing that while AI can be helpful, it cannot replace the role of TCM practitioners. It is paramount to underscore the intrinsic worth of human expertise, accentuating that artificial intelligence (AI) is merely an instrument. On the one hand, AI-enabled tools like intelligent symptom checkers, diagnostic assistance systems, and personalized treatment plans can augment TCM practitioners' expertise and capacity, improving diagnosis accuracy and treatment efficacy. AI-empowered collaborations between Western medicine and TCM can strengthen holistic care. On the other hand, AI may disrupt conventional TCM workflow and doctor-patient relationships. Maintaining the humanistic spirit of TCM while embracing AI requires upholding professional ethics and establishing appropriate regulations. To leverage AI while retaining the essence of TCM, practitioners need to hone holistic analytical skills and see AI as complementary. By highlighting promising applications and potential risks of AI in TCM, this study provides strategic insights for stakeholders to promote the integrated development of AI and TCM for better patient outcomes. With proper implementation, AI can become a valuable assistant for TCM practitioners to elevate healthcare quality.

Simultaneous nitrogen and phosphorus removal from municipal wastewater by Fe(III)/Fe(II) cycling mediated partial-denitrification/anammox.

The efficient removal of nitrogen and phosphorus remains challenging for traditional wastewater treatment. In this study, the feasibility for enhancing the partial-denitrification and anammox process by Fe (III) reduction coupled to anammox and nitrate-dependent Fe (II) oxidation was explored using municipal wastewater. The nitrogen removal efficiency increased from 75.5 % to 83.0 % by adding Fe (III). Batch tests showed that NH4+-N was first oxidized to N2 or NO2--N by Fe (III), then NO3--N was reduced to NO2--N and N2 by Fe (II), and finally, NO2--N was utilized by anammox. Furthermore, the performance of phosphorus removal improved by Fe addition and the removal efficiency increased to 78.7 %. High-throughput sequencing showed that the Fe-reducing bacteria Pseudomonas and Thiobacillus were successfully enriched. The abundance of anammox bacterial increased from 0.03 % to 0.22 % by multiple nitrite supply pathways. Fe addition presents a promising pathway for application in the anammox process.

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Alpine grassland is threatened by the import of chemicals, fertilizers and other external resources with increasing human activities on the Qinghai-Tibet Plateau. It is unclear how carbon cycle of alpine grasslands is affected by the inputs of external resources such as nitrogen, phosphorus, and potassium (N, P, K) and their interactions. We conducted a 3 year experiment on the interactive addition of N, P and K with alpine grassland as the research object to clarify ecosystem carbon exchange process in response to resource addition by measuring community coverage and ecosystem carbon exchange. The results showed the alpine meadow was represented by carbon sequestration during the growing season. The mean value of net ecosystem CO2 exchange (NEE) was -13.0 µmol·m-2·s-1 under the control treatment. NEE, ecosystem respiration (ER), and gross ecosystem productivity (GEP) showed no significant responses when N, P and K were added separately. NEE was significantly increased by 95.3% and 63.9%, GEP was significantly increased by 45.5% and 33.0% under the combined addition of NP and NPK, but ER remained stable. The combined addition of NP or NPK mainly increased NEE and GEP by increasing the coverage of plant communities and affecting ecosystem water use efficiency. Plant community coverage was increased by 18.1% and 21.4%, respectively. The addition of NP increased productivity and autotrophic respiration in alpine meadow. It might cause soil acidification to inhibit heterotrophic respiration, thereby did not change ER due to the two aspects canceling each other out. The addition of N, P, K alone and NK and PK did not change ecosystem carbon exchange, while the combined addition of NP increased NEE and GEP on the nutrient-deficient alpine meadows, indicating that ecosystem carbon uptake was co-limited by N and P in alpine meadow.

Eucommia, Cuscuta, and Drynaria Extracts Ameliorate Glucocorticoid-Induced Osteoporosis by Inhibiting Osteoclastogenesis Through PI3K/Akt Pathway.

Osteoporosis is one of the most common diseases in the world which resulted in heavy socioeconomic burden and a public health threat. Glucocorticoid-induced osteoporosis (GIO) is the most common secondary reason of osteoporosis. Therapeutic strategies using traditional Chinese medicine are under investigation for osteoporosis, with efforts to improve efficacy and clarify the mechanism. The combination of Eucommia, Cuscuta, and Drynaria is widely used in traditional Chinese decoction for osteoporosis treatment, but the experimental efficacy and mechanism are still unclear. Administration of E.C.D. extracts (Eucommia, Cuscuta, and Drynaria) in experimental GIO rats resulted in decreased urinal calcium, phosphorus loss, and decreased expression of RANKL, CTX in serum, increased serum calcium, phosphorus, and OPG level. E.C.D. extracts also improved bone density, structural integrity, and biomechanical function in experimental GIO rats. These finding were associated with E.C.D. extracts' treatment efficacy to GIO in vivo. The balance between osteoclast and osteoblast activity is essential for bone remodeling and bone related disease. The E.C.D. extracts inhibited Raw 264.7 cell differentiation to osteoclast in vitro. On the other hand, it promoted OPG expression of bone marrow mesenchymal stromal cells (MSCs) which can suppress the osteoclast genesis. E.C.D. extracts also increased the Wnt1 and Runx2 expression which are related to osteoblast formation. It also regulated the paracrine effect of MSC to inhibit osteoclast differentiation. The analysis of HPLC and comprehensive pharmacology identified the constituents of E.C.D. extracts and the potential osteoporosis-related targets mediated by E.C.D. extracts. The KEGG enrichment analysis suggested that PI3K/Akt pathway may be involved in the regulation osteoclast genesis by E.C.D. extracts and the result of Western blot of vitro assays proved it. Collectively, these data demonstrate E.C.D. extracts can inhibit osteoclast differentiation to foster experimental osteoporosis both in vivo and in vitro and it may exert the function of inhibiting osteoclast differentiation through PI3K/Akt pathway.

Enhanced simultaneous nitrogen and phosphorus removal from low COD/TIN domestic wastewater through nitritation-denitritation coupling improved anammox process with an optimal Anaerobic/Oxic/Anoxic strategy.

Advanced nitrogen and phosphorus removal in a single-stage suspending-sludge system was achieved by employing a novel Anaerobic/Oxic/Anoxic (AOA) strategy over 200 days. Satisfactory total inorganic nitrogen (TIN) removal efficiency of 90.4% was achieved and effluent phosphorus was below 0.5 mg/L when treating domestic wastewater with the chemical oxygen demand (COD)/TIN as low as 2.98 ± 1.26. Stable nitritation was maintained with the ammonia residual and low dissolved oxygen of 0.2-0.5 mg/L at aerobic stage following by a post anoxic stage. The much higher activity of ammonia oxidation bacteria (12.99 mgN/gVSS/h) was achieved than the nitrite oxidation bacteria (0.09 mgN/gVSS/h). Notably, improved anammox performance was obtained without initial inoculation, contributing 47.4% to TIN removal. The abundance of Nitrosomonas increased from 0.12% to 0.95% (P < 0.001) and self-enrichment of anammox bacteria Ca. Brocadia was confirmed. It provided new insight into the advanced nutrient removal with comprehensible regulation and less aeration requirement.

Clinical outcomes of newly diagnosed primary CNS lymphoma treated with ibrutinib-based combination therapy: A real-world experience of off-label ibrutinib use.

Ibrutinib-based combination therapy with high-dose methotrexate (HD-MTX) has recently shown clinical activity against relapse/refractory (R/R) primary central nervous system lymphoma (PCNSL). Herein, we report our real-world experience of treating 11 newly diagnosed PCNSL patients with the ibrutinib/MTX combination. HD-MTX was given at 3.5 g/m2 every 2-week for eight doses. Ibrutinib was held upon HD-MTX infusion until clearance and was administered daily post-induction until disease progression, intolerable toxicity, or death. Nine out of 11 patients completed the induction phase and received ibrutinib as maintenance therapy. An objective response rate (ORR) of 82% (9/11) was observed including complete response (64%) and partial response (18%). The median progression-free survival (PFS) was 7.4 months while the median overall survival (OS) was not reached. The ibrutinib/MTX combination was well tolerated in these treatment-naïve PCNSL patients with an acceptable safety profile. Moreover, the longitudinal analysis of cerebrospinal fluid (CSF) circulating tumor DNA (ctDNA) revealed that CSF ctDNA detection was closely associated with tumor response, and sustained tumor responses correlated with the clearance of ctDNA from the CSF. In sum, our data not only demonstrated the clinical benefit of the ibrutinib and HD-MTX combination regimen in treating newly diagnosed PCNSL patients in a real-world setting, but also highlighted the significance of liquid biopsy including CSF ctDNA in tracing tumor burden and assessing treatment response.

Selenium Plays a Protective Role in Staphylococcus aureus-Induced Endometritis in the Uterine Tissue of Rats.

The essential trace element selenium (Se) modulates the functions of many regulatory proteins in signal transduction, conferring benefits in inflammatory diseases. Endometritis is a reproductive obstacle disease both in humans and animals. Staphylococcus aureus is the major pathogen that causes endometritis. The present study analyzes the protection and mechanism of Se-methylselenocysteine (MSC) and methylseleninic acid (MSA) on S. aureus-induced endometritis. An atomic fluorescence spectrophotometry study showed that the uterine Se content increased with the addition of MSC and MSA. Histopathology observation and TUNEL detection showed that Se supplementation displayed a greater defense against uterine inflammatory damage. The quantitative PCR (qPCR) and ELISA analyses showed that the expressions of tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6) increased with S. aureus infection and decreased with the addition of MSC and MSA. The Toll-like receptor 2 (TLR2) expression showed the same status as the inflammatory cytokines. The Western blot results showed that the increased phosphorylation of IκBα and NF-κB p65 was also reduced by the addition of MSC and MSA. The qPCR and Western blot results also showed that the transcription expressions and the protein dissociation of caspase-9, caspase-3, caspase-7, caspase-6, and poly(ADP-ribose) polymerase (PARP), which were increased by S. aureus infection, were inhibited by Se supplementation. All of the results displayed that the protection conferred by MSC was stronger than MSA. The present study indicated the Se supplementation might be a potential prevention and control measure for S. aureus-induced endometritis.

Protective Role of Selenium Compounds on the Proliferation, Apoptosis, and Angiogenesis of a Canine Breast Cancer Cell Line.

We herein examined the effects of different doses, forms, and compatibilities of selenium on a canine mammary gland tumor cell line, CTM1211, and explored the related mechanisms. Three selenium compounds, sodium selenite (SSE), methylseleninic acid (MSA), and methylselenocysteine (MSC), were selected for these experiments, and cyclophosphamide (CTX) served as a positive control. In the cell viability assay, the cell viability of each group at 48/72 h decreased significantly compared with the control group (p < 0.05), and the cell viability of the CTX + MSA group was lower than that of CTX and MSA groups (p < 0.05). Moreover, the inhibitory effect of selenium on cell proliferation was time-dependent but not concentration-dependent. In the cell apoptosis assay, the apoptosis values of each group increased significantly compared with the control group, and the apoptosis values of the CTX + MSA group increased the most significantly (p < 0.01). The protein and mRNA expression levels of vascular endothelial growth factor-alpha (VEGF-alpha), angiopoietin-2 (Ang-2), and hypoxia inducible factor-1 alpha (HIF-1 alpha) were downregulated in each group, while that of phosphatase and tensin homolog (PTEN) were upregulated (p < 0.05). In conclusion, these three selenium compounds, especially MSA, could significantly inhibit the viability and growth of the CTM1211 cell line, which is partly due to the induction of apoptosis and regulation of tumor angiogenesis.

Selenium Induces an Anti-tumor Effect Via Inhibiting Intratumoral Angiogenesis in a Mouse Model of Transplanted Canine Mammary Tumor Cells.

Selenium (Se) has been widely reported to possess anti-tumor effects. Angiogenesis is the formation of new blood vessels and is required to supply oxygen, nutrients, and growth factors for tumor growth, progression, and metastasis. To explore whether the anti-tumor effect of Se was associated with angiogenesis in vivo, we studied the effects of sodium selenite (Sel) and methylseleninic acid (MSA) on tumors induced by canine mammary tumor cells (CMT1211) in mice; cyclophosphamide (CTX) served as a positive control. The results showed that the Se content was significantly increased in the Sel and MSA groups. Se significantly inhibited the tumor weights and volumes. Large necrotic areas and scattered and abnormal small necrotic areas were observed in the Se treatment group. Immunofluorescence double staining showed a reduction in the microvessel density (MVD) and increment in the vessel maturation index (VMI) compared with the untreated control group. As expected, the protein and mRNA levels of the angiogenesis factors angiopoietin-2 (Ang-2), platelet-derived growth factor (PDGF), and vascular endothelial growth factor (VEGF) were decreased in the Se-treated tumors by IHC, as shown by western blotting and RT-QPCR. We also found that organic Se MSA provided stronger inhibition of tumor growth compared with inorganic sodium selenite (Sel). Altogether, our results indicated that Se exerted anti-tumor effects in vivo at least partially by inhibiting angiogenic factors.

Mesenchymal Stem Cells Obtained from Synovial Fluid Mesenchymal Stem Cell-Derived Induced Pluripotent Stem Cells on a Matrigel Coating Exhibited Enhanced Proliferation and Differentiation Potential.

Induced pluripotent stem cell-derived mesenchymal stem cells (iPSC-MSCs) serve as a promising source for cell-based therapies in regenerative medicine. However, optimal methods for transforming iPSCs into MSCs and the characteristics of iPSC-MSCs obtained from different methods remain poorly understood. In this study, we developed a one-step method for obtaining iPSC-MSCs (CD146+STRO-1+ MSCs) from human synovial fluid MSC-derived induced iPSCs (SFMSC-iPSCs). CD146-STRO-1-SFMSCs were reprogrammed into iPSCs by transduction with lentivirus-mediated Sox2, Oct-3/4, klf4, and c-Myc. SFMSC-iPSCs were maintained with mTeSR1 medium in Matrigel-coated culture plates. Single dissociated cells were obtained by digesting the SFMSC-iPSCs with trypsin. The dissociated cells were then plated into Matrigel-coated culture plate with alpha minimum essential medium supplemented with 10% fetal bovine serum, 1× Glutamax, and the ROCK inhibitor Y-27632. Cells were then passaged in standard cell culture plates with alpha minimum essential medium supplemented with 10% fetal bovine serum and 1× Glutamax. After passaging in vitro, the cells showed a homogenous spindle-shape similar to their ancestor cells (SFMSCs), but with more robust proliferative activity. Flow cytometric analysis revealed typical MSC surface markers, including expression of CD73, CD90, CD105, and CD44 and lack of CD45, CD34, CD11b, CD19, and HLA-DR. However, these cells were positive for CD146 and stro-1, which the ancestor cells were not. Moreover, the cells could also be induced to differentiate in osteogenic, chondrogenic, and adipogenic lineages in vitro. The differentiation potential was improved compared with the ancestor cells in vitro. The cells were not found to exhibit oncogenicity in vivo. Therefore, the method presented herein facilitated the generation of STRO-1+CD146+ MSCs from SFMSC-iPSCs exhibiting enhanced proliferation and differentiation potential.

Triptolide synergistically enhances temozolomide-induced apoptosis and potentiates inhibition of NF-κB signaling in glioma initiating cells.

Glioblastoma multiforme (GBM) is a lethal solid cancer in adults. Temozolomide (TMZ) is a first-line chemotherapeutic agent but the efficacy is limited by intrinsic and acquired resistance in GBM. Triptolide (TPL), a derivative from traditional Chinese medicine, demonstrated anti-tumor activity. In this study, we explored the interaction of TPL and TMZ in glioma-initiating cells (GICs) and the potential mechanism. A GIC line (GIC-1) was successfully established. Cell viability of GIC-1 after treatment was measured using a CCK-8 assay. The interaction between TPL and TMZ was calculated from Chou-Talalay equations and isobologram. Self-renewal was evaluated with tumor sphere formation assay. Apoptosis was assessed with flow cytometry and western blot. Luciferase assay was employed to measure NF-κB transcriptional activity. The expression of NF-κB downstream genes, NF-κB nuclear translocalization and phoshorylation of IκBα and p65 were evaluated using western blot. We found that GIC-1 cells were resistant to TMZ, with the expected IC50 of 705.7 µmol/L. Co-treatment with TPL yielded a more than three-fold dose reduction of TMZ. TPL significantly increased the percentage of apoptotic cells and suppressed the tumor sphere formation when combined with TMZ. Phosphorylation of IκBα and p65 coupled with NF-κB nuclear translocalization were notably inhibited after a combined treatment. Co-incubation synergistically repressed NF-κB transcriptional activity and downstream gene expression. TPL sensitizes GICs to TMZ by synergistically enhancing apoptosis, which is likely resulting from the augmented repression of NF-κB signaling. TPL is therefore a potential chemosensitizer in the treatment of GBM.

Synthesis and biological evaluation of a series of liver-selective phosphonic acid thyroid hormone receptor agonists and their prodrugs.

Phosphonic acid (PA) thyroid hormone receptor (TR) agonists were synthesized to exploit the poor distribution of PA-based drugs to extrahepatic tissues and thereby to improve the therapeutic index. Nine PAs showed excellent TR binding affinities (TRbeta(1), K(i) < 10 nM), and most of them demonstrated significant cholesterol lowering effects in a cholesterol-fed rat (CFR) model. Unlike the corresponding carboxylic acid analogue and T(3), PA 22c demonstrated liver-selective effects by inducing maximal mitochondrial glycerol-3-phosphate dehydrogenase activity in rat liver while having no effect in the heart. Because of the low oral bioavailability of PA 22c, a series of prodrugs was synthesized and screened for oral efficacy in the CFR assay. The liver-activated cyclic 1-(3-chlorophenyl)-1,3-propanyl prodrug (MB07811) showed potent lipid lowering activity in the CFR (ED(50) 0.4 mg/kg, po) and good oral bioavailability (40%, rat) and was selected for development for the treatment of hypercholesterolemia.