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Metabolomics-driven discovery of therapeutic targets for cancer cachexia.
Cui, P, Li, X, Huang, C, Lin, D
Journal of cachexia, sarcopenia and muscle. 2024
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Abstract
Cancer cachexia (CC) is a devastating metabolic syndrome characterized by skeletal muscle wasting and body weight loss, posing a significant burden on the health and survival of cancer patients. Despite ongoing efforts, effective treatments for CC are still lacking. Metabolomics, an advanced omics technique, offers a comprehensive analysis of small-molecule metabolites involved in cellular metabolism. In CC research, metabolomics has emerged as a valuable tool for identifying diagnostic biomarkers, unravelling molecular mechanisms and discovering potential therapeutic targets. A comprehensive search strategy was implemented to retrieve relevant articles from primary databases, including Web of Science, Google Scholar, Scopus and PubMed, for CC and metabolomics. Recent advancements in metabolomics have deepened our understanding of CC by uncovering key metabolic signatures and elucidating underlying mechanisms. By targeting crucial metabolic pathways including glucose metabolism, amino acid metabolism, fatty acid metabolism, bile acid metabolism, ketone body metabolism, steroid metabolism and mitochondrial energy metabolism, it becomes possible to restore metabolic balance and alleviate CC symptoms. This review provides a comprehensive summary of metabolomics studies in CC, focusing on the discovery of potential therapeutic targets and the evaluation of modulating specific metabolic pathways for CC treatment. By harnessing the insights derived from metabolomics, novel interventions for CC can be developed, leading to improved patient outcomes and enhanced quality of life.
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Targeting aryl hydrocarbon receptor to prevent cancer in barrier organs.
Congues, F, Wang, P, Lee, J, Lin, D, Shahid, A, Xie, J, Huang, Y
Biochemical pharmacology. 2024;:116156
Abstract
The skin, lung, and gut are important barrier organs that control how the body reacts to environmental stressors such as ultraviolet (UV) radiation, air pollutants, dietary components, and microorganisms. The aryl hydrocarbon receptor (AhR) is a ligand-dependent transcription factor that plays an important role in maintaining homeostasis of barrier organs. AhR was initially discovered as a receptor for environmental chemical carcinogens such as polycyclic aromatic hydrocarbons (PAHs). Activation of AhR pathways by PAHs leads to increased DNA damage and mutations which ultimately lead to carcinogenesis. Ongoing evidence reveals an ever-expanding role of AhR. Recently, AhR has been linked to immune systems by the interaction with the development of natural killer (NK) cells, regulatory T (Treg) cells, and T helper 17 (Th17) cells, as well as the production of immunosuppressive cytokines. However, the role of AhR in carcinogenesis is not as straightforward as we initially thought. Although AhR activation has been shown to promote carcinogenesis in some studies, others suggest that it may act as a tumor suppressor. In this review, we aim to explore the role of AhR in the development of cancer that originates from barrier organs. We also examined the preclinical efficacy data of AhR agonists and antagonists on carcinogenesis to determine whether AhR modulation can be a viable option for cancer chemoprevention.
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Sorafenib plus triplet therapy with venetoclax, azacitidine and homoharringtonine for refractory/relapsed acute myeloid leukemia with FLT3-ITD: A multicenter phase 2 study.
Yu, S, Zhang, Y, Yu, G, Wang, Y, Shao, R, Du, X, Xu, N, Lin, D, Zhao, W, Zhang, X, et al
Journal of internal medicine. 2024;(2):216-228
Abstract
BACKGROUND Patients with relapsed or refractory acute myeloid leukemia (R/R AML) and FLT3-internal tandem duplication (FLT3-ITD) respond infrequently to salvage chemotherapy. OBJECTIVE To investigate the efficacy of sorafenib plus triplet therapy with venetoclax, azacitidine, and homoharringtonine (VAH) as a salvage therapy in this population. METHODS This multicenter, single-arm, phase 2 study was conducted at 12 hospitals across China. Eligible patients had R/R AML with FLT3-ITD (aged 18-65 years) who were treated with VAH. The primary endpoint was composite complete remission (CRc) after two cycles. Secondary outcomes included the overall response rate (ORR), safety, and survival. RESULTS Between July 9, 2020, and March 19, 2022, 58 patients were assessed for eligibility, 51 of whom were enrolled. The median patient age was 47 years (interquartile range [IQR] 31-57). CRc was 76.5% with ORR of 82.4%. At a median follow-up of 17.7 months (IQR, 8.7-24.7), the median duration of CRc was not reached (NR), overall survival was 18.1 months (95% confidence interval [CI], 11.8-NR) and event-free survival was 11.4 months (95% CI, 5.6-NR). Grade 3 or 4 adverse events occurring in ≥10% of patients included neutropenia in 47 (92.2%), thrombocytopenia in 41 (80.4%), anemia in 35 (68.6%), febrile neutropenia in 29 (56.9%), pneumonia in 13 (25.5%), and sepsis in 6 (11.8%) patients. Treatment-related death occurred in two (3.9%) patients. CONCLUSIONS The sorafenib plus VAH regimen was well tolerated and highly active against R/R AML with FLT3-ITD. This regimen may be a suitable therapeutic option for this population, but larger population trials are needed to be explored. TRIAL REGISTRATION Clinical Trials Registry: NCT04424147.
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Epidermal microorganisms contributed to the toxic mechanism of nZVI and TCEP in earthworms by robbing metal elements and nutrients.
Hou, J, Yang, M, Wu, X, Chen, Q, Lu, Y, Zhang, J, Lin, D
Eco-Environment & Health. 2024;(1):80-88
Abstract
Disrupting effects of pollutants on symbiotic microbiota have been regarded as an important mechanism of host toxicity, with most current research focusing on the intestinal microbiota. In fact, the epidermal microbiota, which participates in the nutrient exchange between hosts and environments, could play a crucial role in host toxicity via community changes. To compare the contributions of intestinal and epidermal symbiotic microorganisms to host toxicity, this study designed single and combined scenarios of soil contamination [nano zero-valent iron (nZVI) and tris (2-chloroethyl) phosphate (TCEP)], and revealed the coupling mechanisms between intestinal/epidermal symbiotic bacterial communities and earthworm toxicological endpoints. Microbiome analysis showed that 15% of intestinal microbes were highly correlated with host endpoints, compared to 45% of epidermal microbes showing a similar correlation. Functional comparisons revealed that key species on the epidermis were mainly heterotrophic microbes with genetic abilities to utilize metal elements and carbohydrate nutrients. Further verifications demonstrated that when facing the co-contamination of nZVI and TCEP, certain symbiotic microorganisms became dominant and consumed zinc, copper, and manganese along with saccharides and amino acids, which may be responsible for the nutritional deficiencies in the host earthworms. The findings can enrich the understanding of the coupling relationship between symbiotic microorganisms and host toxicity, highlighting the importance of epidermal microorganisms in host resistance to environmental pollution.
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Light-Driven Radiochemistry with Fluorine-18, Carbon-11 and Zirconium-89.
Lin, D, Lechermann, LM, Huestis, MP, Marik, J, Sap, JBI
Angewandte Chemie (International ed. in English). 2024;(14):e202317136
Abstract
This review discusses recent advances in light-driven radiochemistry for three key isotopes: fluorine-18, carbon-11, and zirconium-89, and their applications in positron emission tomography (PET). In the case of fluorine-18, the predominant approach involves the use of cyclotron-produced [18F]fluoride or reagents derived thereof. Light serves to activate either the substrate or the fluorine-18 labeled reagent. Advancements in carbon-11 photo-mediated radiochemistry have been leveraged for the radiolabeling of small molecules, achieving various transformations, including 11C-methylation, 11C-carboxylation, 11C-carbonylation, and 11C-cyanation. Contrastingly, zirconium-89 photo-mediated radiochemistry differs from fluorine-18 and carbon-11 approaches. In these cases, light facilitates a postlabeling click reaction, which has proven valuable for the labeling of large biomolecules such as monoclonal antibodies (mAbs). New technological developments, such as the incorporation of photoreactors in commercial radiosynthesizers, illustrate the commitment the field is making in embracing photochemistry. Taken together, these advances in photo-mediated radiochemistry enable radiochemists to apply new retrosynthetic strategies in accessing novel PET radiotracers.
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Clinical and ocular abnormalities in DEGCAGS syndrome-Developmental delay with gastrointestinal, cardiovascular, genitourinary, and skeletal abnormalities.
Ali, SM, AlMasri, DA, Prada, CE, Lin, D, Bosley, TM, Kozak, I
Molecular genetics & genomic medicine. 2024;(1):e2329
Abstract
PURPOSE To describe clinical and ocular abnormalities in a case of Developmental Delay with Gastrointestinal, Cardiovascular, Genitourinary, and Skeletal Abnormalities (DEGCAGS syndrome). METHODS A clinical report. CASE DESCRIPTION An infant born to a consanguineous Middle Eastern family who was delivered by cesarean section because of in utero growth restriction, premature labor, and breech presentation. Post-partum medical problems included hypotension, generalized hypotonia, bradycardia, apnea requiring resuscitation and positive pressure ventilation, facial dysmorphia, skeletal malformations, and disorders of the gastrointestinal, immune, urinary, respiratory, cardiac, and visual systems. The family reported that a previous child had severe hypotonia at birth and was given the diagnosis of hypoxic ischemic encephalopathy; that child remains on a ventilator in a chronic care facility. Our patient was found to be homozygous for a novel pathogenic missense variant in theZNF699 zinc finger gene on chromosome 19p13 causing a syndrome known as Developmental Delay with Gastrointestinal, Cardiovascular, Genitourinary, and Skeletal Abnormalities (DEGCAGS syndrome). We review this variable syndrome, including abnormalities of the visual system not described previously. CONCLUSIONS We describe the 15th child to be presumably identified with the DEGCAGS syndrome and the first individual with homozygous missense variants in the ZNF699 gene who had complete clinical examination and detailed retinal imaging.
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Developing Ganoderma lucidum as a next-generation cell factory for food and nutraceuticals.
Azi, F, Wang, Z, Chen, W, Lin, D, Xu, P
Trends in biotechnology. 2024;(2):197-211
Abstract
Ganoderma lucidum holds a colossal reservoir of hydrolytic enzymes and therapeutic compounds and can be a sustainable source of proteins and bioactive compounds. Its metabolic versatility, propelled by its rich genome content, provides excellent biosynthetic machinery for innovation-driven pathway engineering. However, robust regulatory networks and low frequency of homologous recombination are critical bottlenecks that limit the development of molecular tools and precise genetic markers for biomanufacturing innovations in this organism. Modern synthetic biology provides tools that could help to accelerate precise multiple gene targeting and editing and untangling the biosynthetic machinery of G. lucidum. This review provides insight into molecular strategies to unwind the regulatory bottlenecks and transform G. lucidum into efficient cell factories for food and nutraceuticals.
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Bamboo leaf: A review of traditional medicinal property, phytochemistry, pharmacology, and purification technology.
Cheng, Y, Wan, S, Yao, L, Lin, D, Wu, T, Chen, Y, Zhang, A, Lu, C
Journal of ethnopharmacology. 2023;:116166
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Bamboos are perennial evergreen plants that belong to the subfamily Bambusoideae of the true grass family Poaceae, with more than thousands of species distributed around the world. They are used as a traditional medicine with demonstrated effects of anti-oxidation, free radical scavenging, anti-inflammatory, liver protection and ameliorating cognitive deficits. Bamboo leaf is mainly used for the treatment of atherosclerotic, diabetic and nervous system diseases. AIM OF THE STUDY This review aims to provide up-to-date information on the traditional medicinal properties, phytochemistry, pharmacology, and purification technologies of bamboo leaf. MATERIALS AND METHODS Relevant information on bamboo leaf was obtained by an online search of worldwide accepted scientific databases (Web of Science, ScienceDirect, Elsevier, SpringerLink, ACS Publications, Wiley Online Library and CNKI). RESULTS More than 100 chemical compounds, including flavonoids and flavonoid glycosides, volatile components, phenolic acids, polysaccharide, coenzyme Q10, phenylpropanoid and amino acids have been reported to be present. These compounds were usually extracted by column chromatography and membrane separation technologies. Preparative high performance liquid chromatography (PHPLC), high-speed counter-current chromatography (HSCCC), simulated moving bed chromatography (SMB) and dynamic axial compression chromatography (DAC) were the advanced separation technologies have been used to isolate C-glycosides from bamboo leaf flavonoid, the main bioactive ingredient of bamboo leaf. Currently, bamboo leaf is mainly used for the treatment of atherosclerotic, diabetic, hepatic diseases and nervous system related symptoms, which are attributed to the presence of bioactive components of bamboo leaf. CONCLUSIONS Phytochemical and pharmacological analyses of bamboo leaf have been revealed in recent studies. However, most of the pharmacological studies on bamboo leaf have focused on bamboo leaf flavonoids. Further studies need to pay more attention to other phytochemical components of bamboo leaf. In addition, there is lack of sufficient clinical data and toxicity studies on bamboo leaf. Therefore, more clinical and toxicity researches on this plant and constituents are recommended.
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Role of breastfeeding on maternal and childhood cancers: An umbrella review of meta-analyses.
Fan, D, Xia, Q, Lin, D, Ma, Y, Rao, J, Liu, L, Tang, H, Xu, T, Li, P, Chen, G, et al
Journal of global health. 2023;:04067
Abstract
BACKGROUND Multiple studies and meta-analyses have claimed that breastfeeding is inversely correlated with maternal and childhood cancers. These results could either be causal or confounded by shared risk factors. By conducting an umbrella review, we aimed to consolidate the relationship between breastfeeding and maternal and childhood cancers. METHODS We searched PubMed, Embase, Web of Science, Elsevier ScienceDirect, and Cochrane Library databases from inception to December 2022. Two reviewers independently extracted the data and assessed the quality of the studies using standardised forms. We considered two types of breastfeeding comparisons ("ever" vs "never" breastfeeding; and "longest" vs "shortest" duration). We estimated the pooled risk and 95% confidence interval (CI) for each meta-analysis. RESULTS We included seventeen meta-analyses with 55 comparisons. There was an inverse correlation between breastfeeding and childhood leukaemia (pooled risk = 0.90, 95% CI = 0.81-0.99), neuroblastoma (pooled risk = 0.81, 95% CI = 0.71-0.93), maternal ovarian cancer (pooled risk = 0.76, CI = 0.71-0.81), breast cancer (pooled risk = 0.85, 95% CI = 0.82-0.88), and oesophageal cancer (pooled risk = 0.67, 95% CI = 0.54-0.81) for "ever" vs "never" breastfeeding; and with childhood leukaemia (pooled risk = 0.94, 95% CI = 0.89-0.98), and maternal ovarian cancer (pooled risk = 0.84, 95% CI = 0.78-0.90) and breast cancer (pooled risk = 0.92, 95% CI = 0.89-0.96) for "longest" vs "shortest" breastfeeding duration. CONCLUSIONS We found evidence that breastfeeding may reduce the risk of maternal breast cancer, ovarian cancers, and childhood leukaemia, suggesting positive implications for influencing women's decision in breastfeeding. REGISTRATION PROSPERO (CRD42021255608).
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WISER Survivor Trial: Combined Effect of Exercise and Weight Loss Interventions on Adiponectin and Leptin Levels in Breast Cancer Survivors with Overweight or Obesity.
Lin, D, Sturgeon, KM, Gordon, BR, Brown, JC, Sears, DD, Sarwer, DB, Schmitz, KH
Nutrients. 2023;(15)
Abstract
Adipocyte dysregulation is one mechanism linking overweight and breast cancer recurrence. Exercise and weight loss are associated with a decreased risk of breast cancer recurrence in breast cancer survivors with overweight or obesity, which may be mediated through reduced leptin levels, increased adiponectin levels, and an elevated adiponectin to leptin (A:L) ratio. The four-arm randomized controlled WISER Survivor trial examined the 12-month intervention effects of exercise, weight loss, and the combination of exercise and weight loss on adipokine levels among breast cancer survivors (n = 339) with overweight or obesity. Compared with Control, the Combination of Exercise and Weight Loss decreased leptin levels (-35.9%; 95% CI: -46.8%, -25.0%) and increased A:L ratio (11.6%; 95% CI: 5.6%, 17.6%) but did not change adiponectin levels (4.1%; 95% CI: -3.1%, 11.2%). Compared with Control, Weight Loss Alone decreased leptin levels (-35.6%; 95% CI: -46.6%, -24.5%) and increased A:L ratio (10.6%; 95% CI: 4.7%, 16.5%) but did not change adiponectin levels (0.9%; 95% CI: -6.0%, 7.9%). Compared with Control, Exercise Alone did not change leptin levels, adiponectin levels, or A:L ratio. In analyses that consolidated intervention groups, compared with Control, weight loss of ≥5% decreased leptin levels (p trend < 0.01) and increased A:L ratio (p trend < 0.01) but did not alter adiponectin levels (p trend = 0.53). Weight loss, with or without exercise, was associated with decreased leptin levels in breast cancer survivors with overweight or obesity. Improvements in the adipokine secretion profile (A:L ratio) were primarily driven by a weight loss-induced change in leptin levels.