Effects of forest management practices on carbon dynamics of China's boreal forests under changing climates.

Climate change and forest management practices influence forest productivity and carbon budgets, and understanding their interactions is necessary to develop accurate predictions of carbon dynamics as many countries in the world strive towards carbon neutrality. Here, we developed a model-coupling framework to simulate the carbon dynamics of boreal forests in China. The expected dynamics of forest recovery and change following intense timber harvesting in the recent past and projected carbon dynamics into the future under different climate change scenarios and forest management practices (e.g., restoration, afforestation, tending, and fuel management). We predict that under current management strategies, climate change would lead to increased fire frequency and intensity, eventually shifting these forests from carbon sinks towards being carbon sources. This study suggests that future boreal forest management should be altered to reduce the probability of fire occurrence and carbon losses caused by catastrophic fires through planting deciduous species, mechanical removal, and prescribed fire.

Repurposing loperamide to overcome gefitinib resistance by triggering apoptosis independent of autophagy induction in KRAS mutant NSCLC cells.

BACKGROUND: Gefitinib is an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) approved for first-line treatment of non-small cell lung cancer (NSCLC) with sensitizing EGFR mutations. However, NSCLC patients bearing mutant KRAS are inherently unresponsive to gefitinib. Defective autophagy was proposed to mediate resistance to EGFR-TKIs. In this study, the reversal of primary resistance to gefitinib in NSCLC by putative autophagy inducers was investigated. MATERIALS AND METHODS: A few putative autophagy inducers were investigated in NSCLC cells harboring KRAS or EGFR mutations. Quantitative real-time PCR and Western blot analysis were used to evaluate expression of autophagy-related genes and proteins. Sulforhodamine B assay was used to evaluate cytotoxicity of drug combinations. Flow cytometric asssays were used to study apoptotic and cell cycle effects. RESULTS: The antidiarrheal agent loperamide was identified as an autophagy inducer. Loperamide promoted the formation of autophagosomes and it potentiated the cytotoxic effect of gefitinib specifically in NSCLC cells bearing mutant KRAS and wild-type EGFR. Gefitinib-loperamide combination enhanced apoptosis and G1 cell cycle arrest, both of which could not be reversed by pharmacological autophagy inhibitor (3-methyladenine). Moreover, synergistic anticancer effect of gefitinib-loperamide combination was observed in both autophagy-proficient (Atg5-wild type) and -deficient (Atg5-knockout) mouse embryonic fibroblasts. Loperamide overcome gefitinib resistance in NSCLC harboring mutant KRAS and wild-type EGFR through increased apoptosis but independent of autophagy induction. CONCLUSION: Loperamide could be repurposed to overcome primary resistance to gefitinib in KRAS-mutation bearing NSCLC as it also helps relieve the common side effect of diarrhea caused by EGFR-TKIs.

Repurposing of niclosamide as a STAT3 inhibitor to enhance the anticancer effect of chemotherapeutic drugs in treating colorectal cancer.

AIMS: Colorectal cancer (CRC) is the third most common cancer worldwide. Mutation of various cell signaling molecules or aberrant activation of signaling pathways leads to poor response to chemotherapy in CRC. Signal transducer and activator of transcription protein 3 (STAT3) is an important signaling molecule, which plays crucial roles in regulating cell survival and growth. In this study, the potentitation of chemotherapy by putative STAT3 inhibitors for treating CRC was investigated. MAIN METHODS: A few putative STAT3 inhibitors were investigated. Niclosamide, originally indicated for the treatment of tapeworm infection, was chosen for further investigation in five CRC cell lines (HCT116, HT29, HCC2998, LoVo and SW480). Western blot analysis was used to evaluate the expression of STAT3/phospho-STAT3 and its downstream targets. Sulforhodamine B assay was used to evaluate the cytotoxicity of drug combinations. Flow cytometric assays were used to investigate the apoptotic and cell cycle effect. KEY FINDINGS: Niclosamide was found to inhibit expression and activation of STAT3 in a concentration- and time-dependent manner, thereby downregulating STAT3 downstream targets including survivin and cyclin-D1 to induce apoptosis and cell cycle arrest. When combined with niclosamide or specific STAT3 inhibitor (C188-9), the cytotoxicity and DNA damage response from SN38 (the active metabolite from irinotecan) were significantly enhanced. The sequential exposure of SN38 followed by niclosamide was found to be the most potent treatment sequence for the drug combination. SIGNIFICANCE: Niclosamide represents a promising candidate for repurposing to potentiate the anticancer activity of chemotherapeutic drugs.